The effects of rapamycin in murine peripheral nerve isografts and allografts.
The FKBP-12-binding ligand FK506 has been successfully used to stimulate nerve regeneration and prevent the rejection of peripheral nerve allografts. The immunosuppressant rapamycin, another FKBP-12-binding ligand, stimulates axonal regeneration in vitro, but its influence on nerve regeneration in peripheral nerve isografts or allografts has not been studied. Sixty female inbred BALB/cJ mice were randomized into six tibial nerve transplant groups, including three isograft and three allograft (C57BL/6J) groups. Grafts were left untreated (groups I and II), treated with FK506 (groups III and IV), or treated with rapamycin (groups V and VI). Nerve regeneration was quantified in terms of histomorphometry and functional recovery, and immunosuppression was confirmed with mixed lymphocyte reactivity assays. Animals treated with FK506 and rapamycin were immunosuppressed and demonstrated significantly less immune cell proliferation relative to untreated recipient animals. Although every animal demonstrated some functional recovery during the study, animals receiving an untreated peripheral nerve allograft were slowest to recover. Isografts treated with FK506 but not rapamycin demonstrated significantly increased nerve regeneration. Nerve allografts in animals treated with FK506, and to a lesser extent rapamycin, however, both demonstrated significantly more nerve regeneration and increased nerve fiber widths relative to untreated controls. The authors suggest that rapamycin can facilitate regeneration through peripheral nerve allografts, but it is not a neuroregenerative agent in this in vivo model. Nerve regeneration in FK506-treated peripheral nerve isografts and allografts was superior to that found in rapamycin-treated animals. Rapamycin may have a role in the treatment of peripheral nerve allografts when used in combination with other medications, or in the setting of renal failure that often precludes the use of calcineurin inhibitors such as FK506.


A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates.
1. A new method has been developed for measuring the total antioxidant capacity of body fluids and drug solutions, based on the absorbance of the ABTS.+ radical cation. 2. An automated method for use on a centrifugal analyser, as well as a manual method, is described. 3. The procedure has been applied to physiological antioxidant compounds and radical-scavenging drugs, and an antioxidant ranking was established based on their reactivity relative to a 1.0 mmol/l Trolox standard. 4. The Trolox equivalent antioxidant capacity of plasma from an adult reference population has been measured, and the method optimized and validated. 5. The method has been applied to investigate the total plasma antioxidant capacity of neonates and how this may be compromised in prematurity.


The impact of internet addiction on depression, physical activity level and trigger point sensitivity in Turkish university students.
Internet addiction (IA), defined as excessive, time consuming, uncontrollable use of the internet, has become a widespread problem. In this study, we investigated the impact of internet addiction on depression, physical activity level, and latent trigger point sensitivity in Turkish university students. A total of 215 university students (155 females and 60 males) who were between 18-25 years of age participated in the study. Using the Addiction Profile Index Internet Addiction Form (APIINT), we identified 51 people as non-internet-addicted (non-IA) (Group 1: 10 male/41 female) and 51 as internet-addicted (IA) (Group 2: 7 male/44 female). APIINT, International Physical Activity Questionnaire-Short-Form (IPAQ), Beck Depression Inventory (BDI), and Neck Disability Index (NDI) were administered to both groups, and the pressure-pain threshold (PPT) in upper/middle trapezius latent trigger points area was measured. The internet addiction rate was 24.3% in our students. Compared with the non-IA group, the daily internet use time and BDI and NDI scores were higher (all p< 0.05), while the IPAQ walking (p< 0.01), IPAQ total (p< 0.05), and PPT values (p< 0.05) were lower in the IA group. IA is a growing problem. This addiction may lead to musculoskeletal problems and can have consequences involving the level of physical activity, depression, and musculoskeletal disorders, particularly in the neck.


Thoracic endovascular aortic repair--indications and evidence.
Since its introduction more than a decade ago, thoracic endovascular aortic repair (TEVAR) has shown promising results for patients with various thoracic aortic diseases. The aim of the current review is to assess the current literature to evaluate the safety and efficacy of TEVAR. A thorough search of the existing literature on TEVAR was conducted on electronic databases, including Medline, Pubmed, EMBASE and Database of Abstracts of Review of Effectiveness. The most recent results were categorized according to the indications of performing TEVAR. A number of case-series studies and reviews have shown reduced early morbidity and mortality rates in a range of thoracic aortic diseases for TEVAR in comparison to open surgical repair. However, there is a lack of robust clinical data to suggest any improvement in long-term overall survival. Despite numerous encouraging results from a large number of publications in recent years, there remains a lack of level 1 evidence to support an improvement of long-term overall survival for patients who underwent TEVAR when compared with traditional treatment modalities. There appears to be an urgent need to conduct well-designed randomized-controlled trials in this rapidly expanding intervention.


Fecal Nutrients Suggest Diets of Higher Fiber Levels in Free-Ranging than in Captive Proboscis Monkeys (Nasalis larvatus).
Understanding the natural diet of species may provide useful information that can contribute to successful captive maintenance. A common problem experienced with captive foregut-fermenting primate (colobine) diets is that they are deficient in fiber and therefore highly digestible. This may contribute to gastrointestinal disorders often observed in zoos. An approach to obtain information relevant for the improvement of diets is to compare the nutrient composition of feces from free-ranging and captive individuals. In theory, fecal material can be considered a proxy for diet intake integrated over a certain period of time. We collected fecal samples from eight free-ranging proboscis monkey (Nasalis larvatus, a highly endangered colobine species) groups from a secondary forest along the Kinabatangan River and four from a mixed mangrove-riverine forest along the Garama River, Sabah, Borneo, Malaysia. We also collected fecal samples from 12 individual captive adult/sub-adult proboscis monkeys from three different zoos. We confirmed that feces from free-ranging monkeys contained more fiber and less metabolic fecal nitrogen than those from captive specimens, indicating a less digestible diet in the wild. Modifying the diets of captive colobines to include more fiber, comparable to those of free-ranging ones, may contribute to their health and survival.


'You're judged all the time!' Students' views on professionalism: a multicentre study.
This study describes how medical students perceive professionalism and the context in which it is relevant to them. An understanding of how Phase 1 students perceive professionalism will help us to teach this subject more effectively. Phase 1 medical students are those in the first 2 years of a 5-year medical degree. Seventy-two undergraduate students from two UK medical schools participated in 13 semi-structured focus groups. Focus groups, carried out until thematic saturation occurred, were recorded and transcribed verbatim. Data were analysed and coded using NVivo 8, using a grounded theory approach with constant comparison. From the analysis, seven themes regarding professionalism emerged: the context of professionalism; role-modelling; scrutiny of behaviour; professional identity; 'switching on' professionalism; leniency (for students with regard to professional standards), and sacrifice (of freedom as an individual). Students regarded professionalism as being relevant in three contexts: the clinical, the university and the virtual. Students called for leniency during their undergraduate course, opposing the guidance from Good Medical Practice. Unique findings were the impact of clothing and the online social networking site Facebook on professional behaviour and identity. Changing clothing was described as a mechanism by which students 'switch on' their professional identity. Students perceived society to be struggling with the distinction between doctors as individuals and professionals. This extended to the students' online identities on Facebook. Institutions' expectations of high standards of professionalism were associated with a feeling of sacrifice by students caused by the perception of constantly 'being watched'; this perception was coupled with resentment of this intrusion. Students described the significant impact that role-modelling had on their professional attitudes. This research offers valuable insight into how Phase 1 medical students construct their personal and professional identities in both the offline and online environments. Acknowledging these learning mechanisms will enhance the development of a genuinely student-focused professionalism curriculum.


Weak-field induced nonmagnetic state in a Co-based honeycomb.
Layered honeycomb magnets are of interest as potential realizations of the Kitaev quantum spin liquid (KQSL), a quantum state with long-range spin entanglement and an exactly solvable Hamiltonian. Conventional magnetically ordered states are present for all currently known candidate materials, however, because non-Kitaev terms in the Hamiltonians obscure the Kitaev physics. Current experimental studies of the KQSL are focused on 4d or 5d transition metal-based honeycombs, in which strong spin-orbit coupling can be expected, yielding Kitaev interaction that dominates in an applied magnetic field. In contrast, for 3d-based layered honeycomb magnets, spin-orbit coupling is weak, and thus, Kitaev physics should be substantially less accessible. Here, we report our studies on BaCo2(AsO4)2, for which we find that the magnetic order associated with the non-Kitaev interactions can be fully suppressed by a relatively low magnetic field, yielding a nonmagnetic material and implying the presence of strong magnetic frustration and weak non-Kitaev interactions.


The crystal structure and luminescence properties of a novel green-yellow emitting Ca1.5Mg0.5Si1-xLixO4-δ:Ce3+ phosphor with high quantum efficiency and thermal stability.
A novel green-yellow emitting Ca1.5Mg0.5Si1-xLixO4-δ:Ce3+ phosphor with high quantum efficiency and thermal stability was discovered for applications in near ultraviolet pumped white light-emitting diodes. Its crystal structure was determined with a single-particle diagnosis approach. The Si sites in the SiO4 tetrahedra are reported for the first time to accommodate Li+ ions. This substitution, confirmed by 6Li solid-state NMR and T.O.F. neutron powder diffraction, causes a disordered occupation of Ca/Mg in the Ca3MgSi2O8 host and favors a phase transformation at ∼330 °C, which results in the formation of the novel phosphor. The produced phosphor was efficiently excited by near UV light peaking at 365 and 410 nm and produced broad green-yellow emission with peaks at 500 and 560 nm, respectively. Its quantum efficiency reached 88.4% (internal) and 55.7% (external) under excitation at 365 nm, and 80.5% (internal) and 42.7% (external) under excitation at 410 nm, while the decrease of luminescence intensity at 200 °C was small (∼26%). A WLED lamp with a high color rendering index of Ra = 92.8 was produced with the combination of a 365 nm emitting chip with blue emitting BaMgAl10O17:Eu2+, green-yellow emitting CMSL:0.01Ce, and red emitting Sr2Si5N8:Eu2+ phosphors.


Dura mater stimulates human adipose-derived stromal cells to undergo bone formation in mouse calvarial defects.
Human adipose-derived stromal cells (hASCs) have a proven capacity to aid in osseous repair of calvarial defects. However, the bone defect microenvironment necessary for osseous healing is not fully understood. In this study, we postulated that the cell-cell interaction between engrafted ASCs and host dura mater (DM) cells is critical for the healing of calvarial defects. hASCs were engrafted into critical sized calvarial mouse defects. The DM-hASC interaction was manipulated surgically by DM removal or by insertion of a semipermeable or nonpermeable membrane between DM and hASCs. Radiographic, histologic, and gene expression analyses were performed. Next, the hASC-DM interaction is assessed by conditioned media (CM) and coculture assays. Finally, bone morphogenetic protein (BMP) signaling from DM was investigated in vivo using novel BMP-2 and anti-BMP-2/4 slow releasing scaffolds. With intact DM, osseous healing occurs both from host DM and engrafted hASCs. Interference with the DM-hASC interaction dramatically reduced calvarial healing with abrogated BMP-2-Smad-1/5 signaling. Using CM and coculture assays, mouse DM cells stimulated hASC osteogenesis via BMP signaling. Through in vivo manipulation of the BMP-2 pathway, we found that BMP-2 plays an important role in DM stimulation of hASC osteogenesis in the context of calvarial bone healing. BMP-2 supplementation to a defect with disrupted DM allowed for bone formation in a nonhealing defect. DM is an osteogenic cell type that both participates in and stimulates osseous healing in a hASC-engrafted calvarial defect. Furthermore, DM-derived BMP-2 paracrine stimulation appears to play a key role for hASC mediated repair.


Development and validation of an immunosuppressant therapy adherence barrier instrument.
To decrease allograft rejection as a result of non-adherence to immunosuppressant therapy (IST), a valid and reliable instrument that measures solid organ transplant patients' adherence barriers is needed. An immunosuppressant therapy barrier scale (ITBS) was developed to assess transplant patients' perceived barriers to IST adherence and was completed by 222 transplant patients who lived in Georgia, USA. A renal transplant population subset was used to test the ITBS reliability and validity. Scale reliability was estimated using Cronbach's alpha coefficient of internal consistency; scale dimensionality was assessed using principal components analysis. The criterion-related validity of the scale was assessed by relating subscale scores to adherence measures and graft rejection. Nomological validity was assessed by relating barrier subscales to specific patient factors. Two subscales that represented 'controllable' and 'uncontrollable' barriers were found. Cronbach's alpha coefficients demonstrated acceptable reliabilities of 0.93, 0.86 and 0.91 for the 'uncontrollable' and 'controllable' subscales, and for the entire ITBS, respectively. The ITBS subscales correlated negatively with a self-reported measure of IST adherence, IST serum concentrations and IST pharmacy refill adherence rate (P<0.01). The 'uncontrollable barrier' subscale was positively correlated to kidney graft rejection (P<0.01), thus demonstrating the ITBS's validity. Males and older patients reported more adherence barriers (P<0.05). The ITBS is a reliable and valid instrument that can be used to measure patients' perceived barriers to IST adherence.


Implementation strategies for interventions to improve the management of chronic kidney disease (CKD) by primary care clinicians: protocol for a systematic review.
There is a considerable implementation gap in managing early stage chronic kidney disease (CKD) in primary care despite the high prevalence and risk for increased morbidity and mortality associated with CKD. This systematic review aims to synthesise the evidence of efficacy of implementation interventions aimed at primary care practitioners (PCPs) to improve CKD identification and management. We further aim to describe the interventions' behavioural change components. We will conduct a systematic review of studies from 2000 to October 2017 that evaluate implementation interventions targeting PCPs and which include at least one clinically meaningful CKD outcome. We will search several electronic data bases and conduct reference mining of related systematic reviews and publications. An interdisciplinary team will independently and in duplicate, screen publications, extract data and assess the risk of bias. Clinical outcomes will include all clinically meaningful medical management outcomes relevant to CKD management in primary care such as blood pressure, chronic heart disease and diabetes target achievements. Quantitative evidence synthesis will be performed, where possible. Planned subgroup analyses include by (1) study design, (2) length of follow-up, (3) type of intervention, (4) type of implementation strategy, (5) whether a behavioural or implementation theory was used to guide study, (6) baseline CKD severity, (7) patient minority status, (8) study location and (9) academic setting or not. Approval by research ethics board is not required since the review will only include published and publicly accessible data. Review findings will inform a future trial of an intervention to promote uptake of CKD diagnosis and treatment guidelines in our primary care setting and the development of complementary tools to support its successful adoption and implementation. We will publish our findings in a peer-reviewed journal and develop accessible summaries of the results. CRD42018102441.


Transmission dynamics of primary pneumonic plague in the USA.
Plague is thought to have killed millions during three catastrophic pandemics. Primary pneumonic plague, the most severe form of the disease, is transmissible from person-to-person and has the potential for propagating epidemics. Efforts to quantify its transmission potential have relied on published data from large outbreaks, an approach that artificially inflates the basic reproductive number (R(0)) and skews the distribution of individual infectiousness. Using data for all primary pneumonic plague cases reported in the USA from 1900 to 2009, we determined that the majority of cases will fail to transmit, even in the absence of antimicrobial treatment or prophylaxis. Nevertheless, potential for sustained outbreaks still exists due to superspreading events. These findings challenge current concepts regarding primary pneumonic plague transmission.


Pharmacological interventions for preventing or delaying onset of type 2 diabetes mellitus.
Prevention or delay of onset of type 2 diabetes in individuals at varying risk across the dysglycaemia continuum before overt diabetes becomes clinically manifest constitutes a leading objective of global disease prevention schemes. Pharmacological intervention has been suggested as a means to help prevent diabetes and reduce the global burden of this chronic condition. However, there is no credible evidence that early pharmacological intervention leads to long-term benefit in reducing diabetes-related complications or preventing early mortality, compared to treating people with diagnosed diabetes who have crossed the glycaemic threshold. In this review, we examine published evidence from trials using pharmacological agents to delay or prevent progression to diabetes. We also explore the benefit/risk impact of such therapies, safety issues and relevant off-target effects. Current evidence suggests none of the drugs currently available sustainably lower cumulative diabetes incidence, none provides a durable delay in diabetes diagnosis and none provides a convincing concomitant excess benefit for microvascular or macrovascular risk.


Association between sickle cell and β-thalassemia genes and hemoglobin concentration and anemia in children and non-pregnant women in Sierra Leone: ancillary analysis of data from Sierra Leone's 2013 National Micronutrient Survey.
By measuring the associations between the presence of sickle cell and β-thalassemia genes, we assessed the extent to which these hemoglobinopathies contribute to the high prevalence of anemia observed in preschool-aged children and women of reproductive age in Sierra Leone. The prevalence of anemia was statistically significantly higher in children with homozygous sickle cell genes (HbSS) than in children with normal hemoglobin genes (HbAA or HbAC), but there was no difference in anemia prevalence in those with heterozygous sickle cell trait (HbAS or HbSC) compared with those with normal hemoglobin genes. In women, there was no difference in anemia prevalence by sickle cell status. In both children and women, there was no difference in the anemia prevalence for individuals with or without the β-thalassemia gene. For both sickle cell and β-thalassemia, there was no significant difference in hemoglobin concentrations by sickle cell or β-thalassemia status. Anemia prevalence was higher in children and women with homozygous sickle cell (HbSS). However, as the prevalence of HbSS children (5.4%) and women (1.6%) was quite small, it is unlikely that these hemoglobinopathies substantially contributed to the high anemia prevalence found in the 2013 national micronutrient survey.


Interstitial magnetic resonance lymphography: is it a new method for the diagnosis of lymphedema?
The aim of this study was to evaluate the method of interstitial magnetic resonance lymphography (MRL) as an examination for the depiction of the lymphatic system in humans in comparison with the method of direct X-ray lymphography. We studied 6 persons, 2 volunteers and 4 patients with clinical suspicion of lymphedema in lower extremities. We administered subcutaneous gadobutrol for the MRL with a volume of 5 mL composed of 4.5 mL of Gadobutrol mixed with 0.5 mL of lidocaine hydrochloride and after 7 days lipiodol in the lymph vessel for the X-ray direct lymphography (in 3 patients) in order to compare the findings of the two We then followed up all individuals for 7 days for any possible side effect of the contrast agents. Using MRL, we depicted the lymphatic system (lymph vessels and inguinal lymph nodes) of volunteers in 60 min. Moreover, in patients we depicted several abnormalities of the lymphatic system including decreased number of lymph vessels, lymphocele and ectatic lymph vessels. X-ray direct lymphography confirmed the findings of the MRL in all cases. No side effects were observed. In our pilot study, Gadobutrol seems to be a good contrast agent for the painless depiction of the lymphatic system in humans through interstitial MRL. More extensive studies are needed in order to establish the efficacy and the dosage of Gadobutrol.


New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.
A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090). Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.


Intensity based surface plasmon resonance sensor using a nanohole rectangular array.
We show high resolution measurements of a surface plasmon resonance (SPR) sensor based on a rectangular nanohole array in a metal film. This SPR setup uses balanced intensity detection between two orthogonal polarizations of a He-Ne laser beam, which allows for sensitivity improvement, noise reduction and rejection of any uncorrelated variation in the intensity signal. A bulk sensitivity resolution of 6.4 x 10(-6) RIU is demonstrated. The proposed methodology is promising for applications in portable nanoplasmonic multisensing and imaging.


Propensity-weighted long-term risk of urinary adverse events after prostate cancer surgery, radiation, or both.
Prostate cancer is the second most common cancer in men and has high survivorship, yet little is known about the long-term risk of urinary adverse events (UAEs) after treatment. To compare the long-term UAE incidence across treatment and control groups. Using a matched-cohort design, we identified elderly men treated with external-beam radiotherapy (EBRT; n=44 318), brachytherapy (BT; n=14 259), EBRT+BT (n=11 835), radical prostatectomy (RP; n=26 970), RP+EBRT (n=1557), or cryotherapy (n=2115) for non-metastatic prostate cancer and 144 816 non-cancer control individuals from the population-based Surveillance, Epidemiology, and End Results-Medicare linked data from 1992-2007 with follow-up through 2009. The incidence of treated UAEs and time from cancer treatment to first UAE were analyzed in terms of propensity-weighted survival. Median follow-up was 4.14 yr. At 10 yr, all treatment groups experienced higher propensity-weighted cumulative UAE incidence than the control group (16.1%; hazard risk [HR] 1.0), with the highest incidence for RP+EBRT (37.8%; HR 3.19, 95% confidence interval [CI] 2.79-3.66), followed by BT+EBRT (28.4%; HR 1.97, CI 1.85-2.10), RP (26.6%; HR 2.44, CI 2.34-2.55), cryotherapy (23.4%; HR 1.56, CI 1.30-1.87), BT (19.8%; HR 1.43, CI 1.33-1.53), and EBRT (19.7%; HR 1.11, CI 1.07-1.16). Bladder outlet obstruction was the most common event. Men undergoing RP, RP+EBRT, and BT+EBRT experienced the highest UAE risk at 10 yr, although UAEs accrued differently over extended follow-up. The significant background UAE rate among non-cancer control individuals yields a risk attributable to prostate cancer treatment that is 17% lower than prior estimates. We show that treatment for prostate cancer, especially combinations of two treatments such as radiation and surgery, carries a significant risk of urinary adverse events such as urethral stricture. This risk increases with time since treatment, emphasizing that treatments have long-term effects.


Development and testing of a new-generation aerosol exposure system: The independent holistic air-liquid exposure system (InHALES).
The dose of inhaled materials delivered to the respiratory tract is to a large extent a function of the kinetics of particle deposition and gas dissolution on or in the airway and lung epithelia, and therefore of the structural and functional properties of the respiratory tract. In vitro aerosol exposure systems commonly do not simulate these properties, which may result in the delivery of non-realistic, non-human-relevant doses of inhalable test substances to the in vitro biological test systems. We developed a new-generation in vitro aerosol exposure system, the InHALES, that can, like the human respiratory tract, actively breathe, operate medical inhalers, or take puffs from tobacco products. Due to its structural and functional similarity to the human respiratory tract, the system is expected to deliver human-relevant doses of inhalable materials to cell cultures representing respiratory tract epithelia. We here describe the proof of concept of the InHALES with respect to aerosol delivery and compatibility with oral, bronchial, and alveolar cell cultures. The results indicate that the system structure and function translate into complex patterns of test atmosphere delivery that, with increasing system complexity, may closely mimic the patterns observable in the human respiratory tract.


Ectopic expression of DREF induces DNA synthesis, apoptosis, and unusual morphogenesis in the Drosophila eye imaginal disc: possible interaction with Polycomb and trithorax group proteins.
The promoters of Drosophila genes encoding DNA replication-related proteins contain transcription regulatory element DRE (5'-TATCGATA) in addition to E2F recognition sites. A specific DRE-binding factor, DREF, positively regulates DRE-containing genes. In addition, it has been reported that DREF can bind to a sequence in the hsp70 scs' chromatin boundary element that is also recognized by boundary element-associated factor, and thus DREF may participate in regulating insulator activity. To examine DREF function in vivo, we established transgenic flies in which ectopic expression of DREF was targeted to the eye imaginal discs. Adult flies expressing DREF exhibited a severe rough eye phenotype. Expression of DREF induced ectopic DNA synthesis in the cells behind the morphogenetic furrow, which are normally postmitotic, and abolished photoreceptor specifications of R1, R6, and R7. Furthermore, DREF expression caused apoptosis in the imaginal disc cells in the region where commitment to R1/R6 cells takes place, suggesting that failure of differentiation of R1/R6 photoreceptor cells might cause apoptosis. The DREF-induced rough eye phenotype was suppressed by a half-dose reduction of the E2F gene, one of the genes regulated by DREF, indicating that the DREF overexpression phenotype is useful to screen for modifiers of DREF activity. Among Polycomb/trithorax group genes, we found that a half-dose reduction of some of the trithorax group genes involved in determining chromatin structure or chromatin remodeling (brahma, moira, and osa) significantly suppressed and that reduction of Distal-less enhanced the DREF-induced rough eye phenotype. The results suggest a possibility that DREF activity might be regulated by protein complexes that play a role in modulating chromatin structure. Genetic crosses of transgenic flies expressing DREF to a collection of Drosophila deficiency stocks allowed us to identify several genomic regions, deletions of which caused enhancement or suppression of the DREF-induced rough eye phenotype. These deletions should be useful to identify novel targets of DREF and its positive or negative regulators.


A FRET method for investigating dimer/monomer status and conformation of the UVR8 photoreceptor.
The photoreceptor UVR8 has a pivotal role in mediating plant responses to UV-B wavelengths. Dimeric UVR8 dissociates into monomers following UV-B photoreception, and there is evidence that this process is accompanied by conformational changes that may facilitate interaction of UVR8 with other proteins to initiate signaling. Hence monitoring UVR8 dimer/monomer status and conformation is key to understanding UVR8 action. Here we have used Fluorescence Resonance Energy Transfer (FRET) to study these processes in both wild-type and mutant UVR8 proteins in vivo. UVR8 was fused to GFP and mCherry at the C- and N-termini, respectively and both the FRET efficiency and loss of GFP fluorescence after photobleaching were measured. In addition, measurements were made for UVR8 fused to either GFP or mCherry to eliminate intra-molecular FRET signals. The results indicate that dissociation of UVR8 dimer to monomer principally accounts for the loss of FRET signal for wild-type UVR8 and there is little evidence of a contribution from conformational change in vivo. Examination of plants expressing UVR8W285F and UVR8D96N,D107N are consistent with these mutant proteins being constitutively dimeric and monomeric, respectively. The methods employed here will be valuable for monitoring UVR8 dimer/monomer status in vivo in relation to signaling, and will facilitate characterization of dimer/monomer status and conformation of further UVR8 mutants.


Development and evaluation of a bladder Cancer specific survivorship care plan by patients and clinical care providers: a multi-methods approach.
In spite of the mixed evidence for their impact, survivorship Care Plans (SCPs) are recommended to enhance quality of care for cancer survivors. Data on the feasibility of SCPs in bladder cancer (BC) is sparse. Using a mixed-methods approach, this study describes the iterative development, acceptability and feasibility of BC specific SCP (BC-SCP) in clinical settings. In Phase I, we developed the BC-SCP. In Phase II, we conducted four focus groups with 19 patients and 15 providers to examine its acceptability and usability challenges. Data analyses using the Atlas.ti program, informed refinement of the BC-SCP. In Phase III, we conducted feasibility testing of the refined BC-SCP with 18 providers from 12 health-centers. An encounter survey was completed after each assessment to examine the feasibility of the BC-SCP. Chi-square and Fisher Exact tests were used for comparative analyses. During phase I, we observed high patient and provider acceptability of the BC-SCP and substantial engagement in improving its content, design, and structure. In Phase II, providers completed 59 BC-SCPs. Mean time for BC-SCP completion was 12.3 min. Providers reported that BC-SCP content was clear, did not hamper clinic flow and was readily completed with easy-to-access information. Comparative analyses to examine differences in SCP completion time by patient clinico-demographic characteristics and provider type revealed no significant differences. Our BC-SCP has clinical relevance, and can be used in an active practice setting. However, considerable progress will be necessary to achieve implementation of and sharing the BC-SCP with patients and care providers, particularly within the electronic medical record. In summary, BC-SCPs are essential to improve the follow up care of BC survivors. Clinical resources are required to ensure appropriate implementation of BC-SCPs. Study HUM00056082.


Mortality after in-hospital cardiopulmonary resuscitation: multicenter analysis in Korea.
The purpose of this study is to evaluate factors associated with the mortality of patients admitted to intensive care units (ICUs) after in-hospital cardiopulmonary resuscitation (CPR) and the impact of a hospital rapid response system (RRS) on patient mortality in Korea. A prospective multicenter cohort study was done in 22 ICUs of 15 centers from July 1, 2010, to January 31, 2011. We only enrolled patients admitted to ICUs after in-hospital CPR and divided eligible patients into 2 groups-survivors and nonsurvivors. Among 4617 patients, 150 patients were admitted post-CPR, 76 died, and 74 survived. At 24 hours, the Sequential Organ Failure Assessment score, Simplified Acute Physiology Score II, and the best Glasgow Coma Scale were significantly lower in the nonsurvivors than in the survivors. In multivariate analysis, the Simplified Acute Physiology Score II and presence of lower respiratory infection were both independently associated with mortality. At the first hour after admission, lowest serum potassium and highest heart rate were associated with mortality. At 24 hours after admission, lowest mean arterial pressure, HCO3 level, and venous oxygen saturation level; highest heart rate; and use of vasoactive drugs were associated with mortality. The mortality of patients in hospitals with an RRS was not significantly different from that of hospitals without an RRS. Various physiologic and laboratory parameters were associated with the mortality of post-CPR ICU admitted patients, and the presence of an RRS did not reduce mortality of these patients in our study.


Humanitarian Outreach in Cardiothoracic Surgery: From Setup to Sustainability.
Noncommunicable diseases account for 38 million deaths each year, and approximately 75% of these deaths occur in the developing world. The most common causes include cardiovascular diseases, cancer, respiratory diseases, and diabetes mellitus. Many adults with acquired cardiothoracic disease around the world have limited access to health care. In addition, congenital heart disease is present in approximately 1% of live births and is therefore the most common congenital abnormality. More than one million children in the world are born with congenital heart disease each year, and approximately 90% of these children receive suboptimal care or have no access to care. Furthermore, many children affected by noncongenital cardiac conditions also require prevention, diagnosis, and treatment. Medical and surgical volunteerism can help facilitate improvement in cardiothoracic health care in developing countries. As we move into the future, it is essential for physicians and surgeons to be actively involved in political, economic, and social aspects of society to serve health care interests of the underprivileged around the world. Consequently, in developing countries, a critical need exists to establish an increased number of reputable cardiothoracic programs and to enhance many of the programs that already exist. The optimal strategy is usually based on a long-term educational and technical model of support so that as case volumes increase, quality improves and mortality and morbidity decrease. Humanitarian outreach activities should focus on education and sustainability, and surgical tourism should be limited to those countries that will never have the capability to have free-standing cardiothoracic programs.


Low- and high-carbohydrate weight-loss diets have similar effects on mood but not cognitive performance.
Low-carbohydrate diets are often used to promote weight loss, but their effects on psychological function are largely unknown. We compared the effects of a low-carbohydrate, high-fat (LCHF) diet with a conventional high-carbohydrate, low-fat (HCLF) diet on mood and cognitive function. Ninety-three overweight or obese participants [x +/- SEM age: 50.2 +/- 0.8 y; body mass index (in kg/m2): 33.6 +/- 0.4] were randomly assigned to an energy-restricted ( approximately 6-7 MJ, 30% deficit), planned isocaloric LCHF diet or an HCLF diet for 8 wk. Body weight and psychological well-being were measured by using the Profile of Mood States, Beck Depression Inventory, and Spielberger State Anxiety Inventory instruments at baseline and fortnightly. Cognitive functioning (working memory and speed of processing) was assessed at baseline and week 8. The LCHF diet resulted in significantly greater weight loss than did the HCLF diet (7.8 +/- 0.4 and 6.4 +/- 0.4 kg, respectively; P = 0.04). Both groups showed improvements in psychological well-being (P < 0.01 for time), with the greatest effect occurring during the first 2 wk, but there was no significant difference between groups. There were no significant between-group differences in working memory (P = 0.68), but there was a significant time x diet interaction for speed of processing (P = 0.04), so that this measure improved less in the LCHF than in the HCLF diet group. Both dietary patterns significantly reduced body weight and were associated with improvements in mood. There was some evidence for a smaller improvement in cognitive functioning with the LCHF diet with respect to speed of processing, but further studies are required to determine the replicability of this finding.


Identification of a novel methyltransferase, Bmt2, responsible for the N-1-methyl-adenosine base modification of 25S rRNA in Saccharomyces cerevisiae.
The 25S rRNA of yeast contains several base modifications in the functionally important regions. The enzymes responsible for most of these base modifications remained unknown. Recently, we identified Rrp8 as a methyltransferase involved in m(1)A645 modification of 25S rRNA. Here, we discovered a previously uncharacterized gene YBR141C to be responsible for second m(1)A2142 modification of helix 65 of 25S rRNA. The gene was identified by reversed phase-HPLC screening of all deletion mutants of putative RNA methyltransferase and was confirmed by gene complementation and phenotypic characterization. Because of the function of its encoded protein, YBR141C was named BMT2 (base methyltransferase of 25S RNA). Helix 65 belongs to domain IV, which accounts for most of the intersubunit surface of the large subunit. The 3D structure prediction of Bmt2 supported it to be an Ado Met methyltransferase belonging to Rossmann fold superfamily. In addition, we demonstrated that the substitution of G180R in the S-adenosyl-L-methionine-binding motif drastically reduces the catalytic function of the protein in vivo. Furthermore, we analysed the significance of m(1)A2142 modification in ribosome synthesis and translation. Intriguingly, the loss of m(1)A2142 modification confers anisomycin and peroxide sensitivity to the cells. Our results underline the importance of RNA modifications in cellular physiology.


Deep aspirations: towards a sustainable offshore Blue Economy.
The ocean economy is experiencing rapid growth that will provide benefits but will also pose environmental and social risks. With limited space and degraded resources in coastal areas, offshore waters will be a particular focus of Blue Economy expansion over the next decade. When emerging and established economic sectors expand in offshore waters (within national Exclusive Economic Zones), different potential Blue Economy opportunities and challenges will arise. Following a series of interdisciplinary workshops, we imagine two technically possible futures for the offshore Blue Economy and we identify the actions required to achieve the more sustainable outcome. Under a business as usual scenario the focus will remain on economic growth, the commodification of nature, the dominance of private over public and cultural interests, and prioritisation of the interests of current over future generations. A more sustainable scenario would meet multiple UN Sustainable Development Goals and ensure inclusive economic developments, environmental sustainability, and fair and equitable access to resources and technologies across users, nations, and generations. Challenges to this more sustainable future are a lack of infrastructure and technology to support emerging offshore sectors, limited understanding of environmental impacts, inequitable outcomes, and a lack of planning and governmental oversight. Addressing these challenges will require a shift in societal values, a more balanced allocation of funding to offshore activities, transparency in information sharing between industries and across nations, and adjustment of international legal and institutional mechanisms. The sustainable and equitable offshore Blue Economy we envisage is achievable and provides a unique opportunity to build global capacity and partnership.


Cytokinetic bridge triggers de novo lumen formation in vivo.
Multicellular rosettes are transient epithelial structures that serve as intermediates during diverse organ formation. We have identified a unique contributor to rosette formation in zebrafish Kupffer's vesicle (KV) that requires cell division, specifically the final stage of mitosis termed abscission. KV utilizes a rosette as a prerequisite before forming a lumen surrounded by ciliated epithelial cells. Our studies identify that KV-destined cells remain interconnected by cytokinetic bridges that position at the rosette's center. These bridges act as a landmark for directed Rab11 vesicle motility to deliver an essential cargo for lumen formation, CFTR (cystic fibrosis transmembrane conductance regulator). Here we report that premature bridge cleavage through laser ablation or inhibiting abscission using optogenetic clustering of Rab11 result in disrupted lumen formation. We present a model in which KV mitotic cells strategically place their cytokinetic bridges at the rosette center, where Rab11-associated vesicles transport CFTR to aid in lumen establishment.


Prevalence and characterization of multidrug-resistant (type ACSSuT) Salmonella enterica serovar Typhimurium strains in isolates from four gosling farms and a hatchery farm.
Salmonella enterica serovar Typhimurium strains of phage types DT104 and U302 are often resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline (the ACSSuT resistance type) and are major zoonotic pathogens. Increased consumption of goose meat may enhance the risk of transferring S. enterica serovar Typhimurium and other enteric pathogens from geese to human due to the consumption of meats from infected geese or improper preparation of meats. Therefore, we characterized S. enterica serovar Typhimurium strains isolated from four goose farms (farms A, B, C, and D) and one hatchery farm (farm E) to determine the epidemic and genetic differences among them. Antibiotic susceptibility tests and multiplex PCR confirmed that 77.6% (52/67) of strains were ACSSuT strains isolated from farms A, C, and E. Antibiotic-susceptible strains were isolated mostly from farm B, and no strain was observed in farm D. All ACSSuT strains harbored a 94.7-kb virulence plasmid and contained one 1.1-kb conserved segment identical to that of Salmonella genomic island 1. Four genotypes were determined among these S. enterica serovar Typhimurium isolates by pulsed-field gel electrophoresis analysis of XbaI-digested DNA fragments. Most isolates (85.29%; 29/34) of major genotype Ib were ACSSuT strains isolated mainly from goslings of farm C and egg membranes of farm E, a hatchery farm, suggesting that S. enterica serovar Typhimurium strains in isolates from goslings might originate from its hatchery, from the egg membranes to the gosling fluff after hatching. Multiple phage types, types 8, 12, U283, DT104, and U302, were identified. In conclusion, geese were a reservoir of diverse multidrug-resistant (type ACSSuT) S. enterica serovar Typhimurium strains, and each farm was colonized with genetically closely related S. enterica serovar Typhimurium strains.


Issues in the Economic Evaluation of Prevention Programs.
Economic analysis plays an increasingly important role in prevention research. In this article, we describe one form of economic analysis, a cost analysis. Such an analysis captures not only the direct costs of an intervention but also its impact on the broader social costs of the illness or problem targeted. The key question is whether the direct costs are offset by reductions in the other, morbidity-related costs, such as the use of expensive services. We begin by describing how economists think about costs. We then outline the steps involved in calculating the costs of delivering an intervention, including both implicit and explicit costs. Next we examine methods for estimating the morbidity-related costs of the illness or problem targeted by the intervention. Finally, we identify the challenges one faces when conducting such an analysis. Throughout the article, we illustrate key points using our experiences with evaluating the Fast Track intervention, a multiyear, multicomponent intervention targeted to children at risk of emotional and behavioral problems.


Individualized treatment of eating disorders.
The goal of this study is to determine how a comprehensive approach comprising a combination of a particular psychotherapeutic programme and antidepressant treatment influences the signs and symptoms of eating disorders. Inpatients entering a particular 6-week programme were assessed using body mass index (BMI), Eating Disorder Inventory (EDI), Eating Attitudes Test (EAT-26) and psychological symptoms using Symptom Checklist (SCL-90). In the whole group (n=84) the mean BMI remained stable (17.9, 17.8). There was a significant effect of TIME in the repeated measures ANOVA with most of dependent variables. The "TREATMENT" had no effect (antidepressants, no antidepressants) and there was no significant interaction between "TREATMENT" and "TIME". Post-hoc analysis revealed significant differences between baseline and end-point values of all but two EDI, all EAT items and some SCL dimensions in the antidepressant-treated group. The comprehensive and individualized approach is able to achieve weight stabilization, and improvement in attitudes, pathological eating behaviour and psychopathology.


Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling.
Oligodendrocyte precursors (OPs) continue to proliferate and generate myelinating oligodendrocytes (OLs) well into adulthood. It is not known whether adult-born OLs ensheath previously unmyelinated axons or remodel existing myelin. We quantified OP division and OL production in different regions of the adult mouse CNS including the 4-month-old optic nerve, in which practically all axons are already myelinated. Even there, all OPs were dividing and generating new OLs and myelin at a rate higher than can be explained by first-time myelination of naked axons. We conclude that adult-born OLs in the optic nerve are engaged in myelin remodeling, either replacing OLs that die in service or intercalating among existing myelin sheaths. The latter would predict that average internode length should decrease with age. Consistent with that, we found that adult-born OLs elaborated much shorter but many more internodes than OLs generated during early postnatal life.


Long-term follow-up after total lymphoid irradiation in pediatric heart transplant recipients.
Total lymphoid irradiation (TLI) is used to treat recurrent allograft rejection. Short-term success and complication rates have been reported in pediatric and adult cardiac transplant populations. We report the long-term efficacy and safety of TLI in treating intractable rejection in pediatric patients. Eight pediatric patients were treated with TLI (7 for recurrent rejection, 1 for risk of medication non-compliance). Therapy consisted of a mid-plane dose of 8 Gy administered with a 6-MeV linear accelerator using an anterior-posterior opposed technique. We reviewed outcomes for a total of 40 patient-years of follow-up. We encountered rejection (>Grade 2 by International Society for Heart and Lung Transplantation criteria) in 56.7% +/- 34.7% of biopsies performed within 90 days before TLI. Rejection rates dropped to 3.1% +/- 8.8% within the first 90 days (p < 0.005) after therapy and remained low at 5.6% +/- 1.3% (p < 0.05) during the first year after completion of TLI. Median time from TLI to the first subsequent rejection episode was 305 days (range, 77-1,920 days). Long-term follow-up (>3 years) of 5 patients demonstrated a continuing low incidence of rejection. Non-Hodgkin's lymphoma was diagnosed in 1 of 8 patients, graft coronary artery disease in 4 of 8 patients, and restrictive cardiomyopathy in 1 of 8 patients after TLI. Total lymphoid irradiation is an effective treatment for recurrent rejection and has short- and long-term efficacy. Morbid events may include cancer, graft coronary artery disease, and restrictive cardiomyopathy.


Building better research partnerships by understanding how Aboriginal health communities perceive and use data: a semistructured interview study.
To describe the attitudes and beliefs of health professionals working in Aboriginal Community Controlled Health Services (ACCHS) towards the access, usage and potential value of routinely obtained clinical and research data. Face-to-face, semistructured interviews were conducted with 35 health professionals from 2 urban and 1 regional ACCHS in New South Wales. The interviews were transcribed and themes were identified using an adapted grounded theory approach. Six major themes were identified: occupational engagement (day-to-day relevance, contingent on professional capacity, emphasising clinical relevance), trust and assurance (protecting ownership, confidence in narratives, valuing local sources), motivation and empowerment (engaging the community, influencing morale, reassuring and encouraging clients), building research capacity (using cultural knowledge, promoting research aptitude, prioritising specific data), optimising service provision (necessity for sustainable services, guiding and improving services, supporting best practice), and enhancing usability (ensuring ease of comprehension, improving efficiency of data management, valuing accuracy and accessibility). Participants were willing to learn data handling procedures that could further enhance health service delivery and enable more ACCHS-led research, but busy workloads restrict these opportunities. Staff held concerns regarding the translation of research data into beneficial services, and believed that the outcome and purpose of data collection could be communicated more clearly. Promoting research partnerships, ensuring greater awareness of positive health data and the purposes of data collection, and communicating data in a user-friendly format are likely to encourage greater data use, build research capacity and improve health services within the Aboriginal community.


Efficacy and safety of a loading-dose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer's disease: a randomized, double-masked, placebo-controlled trial. Metrifonate Study Group.
This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 of 2 regimens. The loading-dose group (n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS-Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed in this study, the no-loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity.


Abnormalities on Chest Computed Tomography and Lung Function Following an Intense Dust Exposure: A 17-Year Longitudinal Study.
Fire Department of the City of New York (FDNY) firefighters experienced intense dust exposure working at the World Trade Center (WTC) site on and after 11/9/2001 (9/11). We hypothesized that high-intensity WTC exposure caused abnormalities found on chest computed tomography (CT). Between 11/9/2001-10/9/2018, 4277 firefighters underwent a clinically-indicated chest CT. Spirometric measurements and symptoms were recorded during routine medical examinations. High-intensity exposure, defined as initial arrival at the WTC on the morning of 9/11, increased the risk of bronchial wall thickening, emphysema, and air trapping. Early post-9/11 symptoms of wheeze and shortness of breath were associated with bronchial wall thickening, emphysema, and air trapping. The risk of accelerated forced expiratory volume at one second (FEV1) decline (>64 mL/year decline) increased with bronchial wall thickening and emphysema, but decreased with air trapping. The risk of airflow obstruction also increased with bronchial wall thickening and emphysema but decreased with air trapping. In a previously healthy occupational cohort, high-intensity WTC exposure increased the risk for CT abnormalities. Bronchial wall thickening and emphysema were associated with respiratory symptoms, accelerated FEV1 decline, and airflow obstruction. Air trapping was associated with respiratory symptoms, although lung function was preserved. Physiologic differences between CT abnormalities suggest that distinct types of airway injury may result from a common exposure.


Binocular interactions in random chromatic changes at isoluminance.
To examine the type of chromatic interactions at isoluminance in the phenomenon of binocular vision, I have determined simple visual reaction times (VRT) under three observational conditions (monocular left, monocular right, and binocular) for different chromatic stimuli along random color axes at isoluminance (simultaneous L-, M-, and S-cone variations). Upper and lower boundaries of probability summation as well as the binocular capacity coefficient were estimated with observed distributions of reaction times. The results were not consistent with the notion of independent chromatic channels between eyes, suggesting the existence of excitatory and inhibitory binocular interactions at suprathreshold isoluminance conditions.


Immune-modifying and antimicrobial effects of Eucalyptus oil and simple inhalation devices.
Eucalyptus oil (EO) and its major component, 1,8-cineole, have antimicrobial effects against many bacteria, including Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus (MRSA), viruses, and fungi (including Candida). Surprisingly for an antimicrobial substance, there are also immune-stimulatory, anti-inflammatory, antioxidant, analgesic, and spasmolytic effects. Of the white blood cells, monocytes and macrophages are most affected, especially with increased phagocytic activity. Application by either vapor inhalation or oral route provides benefit for both purulent and non-purulent respiratory problems, such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). There is a long history of folk usage with a good safety record. More recently, the biochemical details behind these effects have been clarified. Although other plant oils may be more microbiologically active, the safety of moderate doses of EO and its broad-spectrum antimicrobial action make it an attractive alternative to pharmaceuticals. EO has also been shown to offset the myelotoxicity of one chemotherapy agent. Whether this is a general attribute that does not decrease the benefit of chemotherapy remains to be determined. This article also provides instruction on how to assemble inexpensive devices for vapor inhalation.


Recovery of resting brain connectivity ensuing mild traumatic brain injury.
Brains reveal amplified plasticity as they recover from an injury. We aimed to define time dependent plasticity changes in patients recovering from mild traumatic brain injury (mTBI). Twenty-five subjects with mild head injury were longitudinally evaluated within 36 h, 3 and 6 months using resting state functional connectivity (RSFC). Region of interest (ROI) based connectivity differences over time within the patient group and in comparison with a healthy control group were analyzed at p < 0.005. We found 33 distinct ROI pairs that revealed significant changes in their connectivity strength with time. Within 3 months, the majority of the ROI pairs had decreased connectivity in mTBI population, which increased and became comparable to healthy controls at 6 months. Within this diffuse decreased connectivity in the first 3 months, there were also few regions with increased connections. This hyper connectivity involved the salience network and default mode network within 36 h, and lingual, inferior frontal and fronto-parietal networks at 3 months. Our findings in a fairly homogenous group of patients with mTBI evaluated during the 6 month window of recovery defines time varying brain connectivity changes as the brain recovers from an injury. A majority of these changes were seen in the frontal and parietal lobes between 3 and 6 months after injury. Hyper connectivity of several networks supported normal recovery in the first 6 months and it remains to be seen in future studies whether this can predict an early and efficient recovery of brain function.


Micro-computed tomography study of oval-shaped canals prepared with the self-adjusting file, Reciproc, WaveOne, and ProTaper universal systems.
The newly developed single-file systems claimed to be able to prepare the root canal space with only 1 instrument. The present study was designed to test the null hypothesis that there is no significant difference in the preparation of oval-shaped root canals using single- or multiple-file systems. Seventy-two single-rooted mandibular canines were matched based on similar morphologic dimensions of the root canal achieved in a micro-computed tomographic evaluation and assigned to 1 of 4 experimental groups (n = 18) according to the preparation technique (ie, Self-Adjusting File [ReDent-Nova, Ra'anana, Israel], WaveOne [Dentsply Maillefer, Ballaigues, Switzerland], Reciproc [VDW, Munich, Germany], and ProTaper Universal [Dentsply Maillefer] systems). Changes in the 2- and 3-dimensional geometric parameters were compared with preoperative values using analysis of variance and the post hoc Tukey test between groups and the paired sample t test within groups (α = 0.05). Preparation significantly increased the analyzed parameters; the outline of the canals was larger and showed a smooth taper in all groups. Untouched areas occurred mainly on the lingual side of the middle third of the canal. Overall, a comparison between groups revealed that SAF presented the lowest, whereas WaveOne and ProTaper Universal showed the highest mean increase in most of the analyzed parameters (P < .05). All systems performed similarly in terms of the amount of touched dentin walls. Neither technique was capable of completely preparing the oval-shaped root canals.


Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types.
We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We applied our approach to gene expression data from several sources together with GWAS summary statistics for 48 diseases and traits (average N = 169,331) and found significant tissue-specific enrichments (false discovery rate (FDR) < 5%) for 34 traits. In our analysis of multiple tissues, we detected a broad range of enrichments that recapitulated known biology. In our brain-specific analysis, significant enrichments included an enrichment of inhibitory over excitatory neurons for bipolar disorder, and excitatory over inhibitory neurons for schizophrenia and body mass index. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signals.


Breast cancer stem cells-from origins to targeted therapy.
Breast cancer is marked as one of the leading causes of malignancy-related morbidities worldwide. In spite of aggressive interventions, the inevitability of relapse and metastasis severely impede survival rates. Mounting evidence highlight the insidious role of cancer stem cells (CSCs), a small but significant subpopulation of undifferentiated cells that drive tumour progression, spread and resistance to conventional therapy. The nature and significance of breast CSCs remains poorly understood, and even disputed by many researchers. This review discusses the origins, biomarkers, signalling pathways, regulatory mechanisms, and targeted therapy of breast CSCs.


Changes to publication requirements made at the XVIII International Botanical Congress in Melbourne-what does e-publication mean for you?
Changes to the International Code of Botanical Nomenclature are decided on every 6 years at Nomenclature Sections associated with International Botanical Congresses (IBC). The XVIII IBC was held in Melbourne, Australia; the Nomenclature Section met on 18-22 July 2011 and its decisions were accepted by the Congress at its plenary session on 30 July. Several important changes were made to the Code as a result of this meeting that will affect publication of new names. Two of these changes will come into effect on 1 January 2012, some months before the Melbourne Code is published. Electronic material published online in Portable Document Format (PDF) with an International Standard Serial Number (ISSN) or an International Standard Book Number (ISBN) will constitute effective publication, and the requirement for a Latin description or diagnosis for names of new taxa will be changed to a requirement for a description or diagnosis in either Latin or English. In addition, effective from 1 January 2013, new names of organisms treated as fungi must, in order to be validly published, include in the protologue (everything associated with a name at its valid publication) the citation of an identifier issued by a recognized repository (such as MycoBank). Draft text of the new articles dealing with electronic publication is provided and best practice is outlined.


2018 EULAR recommendations for a core data set to support observational research and clinical care in giant cell arteritis.
Giant cell arteritis (GCA) represents the most common form of primary systemic vasculitis and is frequently associated with comorbidities related to the disease itself or induced by the treatment. Systematically collected data on disease course, treatment and outcomes of GCA remain scarce. The aim of this EULAR Task Force was to identify a core set of items which can easily be collected by experienced clinicians, in order to facilitate collaborative research into the course and outcomes of GCA. A multidisciplinary EULAR task force group of 20 experts including rheumatologists, internists, epidemiologists and patient representatives was assembled. During a 1-day meeting, breakout groups discussed items from a previously compiled collection of parameters describing GCA status and disease course. Feedback from breakout groups was further discussed. Final consensus was achieved by means of several rounds of email discussions after the meeting. A three-round Delphi survey was conducted to determine a core set of parameters including the level of agreement. 117 parameters were regarded as relevant. Potential items were subdivided into the following categories: General, demographics, GCA-related signs and symptoms, other medical conditions and treatment. Possible instruments and assessment intervals were proposed for documentation of each item. To facilitate implementation of the recommendations in clinical care and clinical research, a minimum core set of 50 parameters was agreed. This proposed core set intends to ensure that relevant items from different GCA registries and databases can be compared for the dual purposes of facilitating clinical research and improving clinical care.


Diagnostic utility of aquaporin-4 in the analysis of active demyelinating lesions.
To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4-immunoglobulin G (IgG) serologic testing. This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury. AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)-positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy. AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS.


The multiplicity of malaria transmission: a review of entomological inoculation rate measurements and methods across sub-Saharan Africa.
Plasmodium falciparum malaria is a serious tropical disease that causes more than one million deaths each year, most of them in Africa. It is transmitted by a range of Anopheles mosquitoes and the risk of disease varies greatly across the continent. The "entomological inoculation rate" is the commonly-used measure of the intensity of malaria transmission, yet the methods used are currently not standardized, nor do they take the ecological, demographic, and socioeconomic differences across populations into account. To better understand the multiplicity of malaria transmission, this study examines the distribution of transmission intensity across sub-Saharan Africa, reviews the range of methods used, and explores ecological parameters in selected locations. It builds on an extensive geo-referenced database and uses geographical information systems to highlight transmission patterns, knowledge gaps, trends and changes in methodologies over time, and key differences between land use, population density, climate, and the main mosquito species. The aim is to improve the methods of measuring malaria transmission, to help develop the way forward so that we can better assess the impact of the large-scale intervention programmes, and rapid demographic and environmental change taking place across Africa.


Dependence on public financial support early in the course of schizophrenia.
Although most patients with schizophrenia rely on public financial support, little is known about how soon after the onset of illness such dependence occurs. Forty-eight patients with schizophrenia were followed for a mean of five years after their first hospitalization to examine their reliance on public support. At one year after their first hospitalization, 27 subjects (56 percent) were primarily supported by social service agencies. Once such support was initiated, it was maintained throughout the entire follow-up period for all patients except two. The findings indicate that dependence on public financial assistance begins very early in the course of illness for most hospitalized patients with schizophrenia.


Plasma concentrations, analgesic and physiological assessments in horses with chronic laminitis treated with two doses of oral tramadol.
Laminitis is a painful disease for which adequate pain management remains a challenging and largely unmet medical need. To investigate plasma concentrations, analgesic and physiological effects of 2 doses of tramadol in horses with chronic laminitis. Nonrandomised trial. Four horses with naturally occurring chronic laminitis received 5 mg/kg bwt and then 10 mg/kg bwt tramadol orally every 12 h for one week with a one-week washout between. Noninvasive arterial blood pressure, heart and respiratory rates, intestinal sounds and forelimb off-loading frequency were evaluated before and during treatments. Plasma tramadol and metabolite (M1 and M2) concentrations were measured on predetermined days and times after the morning dosing. Forelimb off-loading frequency decreased significantly with 10 mg/kg bwt (40%, P = 0.02) but not with 5 mg/kg bwt (9%, P = 0.4). Physiological variables did not change significantly with either treatment. For 5 and 10 mg/kg bwt treatments, respectively, individual maximum plasma concentrations (μg/l) ranged from 329 to 728 and 628 to 1330 (tramadol), 12-24 and 32-80 (M1), and 90-157 and 239-362 (M2). Respective median area under the concentration vs. time curves (h μg/l) were 727 and 1426, 33 and 88, 303 and 1003. Twice daily oral tramadol at 10 mg/kg bwt may produce analgesic plasma levels in horses with chronic laminitis.


TRAF2 mediates JNK and STAT3 activation in response to IL-1β and IFNγ and facilitates apoptotic death of insulin-producing β-cells.
Interleukin-1β (IL-1β) and interferon-γ (IFNγ) contribute to type 1 diabetes (T1D) by inducing β-cell death. Tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins are adaptors that transduce signaling from a variety of membrane receptors including cytokine receptors. We show here that IL-1β and IFNγ upregulate the expression of TRAF2 in insulin-producing INS-1E cells and isolated rat pancreatic islets. siRNA-mediated knockdown (KD) of TRAF2 in INS-1E cells reduced IL-1β-induced phosphorylation of JNK1/2, but not of p38 or ERK1/2 mitogen-activated protein kinases. TRAF2 KD did not modulate NFκB activation by cytokines, but reduced cytokine-induced inducible nitric oxide synthase (iNOS) promotor activity and expression. We further observed that IFNγ-stimulated phosphorylation of STAT3 required TRAF2. KD of TRAF2 or STAT3 reduced cytokine-induced caspase 3/7 activation, but, intriguingly, potentiated cytokine-mediated loss of plasma membrane integrity and augmented the number of propidium iodide-positive cells. Finally, we found that TRAF2 KD increased cytokine-induced production of reactive oxygen species (ROS). In summary, our data suggest that TRAF2 is an important mediator of IL-1β and IFNγ signaling in pancreatic β-cells.


Diet, physical activity, sedentary behaviour and perceptions of the environment in young adults.
Few studies have explored both food behaviour and physical activity in an environmental context. Most research in this area has focused on adults; the aim of the present study was to describe perceptions of the environment, diet, physical activity and sedentary behaviour patterns in 16-20 year olds in full-time education (Newcastle, UK). Participants (n = 73) recruited from a college and sixth-form college completed a UK version of the Youth Neighbourhood Environment Walkability Survey, which included measures of sedentary behaviour. A validated food frequency questionnaire was completed and a factor applied to produce an estimated mean daily frequency of intake of each item, which was converted to nutrient intakes. A rank for Index of Multiple Deprivation (IMD) was assigned to their home postcode. Analysis explored associations between sedentary behaviours and nutrient intake. In this descriptive cross-sectional study, most participants reported being physically active for at least 1 h day(-1) on 3-4 (n = 28) or 5-7 days (n = 31). There were no significant differences in nutrient intake according to sample quartile IMD position. Sedentary behaviours were significantly associated with less healthy eating patterns. Higher total energy (P = 0.02), higher fat (P = 0.005), percentage energy from fat (P = 0.035) and lower carbohydrate intakes (P = 0.004) were significantly associated with more time spent watching DVDs at the weekend. This combination of sedentary behaviour and less healthy eating patterns has important implications for long-term health (e.g. the tracking of being overweight and obesity from adolescence into adulthood). Understanding behaviour relationships is an important step in developing interventions in this age group.


Expression of the Oct-1 transcription factor and characterization of its interactions with the Bob1 coactivator.
The Oct-1 transcription factor regulates a variety of tissue-specific and general housekeeping genes by recruiting specialized coactivators of transcription. It acts synergistically with the B-cell-specific coactivator Bob1 (OCA-B, OBF-1) to stimulate transcription of immunoglobulin genes. To analyze Oct-1's interactions with Bob1 and other regulatory proteins, we have overexpressed and purified different functional domains of the recombinant proteins. A version of Oct-1 that encompasses the amino-terminal activation region and the POU DNA-binding domain was extensively characterized (OctDeltaC1; comprising residues 1-445). Using an in vitro transcription assay, we demonstrate that this fragment is sufficient and necessary to stimulate transcription from an immunoglobulin promoter with Bob1. It also coactivates from the herpes simplex virus ICPO promoter element in the presence of VP16. Using a range of spectroscopic and biophysical techniques, we demonstrate that the activation domains of Oct-1 and Bob1 have little globular structure and that they do not physically interact. Thus, their functional synergy is likely to arise by the co-recruitment of common factors as part of a larger regulatory assembly. We propose a hypothesis to explain why the activation domains of these and other transcription factors of metazoans have little if any intrinsic structure.


Hidden sources of phosphorus in the typical American diet: does it matter in nephrology?
Elevated serum phosphorus is a major, preventable etiologic factor associated with the increased cardiovascular morbidity and mortality of dialysis patients. An important determinant of serum phosphorus is the dietary intake of this mineral; this makes dietary restriction of phosphorus a cornerstone for the prevention and treatment of hyperphosphatemia. The average daily dietary intake of phosphorus is about 1550 mg for males and 1000 mg for females. In general, foods high in protein are also high in phosphorus. These figures, however, are changing as phosphates are currently being added to a large number of processed foods including meats, cheeses, dressings, beverages, and bakery products. As a result, and depending on the food choices, such additives may increase the phosphorus intake by as a much as 1 g/day. Moreover, nutrient composition tables usually do not include the phosphorus from these additives, resulting in an underestimate of the dietary intake of phosphorus in our patients. Our goal is to convey an understanding of the phosphorus content of the current American diet to better equip nephrologists in their attempt to control hyperphosphatemia.


Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin.
Insulin-like growth factors control numerous processes, namely somatic growth, metabolism and stress resistance, connecting this pathway to aging and age-related diseases. Insulin-like growth factor signaling also impacts on neurogenesis, neuronal survival and structural plasticity. Recent reports demonstrated that diminished insulin-like growth factor signaling confers increased stress resistance in brain and other tissues. To better understand the role of neuronal insulin-like growth factor signaling in neuroprotection, we inactivated insulin-like growth factor type-1-receptor in forebrain neurons using conditional Cre-LoxP-mediated gene targeting. We found that brain structure and function, including memory performance, were preserved in insulin-like growth factor receptor mutants, and that certain characteristics improved, notably synaptic transmission in hippocampal neurons. To reveal stress-related roles of insulin-like growth factor signaling, we challenged the brain using a stroke-like insult. Importantly, when charged with hypoxia-ischemia, mutant brains were broadly protected from cell damage, neuroinflammation and cerebral edema. We also found that in mice with insulin-like growth factor receptor knockout specifically in forebrain neurons, a substantial systemic upregulation of growth hormone and insulin-like growth factor-I occurred, which was associated with significant somatic overgrowth. Collectively, we found strong evidence that blocking neuronal insulin-like growth factor signaling increases peripheral somatotropic tone and simultaneously protects the brain against hypoxic-ischemic injury, findings that may contribute to developing new therapeutic concepts preventing the disabling consequences of stroke.


Nonpolar inactivation of the hypervariable streptococcal inhibitor of complement gene (sic) in serotype M1 Streptococcus pyogenes significantly decreases mouse mucosal colonization.
Group A Streptococcus (GAS) is a human pathogen that commonly infects the upper respiratory tract. GAS serotype M1 strains are frequently isolated from human infections and contain the gene encoding the hypervariable streptococcal inhibitor of complement protein (Sic). It was recently shown that Sic variants were rapidly selected on mucosal surfaces in epidemic waves caused by M1 strains, an observation suggesting that Sic participates in host-pathogen interactions on the mucosal surface (N. P. Hoe, K. Nakashima, S. Lukomski, D. Grigsby, M. Liu, P. Kordari, S.-J. Dou, X. Pan, J. Vuopio-Varkila, S. Salmelinna, A. McGeer, D. E. Low, B. Schwartz, A. Schuchat, S. Naidich, D. De Lorenzo, Y.-X. Fu, and J. M. Musser, Nat. Med. 5:924-929, 1999). To test this idea, a new nonpolar mutagenesis method employing a spectinomycin resistance cassette was used to inactivate the sic gene in an M1 GAS strain. The isogenic Sic-negative mutant strain was significantly (P < 0.019) impaired in ability to colonize the mouse mucosal surface after intranasal infection. These results support the hypothesis that the predominance of M1 strains in human infections is related, in part, to a Sic-mediated enhanced colonization ability.


A Sensorised Surgical Glove to Analyze Forces During Neurosurgery.
Measuring intraoperative forces in real time can provide feedback mechanisms to improve patient safety and surgical training. Previous force monitoring has been achieved through the development of specialized and adapted instruments or use designs that are incompatible with neurosurgical workflow. To design a universal sensorised surgical glove to detect intraoperative forces, applicable to any surgical procedure, and any surgical instrument in either hand. We created a sensorised surgical glove that was calibrated across 0 to 10 N. A laboratory experiment demonstrated that the sensorised glove was able to determine instrument-tissue forces. Six expert and 6 novice neurosurgeons completed a validated grape dissection task 20 times consecutively wearing the sensorised glove. The primary outcome was median and maximum force (N). The sensorised glove was able to determine instrument-tissue forces reliably. The average force applied by experts (2.14 N) was significantly lower than the average force exerted by novices (7.15 N) ( P = .002). The maximum force applied by experts (6.32 N) was also significantly lower than the maximum force exerted by novices (9.80 N) ( P = .004). The sensorised surgical glove's introduction to operative workflow was feasible and did not impede on task performance. We demonstrate a novel and scalable technique to detect forces during neurosurgery. Force analysis can provide real-time data to optimize intraoperative tissue forces, reduce the risk of tissue injury, and provide objective metrics for training and assessment.


Cerebral deep venous thrombosis and COVID-19: case report.
Herein, the authors present the case of a 54-year-old male diagnosed with coronavirus disease 2019 (COVID-19) during a screening test. The patient was asked to self-isolate at home and report with any exacerbations of symptoms. He presented later with pneumonia complicated by encephalopathy at days 14 and 15 from initial diagnosis, respectively. MRI of the brain showed bithalamic and gangliocapsular FLAIR signal abnormality with mild right-sided thalamic and periventricular diffusion restriction. A CT venogram was obtained given the distribution of edema and demonstrated deep venous thrombosis involving the bilateral internal cerebral veins and the vein of Galen. CSF workup was negative for encephalitis, as the COVID-19 polymerase chain reaction (PCR) test and bacterial cultures were negative. A complete hypercoagulable workup was negative, and the venous thrombosis was attributed to a hypercoagulable state induced by COVID-19. The mental decline was attributed to bithalamic and gangliocapsular venous infarction secondary to deep venous thrombosis. Unfortunately, the patient's condition continued to decline, and care was withdrawn.


Assessing the contribution of mangrove carbon and of other basal sources to intertidal flats adjacent to one of the largest West African mangrove forests.
Mangrove forests are productive habitats and major potential exporters of organic matter and nutrients to adjacent habitats. Here we examine the extent to which mangrove carbon is transferred to adjacent intertidal food webs in the second largest mangrove-covered area in Africa, in Guinea-Bissau. Applying stable isotope analysis and mixing models, we made comparisons at two spatial scales: (1) a large scale, comparing intertidal flats with (mangrove sites) and without (control sites) adjacent mangrove forests regarding the carbon isotopic signature of macrozoobenthos and sediment organic matter (SOM), and the relative importance of potential primary food sources in sustaining macrozoobenthos, and (2) a fine scale, performing stable carbon isotope measurements along 200 m transects from the coastline out to open intertidal flats, to trace mangrove carbon in macrozoobenthos and in the SOM. We found no evidence that mangrove carbon sustains intertidal food webs, despite SOM being significantly more depleted in 13C in mangrove sites. Mangrove leaves had the lowest relative contribution to the diet of macrozoobenthos, while macroalgae, benthic microalgae and POM showed variable but overall relevant contributions. Yet, at a smaller scale, mangrove carbon was detectable in SOM and in most macrozoobenthos, being strongest within 50 m of the mangrove edge and quickly fading with increasing distance. Our results suggest that there is only a marginal input of mangrove carbon into the food webs of unvegetated intertidal flats. Still, this leaves open the possibility of mangrove forests acting as sources of dissolved inorganic carbon and processed nitrogen, which can be assimilated by the algae and subsequently fuel adjacent food webs.


Design of CIAO, a research program to support the development of an integrated approach to prevent overweight and obesity in the Netherlands.
The aim of this paper is to describe the research aims, concepts and methods of the research Consortium Integrated Approach of Overweight (CIAO). CIAO is a concerted action of five Academic Collaborative Centres, local collaborations between academic institutions, regional public health services, local authorities and other relevant sectors in the Netherlands. Prior research revealed lacunas in knowledge of and skills related to five elements of the integrated approach of overweight prevention in children (based upon the French EPODE approach), namely political support, parental education, implementation, social marketing and evaluation. CIAO aims to gain theoretical and practical insight of these elements through five sub-studies and to develop, based on these data, a framework for monitoring and evaluation. For this research program, mixed methods are used in all the five sub-studies. First, problem specification through literature research and consultation of stakeholders, experts, health promotion specialists, parents and policy makers will be carried out. Based on this information, models, theoretical frameworks and practical instruments will be developed, tested and evaluated in the communities that implement the integrated approach to prevent overweight in children. Knowledge obtained from these studies and insights from experts and stakeholders will be combined to create an evaluation framework to evaluate the integrated approach at central, local and individual levels that will be applicable to daily practice. This innovative research program stimulates sub-studies to collaborate with local stakeholders and to share and integrate their knowledge, methodology and results. Therefore, the output of this program (both knowledge and practical tools) will be matched and form building blocks of a blueprint for a local evidence- and practice-based integrated approach towards prevention of overweight in children. The output will then support various communities to further optimize the implementation and subsequently the effects of this approach.


Genetic effects on planum temporale asymmetry and their limited relevance to neurodevelopmental disorders, intelligence or educational attainment.
Previous studies have suggested that altered asymmetry of the planum temporale (PT) is associated with neurodevelopmental disorders, including dyslexia, schizophrenia, and autism. Shared genetic factors have been suggested to link PT asymmetry to these disorders. In a dataset of unrelated subjects from the general population (UK Biobank, N = 18,057), we found that PT volume asymmetry had a significant heritability of roughly 14%. In genome-wide association analysis, two loci were significantly associated with PT asymmetry, including a coding polymorphism within the gene ITIH5 that is predicted to affect the protein's function and to be deleterious (rs41298373, p = 2.01 × 10-15), and a locus that affects the expression of the genes BOK and DTYMK (rs7420166, p = 7.54 × 10-10). DTYMK showed left-right asymmetry of mRNA expression in post mortem PT tissue. Cortex-wide mapping of these SNP effects revealed influences on asymmetry that went somewhat beyond the PT. Using publicly available genome-wide association statistics from large-scale studies, we saw no significant genetic correlations of PT asymmetry with autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, educational attainment or intelligence. Of the top two individual loci associated with PT asymmetry, rs41298373 showed a tentative association with intelligence (unadjusted p = .025), while the locus at BOK/DTYMK showed tentative association with educational attainment (unadjusted Ps < .05). These findings provide novel insights into the genetic contributions to human brain asymmetry, but do not support a substantial polygenic association of PT asymmetry with cognitive variation and mental disorders, as far as can be discerned with current sample sizes.


Mitochondrial phylogeography of the Eurasian beaver Castor fiber L.
Nucleotide variation in an approximately 490 bp fragment of the mitochondrial DNA control region (mtDNA CR) was used to describe the genetic variation and phylogeographical pattern in the Eurasian beaver (Castor fiber) over its entire range. The sampling effort was focused on the relict populations that survived a drastic population bottleneck, caused by overhunting, at the end of the 19th century. A total of 152 individuals grouped into eight populations representing all currently recognized subspecies were studied. Sixteen haplotypes were detected, none of them shared among populations. Intrapopulation sequence variation was very low, most likely a result of the severe bottleneck. Extreme genetic structure could result from human-mediated extinction of intermediate populations, but it could also be an effect of prior substantial structuring of the beaver populations with watersheds of major Eurasian rivers acting as barriers to gene flow. Phylogenetic analysis revealed the presence of two mtDNA lineages: eastern (Poland, Lithuania, Russia and Mongolia) and western (Germany, Norway and France), the former comprising more divergent haplotypes. The low level of sequence divergence of the entire cytochrome b gene among six individuals representing six subspecies suggests differentiation during the last glacial period and existence of multiple glacial refugia. At least two evolutionary significant units (ESU) can be identified, the western and the eastern haplogroup. The individual relict populations should be regarded as management units, the eastern subspecies possibly also as ESUs. Guidelines for future translocations and reintroductions are proposed.


Aboriginal and Torres Strait Islander people's domains of wellbeing: A comprehensive literature review.
There are significant health and social disparities between the world's Indigenous and non-Indigenous people on factors likely to influence quality of life (QOL) and wellbeing. However, these disparities in wellbeing are not captured in conventional QOL instruments, as they often do not include dimensions that are likely to be relevant to Indigenous people. The objective of this comprehensive literature review was to identify these wellbeing domains for Aboriginal and Torres Strait Islander people in Australia (hereafter, respectfully referred to collectively as Indigenous Australians). We searched PsycINFO, MEDLINE, Econlit, CINAHL, and Embase (from inception to June 2017, and updated in March 2019), and grey literature sources using keywords relating to adult Indigenous Australians' QOL and wellbeing. From 278 full-text articles assessed for eligibility, 95 were included in a thematic analysis. This synthesis revealed nine broad interconnected wellbeing dimensions: autonomy, empowerment and recognition; family and community; culture, spirituality and identity; Country; basic needs; work, roles and responsibilities; education; physical health; and mental health. The findings suggest domains of wellbeing relevant to and valued by Indigenous Australians that may not be included in existing QOL and wellbeing instruments, domains that may be shared with Indigenous populations globally. This indicates the need for a tailored wellbeing instrument that includes factors relevant to Indigenous Australians. Developing such an instrument will ensure meaningful, culturally-relevant measurement of Indigenous Australians' wellbeing.


Effectiveness of Strontium Ranelate in the Treatment of Rat Model of Legg-Calve-Perthes Disease.
Legg-Calve-Perthes disease (LCPD) causes osteonecrosis of the femoral head (ONFH) by temporarily interrupting the blood supply in children. Even with potential toward bone regeneration and revascularization in LCPD, the prognosis depends on the deformity of femoral heads, and successful rate with the current treatments varies. Antiresorptive therapy such as bisphosphonate, which maintains mechanical stability of the femoral head by inhibiting necrotic bone resorption, has proven effective in animal models. However, concerns on simultaneous decline in bone turnover rate still leave room for improvement. Strontium ranelate with dual effect on inhibiting bone resorption and accelerating bone formation is presumed to be an ideal therapy for reserving sphericity of femoral heads in LCPD. In this study of a rat model of ONFH, randomized groups of rats treated with strontium ranelate or normal saline are compared at different time points in analysis of radiological, histological, and bone morphometric changes. Gait analysis was also compared between the two groups. The group treated with strontium ranelate recovered their normal gait earlier than the control group did. Bone density, trabecular thickness, sphericity of the femoral head, and bone regeneration potential were also preserved in the strontium ranelate group. Strontium ranelate effectively prevented collapse of the ischemic femoral head and enhanced trabecular thickness in the rat model of LCPD. Hopefully, this preclinical experiment can improve the effectiveness of strontium ranelate treatment for pediatric ONFH.