Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression.
Alzheimer's disease (AD) is a heterogeneous disorder. To investigate whether cognitive AD subtypes are associated with different rates of disease progression. We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses. Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00-1.85, p = 0.05). AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment.


Role of lipids in spheroidal high density lipoproteins.
We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules surrounding the lipid compartment. The present models are the first ones among computational studies where the size and lipid composition of HDL are realistic, corresponding to human serum HDL. We focus on the role of lipids in HDL structure and dynamics. Particular attention is paid to the assembly of lipids and the influence of lipid-protein interactions on HDL properties. We find that the properties of lipids depend significantly on their location in the particle (core, intermediate region, surface). Unlike the hydrophobic core, the intermediate and surface regions are characterized by prominent conformational lipid order. Yet, not only the conformations but also the dynamics of lipids are found to be distinctly different in the different regions of HDL, highlighting the importance of dynamics in considering the functionalization of HDL. The structure of the lipid droplet close to the HDL-water interface is altered by the presence of apoA-Is, with most prominent changes being observed for cholesterol and polar lipids. For cholesterol, slow trafficking between the surface layer and the regimes underneath is observed. The lipid-protein interactions are strongest for cholesterol, in particular its interaction with hydrophobic residues of apoA-I. Our results reveal that not only hydrophobicity but also conformational entropy of the molecules are the driving forces in the formation of HDL structure. The results provide the first detailed structural model for HDL and its dynamics with and without apoA-I, and indicate how the interplay and competition between entropy and detailed interactions may be used in nanoparticle and drug design through self-assembly.


Prediction of MCI to AD conversion, via MRI, CSF biomarkers, and pattern classification.
Magnetic resonance imaging (MRI) patterns were examined together with cerebrospinal fluid (CSF) biomarkers in serial scans of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with mild cognitive impairment (MCI). The SPARE-AD score, summarizing brain atrophy patterns, was tested as a predictor of short-term conversion to Alzheimer's disease (AD). MCI individuals that converted to AD (MCI-C) had mostly positive baseline SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD) and atrophy in temporal lobe gray matter (GM) and white matter (WM), posterior cingulate/precuneous, and insula. MCI individuals that converted to AD had mostly AD-like baseline CSF biomarkers. MCI nonconverters (MCI-NC) had mixed baseline SPARE-AD and CSF values, suggesting that some MCI-NC subjects may later convert. Those MCI-NC with most negative baseline SPARE-AD scores (normal brain structure) had significantly higher baseline Mini Mental State Examination (MMSE) scores (28.67) than others, and relatively low annual rate of Mini Mental State Examination decrease (-0.25). MCI-NC with midlevel baseline SPARE-AD displayed faster annual rates of SPARE-AD increase (indicating progressing atrophy). SPARE-AD and CSF combination improved prediction over individual values. In summary, both SPARE-AD and CSF biomarkers showed high baseline sensitivity, however, many MCI-NC had abnormal baseline SPARE-AD and CSF biomarkers. Longer follow-up will elucidate the specificity of baseline measurements.


A study of intraluminal peptide hydrolase activity in the rat.
1. Uncentrifuged and centrifuged rat intestinal contents were assayed for peptide hydrolase activity with glycyl-L-phenylalanine (Gly-Phe) and L-phenylalanyl-glycine (Phe-Gly) as substrates in the absence and presence of the intestinal cytosol peptide hydrolase inhibitor p-hydroxymercuribenzoate. 2. Jejunal contents hydrolysed Gly-Phe faster than Phe-Gly. Conversely, ileal contents hydrolysed Phe-Gly faster than Gly-Phe. 3. p-Hydroxymercuribenzoate markedly inhibited jejunal peptide hydrolase activity. There was ten times as much PHMB-resistant activity towards both dipeptides in ileal contents as in jejunal contents. 4. Most of the luminal enzyme activity was present in the supernatants after centrifugation, indicating the luminal enzymes exist in the soluble form. Although the presence of soluble bacterial enzymes cannot be excluded, peptide hydrolase enzymes in jejunal contents have the characteristics of mucosal cytosol enzymes whereas enzymes in ileal contents have the characteristics of mucosal bruch border as well as cytosol enzymes.


Water, Sanitation and Hygiene (WASH) and environmental risk factors for soil-transmitted helminth intensity of infection in Timor-Leste, using real time PCR.
No investigations have been undertaken of risk factors for intensity of soil-transmitted helminth (STH) infection in Timor-Leste. This study provides the first analysis of risk factors for intensity of STH infection, as determined by quantitative PCR (qPCR), examining a broad range of water, sanitation and hygiene (WASH) and environmental factors, among communities in Manufahi District, Timor-Leste. A baseline cross-sectional survey of 18 communities was undertaken as part of a cluster randomised controlled trial, with additional identically-collected data from six other communities. qPCR was used to assess STH infection from stool samples, and questionnaires administered to collect WASH, demographic, and socioeconomic data. Environmental information was obtained from open-access sources and linked to infection outcomes. Mixed-effects multinomial logistic regression was undertaken to assess risk factors for intensity of Necator americanus and Ascaris infection. 2152 participants provided stool and questionnaire information for this analysis. In adjusted models incorporating WASH, demographic and environmental variables, environmental variables were generally associated with infection intensity for both N. americanus and Ascaris spp. Precipitation (in centimetres) was associated with increased risk of moderate-intensity (adjusted relative risk [ARR] 6.1; 95% confidence interval [CI] 1.9-19.3) and heavy-intensity (ARR 6.6; 95% CI 3.1-14.1) N. americanus infection, as was sandy-loam soil around households (moderate-intensity ARR 2.1; 95% CI 1.0-4.3; heavy-intensity ARR 2.7; 95% CI 1.6-4.5; compared to no infection). For Ascaris, alkaline soil around the household was associated with reduced risk of moderate-intensity infection (ARR 0.21; 95% CI 0.09-0.51), and heavy-intensity infection (ARR 0.04; 95% CI 0.01-0.25). Few WASH risk factors were significant. In this high-prevalence setting, strong risk associations with environmental factors indicate that anthelmintic treatment alone will be insufficient to interrupt STH transmission, as conditions are favourable for ongoing environmental transmission. Integrated STH control strategies should be explored as a priority.


Evidence on the Association Between Cigarette Smoking and Incident Depression From the South African National Income Dynamics Study 2008-2015: Mental Health Implications for a Resource-Limited Setting.
As a leading global disease risk factor, cigarette smoking has declined in some developed countries, but its health consequences are not well established in sub-Saharan Africa. This is particularly evident in South Africa, where few investigations have quantified the dually neglected challenges of cigarette smoking and depression, despite decades of research from developed countries. We investigated the association between cigarette smoking and incident depression, with the hypothesis that adolescents are particularly vulnerable. Panel data from the South African National Income Dynamics Study, a nationally representative sample of households at follow-up periods (years 2008-2015), were used. Our incident cohort consists of 14 118 adult participants who were depression free at baseline. The generalized estimating equation models were fitted to assess the association between current cigarette smoking and incident depression. Current cigarette smoking among individuals aged at least 15 was significantly associated with incidents of depression among men (adjusted relative risk [aRR] = 1.16, 95% CI = 1.01 to 1.34), but not women. When the analyses were restricted to a sample population of older adolescents (ages 15-19), current cigarettes smoking was significantly associated with incident depression in both men (aRR = 1.84, 95% CI = 1.18 to 2.88) and women (aRR = 2.47, 95% CI = 1.15 to 5.29). The results suggest an important relationship between cigarette smoking and incident depression, particularly among older adolescents, who are developmentally vulnerable and socioeconomically disadvantaged to experiencing depression. There is a considerable need to implement and prioritize culturally and developmentally appropriate prevention and cessation measures to reduce cigarette smoking and depression directed at adolescent populations. There has been little population level research into the role of smoking on depression in sub-Saharan Africa, a region classified as a tobacco epidemic in the making. Our results have major implications for the often neglected crosscutting issues of tobacco control (Sustainable Development Goal 3.9) and mental health (Sustainable Development Goal 3.4). They indicate the role of smoking on depression, with the association being particularly pronounced among adolescent who are developmentally vulnerable and socioeconomically disadvantaged, and emphasize the need to implement and prioritize prevention and cessation measures directed at this population.


Eye discomfort, headache and back pain among Mayan Guatemalan women taking part in a randomised stove intervention trial.
Indoor air pollution (IAP) from combustion of biomass fuels represents a global health problem, estimated to cause 1.6 million premature deaths annually. RESPIRE (Randomised Exposure Study of Pollution Indoors and Respiratory Effects) Guatemala is the first randomised controlled trial ever performed on health effects from solid fuel use. Its goal is to assess the effect of improved stoves (planchas) on exposure and health outcomes in a rural population reliant on wood fuel. Questions about symptoms were asked at baseline and periodically after the intervention, to an initial group of 504 women (259 randomly assigned to planchas (mean (standard deviation) age 27.4 (7.2) years) and 245 using traditional open fires (28.1 (7.1) years)). Levels of carbon monoxide (CO) in exhaled breath, a biomarker of recent exposure to air pollution from biomass combustion, were measured at each visit. In addition to reducing IAP levels, the plancha may also have a positive health effect by changing the working posture to an upright position. A high prevalence of eye discomfort, headache and backache was found. The odds of having sore eyes and headache were substantially reduced in the plancha group relative to the group using open fires for the follow-up period (odds ratio (OR) 0.18, 95% confidence interval (CI) 0.11 to 0.29 and (OR) 0.63, 95% CI 0.42 to 0.94, respectively). Median CO in breath among women in the intervention trial was significantly lower than controls. In addition to reducing discomfort for women, tangible improvements in symptoms experienced by a substantial proportion of women may help to gain acceptance and wider use of planchas.


RTK signaling modulates the Dorsal gradient.
The dorsoventral (DV) axis of the Drosophila embryo is patterned by a nuclear gradient of the Rel family transcription factor, Dorsal (Dl), that activates or represses numerous target genes in a region-specific manner. Here, we demonstrate that signaling by receptor tyrosine kinases (RTK) reduces nuclear levels and transcriptional activity of Dl, both at the poles and in the mid-body of the embryo. These effects depend on wntD, which encodes a Dl antagonist belonging to the Wingless/Wnt family of secreted factors. Specifically, we show that, via relief of Groucho- and Capicua-mediated repression, the Torso and EGFR RTK pathways induce expression of WntD, which in turn limits Dl nuclear localization at the poles and along the DV axis. Furthermore, this RTK-dependent control of Dl is important for restricting expression of its targets in both contexts. Thus, our results reveal a new mechanism of crosstalk, whereby RTK signals modulate the spatial distribution and activity of a developmental morphogen in vivo.


An analysis of the Athetis lepigone transcriptome from four developmental stages.
Athetis lepigone Möschler (Lepidoptera: Noctuidae) has recently become an important insect pest of maize (Zea mays) crops in China. In order to understand the characteristics of the different developmental stages of this pest, we used Illumina short-read sequences to perform de novo transcriptome assembly and gene expression analysis for egg, larva, pupa and adult developmental stages. We obtained 10.08 Gb of raw data from Illumina sequencing and recovered 81,356 unigenes longer than 100 bp through a de novo assembly. The total sequence length reached 49.75 Mb with 858 bp of N50 and an average unigene length of 612 bp. Annotation analysis of predicted proteins indicate that 33,736 unigenes (41.47% of total unigenes) are matches to genes in the Genbank Nr database. The unigene sequences were subjected to GO, COG and KEGG functional classification. A large number of differentially expressed genes were recovered by pairwise comparison of the four developmental stages. The most dramatic differences in gene expression were found in the transitions from one stage to another stage. Some of these differentially expressed genes are related to cuticle and wing formation as well as the growth and development. We identified more than 2,500 microsatellite markers that may be used for population studies of A. lepigone. This study lays the foundation for further research on population genetics and gene function analysis in A. lepigone.


Problematic boundaries in the diagnosis of bipolar disorder: the interface with borderline personality disorder.
It is clinically important to recognize both bipolar disorder and borderline personality disorder (BPD) in patients seeking treatment for depression, and it is important to distinguish between the two. The most studied question on the relationship between BPD and bipolar disorder is their diagnostic concordance. Across studies approximately 10 % of patients with BPD had bipolar I disorder and another 10 % had bipolar II disorder. Likewise, approximately 20 % of bipolar II patients were diagnosed with BPD, though only 10 % of bipolar I patients were diagnosed with BPD. While the comorbidity rates are substantial, each disorder is, nonetheless, diagnosed in the absence of the other in the vast majority of cases (80-90 %). In studies examining personality disorders broadly, other personality disorders were more commonly diagnosed in bipolar patients than was BPD. Likewise, the converse is also true: other axis I disorders such as major depression, substance abuse, and post-traumatic stress disorder are more commonly diagnosed in patients with BPD than is bipolar disorder. Studies comparing patients with BPD and bipolar disorder find significant differences on a range of variables. These findings challenge the notion that BPD is part of the bipolar spectrum. While a substantial literature has documented problems with the under-recognition and under-diagnosis of bipolar disorder, more recent studies have found evidence of bipolar disorder over-diagnosis and that BPD is a significant contributor to over-diagnosis. Re-conceptualizing the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, diagnostic criteria for bipolar disorder as a type of test, rather than the final word on diagnosis, shifts the diagnostician from thinking solely whether a patient does or does not have a disorder to considering the risks of false-positive and false-negative diagnoses, and the ease by which each type of diagnostic error can be corrected by longitudinal observation.


Reduction in summer soil wetness induced by an increase in atmospheric carbon dioxide.
The geographical distribution of the change in soil wetness in response to an increase in atmospheric carbon dioxide was investigated by using a mathematical model of climate. Responding to the increase in carbon dioxide, soil moisture in the model would be reduced in summer over extensive regions of the middle and high latitudes, such as the North American Great Plains, western Europe, northern Canada, and Siberia. These results were obtained from the model with predicted cloud cover and are qualitatively similar to the results from several numerical experiments conducted earlier with prescribed cloud cover.


Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial.
The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [(18)F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.


Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson's disease.
Accumulating evidence supports a role for the immune system in the pathogenesis of Parkinson's disease. Importantly, recent preclinical studies are now suggesting a specific contribution of inflammation to the α-synuclein-induced pathology seen in this condition. We used flow cytometry and western blots to detect toll-like receptor 2 and 4 expression in blood and brain samples of Parkinson's disease patients and mice overexpressing human α-synuclein. To further assess the effects of α-synuclein overexpression on the innate immune system, we performed a longitudinal study using Thy1.2-α-synuclein mice that expressed a bicistronic DNA construct (reporter genes luciferase and green fluorescent protein) under the transcriptional control of the murine toll-like receptor 2 promoter. Here, we report increases in toll-like receptors 2 and 4 expression in circulating monocytes and of toll-like receptor 4 in B cells and in the caudate/putamen of Parkinson's disease patients. Monthly bioluminescence imaging of Thy1.2-α-synuclein mice showed increasing toll-like receptor 2 expression from 10 months of age, although no change in toll-like receptor 2 and 4 expression was observed in the blood and brain of these mice at 12 months of age. Dexamethasone treatment starting at 5 months of age for 1 month significantly decreased the microglial response in the brain of these mice and promoted functional recovery as observed using a wheel-running activity test. Our results show that toll-like receptors 2 and 4 are modulated in the blood and brain of Parkinson's disease patients and that overexpression of α-synuclein leads to a progressive microglial response, the inhibition of which has a beneficial impact on some motor phenotypes of an animal model of α-synucleinopathy.


Contribution of body fatness and adipose tissue distribution to the age variation in plasma steroid hormone concentrations in men: the HERITAGE Family Study.
Obesity has been associated with alterations in plasma steroid hormone concentrations in men. Older men present an altered steroid hormone profile compared to younger individuals, and an increase in body fatness and changes in adipose tissue (AT) distribution are noted with advancing age. Thus, there is a need to examine the relative importance of increased body fatness and changes in AT distribution with advancing age to plasma steroid hormone and sex hormone-binding globulin levels in men. We, therefore, investigated the relationships among age, body fatness, AT distribution, and the plasma steroid hormone profile in a group of 217 Caucasian men (mean age +/- SD, 36.2 +/- 14.9 yr) who covered a wide age range (17-64 yr). Compared to young adult men, older men were characterized by increased adiposity (P < 0.0001) expressed either as body mass index or total body fat mass assessed by underwater weighing. Differences in AT distribution were also noted with a preferential accumulation of abdominal fat as indicated by a larger waist girth (P < 0.0001) and higher visceral AT accumulation (P < 0.0001), measured by computed tomography, in older subjects. Age was associated with decreases (P < 0.0001) in C19 adrenal steroid levels, namely reduced dehydroepiandrosterone (DHEA), DHEA fatty acid ester, DHEA sulfate, as well as androstenedione levels. Androgens, i.e. dihydrotestosterone and testosterone, were also affected by age, with lower levels of both steroids being found in older individuals (P < 0.0005). When statistical adjustment for body fatness and AT distribution was performed, differences in C19 adrenal steroids between the age groups remained significant, whereas differences in androgens and sex hormone-binding globulin concentrations were no longer significant. The present study suggests that age-related differences in plasma steroid hormone levels, especially androgens, are partly mediated by concomitant variation in adiposity in men.


Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines.
In previous studies, it has been demonstrated that ciliary neurotrophic factor (CNTF) has a potent survival effect on various populations of neurons in culture, in particular, neurons isolated from chick ciliary, dorsal root sensory, and sympathetic ganglia (Barbin et al., 1984). After recent investigations demonstrated that CNTF prevents the degeneration of motoneurons in newborn rats after axonal lesion (Sendtner et al., 1990), the question arose as to whether CNTF also has a survival effect on embryonic chick motoneurons at the developmental stage where physiological cell death occurs. To study this, it was essential to develop an isolation and culture procedure for the survival of chick E6 spinal motoneurons in which non-neuronal cells were eliminated and the motoneurons were highly enriched. In these cultures, virtually all of the initially plated motoneurons survived for at least 3 d in the presence of muscle extract, which was chosen as a positive control. Retrograde labeling of the motoneurons prior to their isolation showed that there is more than an 80% enrichment for motoneurons by the method used. The retrogradely labeled neurons also fulfilled the morphological criteria (diameter of neurons, appearance of processes) to identify motoneurons independent of retrograde labeling. Under these conditions, CNTF at a concentration of 1.5 ng/ml (EC50, 0.023 ng/ml) supported maximally 64% of the initially plated spinal motoneurons after 3 d and 53% after 6 d (the longest time period investigated). Other neurotrophic factors, such as NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3, had no survival effect at all, even at concentrations up to 10 micrograms/ml for NGF and BDNF.(ABSTRACT TRUNCATED AT 250 WORDS)


A phylogeny of Diprotodontia (Marsupialia) based on sequences for five nuclear genes.
Even though the marsupial order Diprotodontia is one of the most heavily studied groups of Australasian marsupials, phylogenetic relationships within this group remain contentious. The more than 125 living species of Diprotodontia can be divided into two main groups: Vombatiformes (wombats and koalas) and Phalangerida. Phalangerida is composed of the kangaroos (Macropodidae, Potoroidae, and Hypsiprymnodontidae) and possums (Phalangeridae, Burramyidae, Petauridae, Pseudocheiridae, Tarsipedidae, and Acrobatidae). Much of the debate has focused on relationships among the families of possums and whether possums are monophyletic or paraphyletic. A limitation of previous investigations is that no study to date has investigated diprotodontian relationships using all genera. Here, we examine diprotodontian interrelationships using a nuclear multigene molecular data set representing all recognized extant diprotodontian genera. Maximum parsimony, maximum likelihood, and Bayesian methods were used to analyze sequence data obtained from protein-coding portions of ApoB, BRCA1, IRBP, Rag1, and vWF. We also applied a Bayesian relaxed molecular clock method to estimate times of divergence. Diprotodontia was rooted between Vombatiformes and Phalangerida. Within Phalangerida, the model-based methods strongly support possum paraphyly with Phalangeroidea (Burramyidae+Phalangeridae) grouping with the kangaroos (Macropodiformes) to the exclusion of Petauroidea (Tarsipedidae, Acrobatidae, Pseudocheiridae, and Petauridae). Within Petauroidea, Tarsipedidae grouped with both Petauridae and Pseudocheiridae to the exclusion of Acrobatidae. Our analyses also suggest that the diprotodontian genera Pseudochirops and Strigocuscus are paraphyletic and diphyletic, respectively, as currently recognized. Dating analyses suggest Diprotodontia diverged from other australidelphians in the late Paleocene to early Eocene with all interfamilial divergences occurring prior to the early Miocene except for the split between the Potoroidae and Macropodidae, which occurred sometime in the mid-Miocene. Ancestral state reconstructions using a Bayesian method suggest that the patagium evolved independently in the Acrobatidae, Petauridae, and Pseudocheiridae. Ancestral state reconstructions of ecological venue suggest that the ancestor of Diprotodontia was arboreal. Within Diprotodontia, the common ancestor of Macropodidae was reconstructed as terrestrial, suggesting that tree kangaroos (Dendrolagus) are secondarily arboreal.


Human metapneumovirus infection activates the TSLP pathway that drives excessive pulmonary inflammation and viral replication in mice.
Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infections in children and the elderly. The mechanism by which this virus triggers an inflammatory response still remains unknown. Here, we evaluated whether the thymic stromal lymphopoietin (TSLP) pathway contributes to lung inflammation upon hMPV infection. We found that hMPV infection promotes TSLP expression both in human airway epithelial cells and in the mouse lung. hMPV infection induced lung infiltration of OX40L(+) CD11b(+) DCs. Mice lacking the TSLP receptor deficient mice (tslpr(-/-) ) showed reduced lung inflammation and hMPV replication. These mice displayed a decreased number of neutrophils as well a reduction in levels of thymus and activation-regulated chemokine/CCL17, IL-5, IL-13, and TNF-α in the airways upon hMPV infection. Furthermore, a higher frequency of CD4(+) and CD8(+) T cells was found in tslpr(-/-) mice compared to WT mice, which could contribute to controlling viral spread. Depletion of neutrophils in WT and tslpr(-/-) mice decreased inflammation and hMPV replication. Remarkably, blockage of TSLP or OX40L with specific Abs reduced lung inflammation and viral replication following hMPV challenge in mice. Altogether, these results suggest that activation of the TSLP pathway is pivotal in the development of pulmonary pathology and pulmonary hMPV replication.


Browsing (Epi)genomes: a guide to data resources and epigenome browsers for stem cell researchers.
Over the past years we have witnessed an explosion in the generation of freely available genome-wide data sets, including maps of various histone modifications, transcription factor binding, DNase hypersensitivity, and DNA methylation, which provide valuable resources for data validation, exploration, and hypothesis generation. The goal of this review is to provide the reader with information on where to find many of the data sets and how to utilize the various (epi)genome browsers for display and initial analysis. We provide selected examples to highlight key features and demonstrate the application of these browsers to stem cell biology.


Job strain as a risk factor for clinical depression: systematic review and meta-analysis with additional individual participant data.
Adverse psychosocial working environments characterized by job strain (the combination of high demands and low control at work) are associated with an increased risk of depressive symptoms among employees, but evidence on clinically diagnosed depression is scarce. We examined job strain as a risk factor for clinical depression. We identified published cohort studies from a systematic literature search in PubMed and PsycNET and obtained 14 cohort studies with unpublished individual-level data from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium. Summary estimates of the association were obtained using random-effects models. Individual-level data analyses were based on a pre-published study protocol. We included six published studies with a total of 27 461 individuals and 914 incident cases of clinical depression. From unpublished datasets we included 120 221 individuals and 982 first episodes of hospital-treated clinical depression. Job strain was associated with an increased risk of clinical depression in both published [relative risk (RR) = 1.77, 95% confidence interval (CI) 1.47-2.13] and unpublished datasets (RR = 1.27, 95% CI 1.04-1.55). Further individual participant analyses showed a similar association across sociodemographic subgroups and after excluding individuals with baseline somatic disease. The association was unchanged when excluding individuals with baseline depressive symptoms (RR = 1.25, 95% CI 0.94-1.65), but attenuated on adjustment for a continuous depressive symptoms score (RR = 1.03, 95% CI 0.81-1.32). Job strain may precipitate clinical depression among employees. Future intervention studies should test whether job strain is a modifiable risk factor for depression.


Can individual conditions during childhood mediate or moderate the long-term cognitive effects of poor economic environments at birth?
Recent analyses revealed that the business cycle at the time of birth influences cognitive functioning at older ages, and that those individuals born during economic boom periods on average display better cognitive functioning later in life. The current study examines the impact of childhood conditions on late-life cognitive functioning and investigates whether they mediate or moderate the effects of the business cycle at the time of birth. The underlying purpose is to find potential starting points for societal interventions that may counterbalance the negative long-term outcomes of adverse living conditions early in life. We use data from 7935 respondents at ages 60+ in eleven European countries from the first three waves of the Survey of Health, Ageing and Retirement in Europe (SHARE). The survey data was collected in 2004, 2006/07, and 2008/09. Country fixed-effects models are used to examine the impact of macro-economic deviations in the year of birth and the indicators of childhood circumstances on late-life cognitive functioning. This study shows that the effects of boom and recession periods at birth are not simply mediated or moderated by living conditions during childhood. Conditions at birth have biological long-run effects on late-life cognitive functioning. Individuals born during boom periods display signs of having better cognitive functioning later in life, whereas recessions negatively influence cognition. Furthermore, a series of childhood conditions in and of themselves influence late-life cognition. Good childhood cognition, high education as well as a high social status, favourable living arrangements, and good health have a positive impact. Policy interventions should aim at a better access to school or measures to improve the economic and social situations of disadvantaged households.


The utility of multiple imaging modalities to diagnose acute aortic dissection.
A 21-year-old man with Marfan syndrome and known aortic root aneurysm presented to our emergency department with symptoms suggestive of acute aortic dissection. The patient was hemodynamically stable and bilateral upper extremity blood pressures were similar. There was no mediastinal widening on portable chest radiograph. Both contrast CT and retrograde angiography of the aorta failed to identify dissection. Subsequent transesophageal echocardiography demonstrated a Stanford classification type A dissection. This case demonstrates the utility of multiple imaging modalities for identifying aortic dissection in high-risk patients.


The putative iron-responsive element in the human erythroid 5-aminolevulinate synthase mRNA mediates translational control.
The 52-nucleotide 5'-untranslated region of the human erythroid 5-aminolevulinate synthase mRNA contains a 28-nucleotide iron-responsive element-like stem-loop motif. We fused the 5'-untranslated region upstream to the coding sequence of the human growth hormone cDNA. A chimeric construct containing a mutated variant of the presumptive iron-responsive element was similarly synthesized. Translation of the wild type chimeric transcript was markedly repressed (approximately 95%) in rabbit reticulocyte lysates as opposed to the mutant. Both transcripts translated with comparable efficiency in wheat germ extracts. Purified placental iron regulatory factor selectively and markedly inhibited translation of the wild type chimeric transcript (> 90%) when tested in wheat germ extracts. By contrast, translations of either the mutant chimeric transcript or other control mRNA species were unaffected. The proximal position of the iron-responsive element relative to the cap site was shown to be important for translational control, in vitro. Our studies suggest that interaction of the iron regulatory factor with the iron-responsive element sterically hinders formation of the preinitiation complex, resulting in translational repression. Thus inactivation of the repressor protein by critical levels of iron or heme would trigger translation of this mRNA in erythroid cells. Consequently, protoporphyrin and heme synthesis would be subtly coordinated with iron supply.


A new single-photon avalanche diode in 90nm standard CMOS technology.
We report on the first implementation of a single-photon avalanche diode (SPAD) in 90nm complementary metal oxide semiconductor (CMOS) technology. The detector features an octagonal multiplication region and a guard ring to prevent premature edge breakdown using a standard mask set exclusively. The proposed structure emerged from a systematic study aimed at miniaturization, while optimizing overall performance. The guard ring design is the result of an extensive modeling effort aimed at constraining the multiplication region within a well-defined area where the electric field exceeds the critical value for impact ionization. The device exhibits a dark count rate of 8.1 kHz, a maximum photon detection probability of 9% and the jitter of 398ps at a wavelength of 637nm, all of them measured at room temperature and 0.13V of excess bias voltage. An afterpulsing probability of 32% is achieved at the nominal dead time. Applications include time-of-flight 3D vision, fluorescence lifetime imaging microscopy, fluorescence correlation spectroscopy, and time-resolved gamma/X-ray imaging. Standard characterization of the SPAD was performed in different bias voltages and temperatures.


Urea in Water: Structure, Dynamics, and Vibrational Echo Spectroscopy from First-Principles Simulations.
Aqueous solution of urea at a concentration of 4.0 M is studied by using ab initio molecular dynamics simulation. The radial and spatial distribution functions reveal no significant disruption of the local solvent structure by urea even at such a rather high concentration. Although the static structural features are not altered in any significant manner, the translational, rotational, and vibrational dynamics are found to show noticeable slowing down. The diffusion coefficient of urea is found to be three times lower than that of bulk water molecules. Similarly, orientational relaxation of water molecules in the solvation shell of urea is found to be about 5.0 ps which is significantly higher than the average value of 3.8 ps found for all water molecules. The vibrational dynamics is investigated through calculations of frequency-time correlation function (FTCF), joint frequency probability, and frequency-structure correlation functions. The timescale of vibrational spectral diffusion as determined from FTCF is found to be 2.7 ps which is higher than the known calculated timescale of ∼2 ps for spectral diffusion of pure water for similar levels of calculations. The third-order polarization and the corresponding vibrational echo intensity of OD modes are calculated within the Condon and second-order cumulant approximations. The timescales of loss of correlation in the vibrational echo spectrum are calculated from the time dependence of the slope of the 3-pulse photon echo (S3PE) function. The timescales obtained from S3PE are found to be in agreement with the FTCF. The slowing down of vibrational, translational, and rotational dynamics means that urea affects the properties of water from a dynamical perspective.


Mobile Genetic Elements Associated with Antimicrobial Resistance.
Strains of bacteria resistant to antibiotics, particularly those that are multiresistant, are an increasing major health care problem around the world. It is now abundantly clear that both Gram-negative and Gram-positive bacteria are able to meet the evolutionary challenge of combating antimicrobial chemotherapy, often by acquiring preexisting resistance determinants from the bacterial gene pool. This is achieved through the concerted activities of mobile genetic elements able to move within or between DNA molecules, which include insertion sequences, transposons, and gene cassettes/integrons, and those that are able to transfer between bacterial cells, such as plasmids and integrative conjugative elements. Together these elements play a central role in facilitating horizontal genetic exchange and therefore promote the acquisition and spread of resistance genes. This review aims to outline the characteristics of the major types of mobile genetic elements involved in acquisition and spread of antibiotic resistance in both Gram-negative and Gram-positive bacteria, focusing on the so-called ESKAPEE group of organisms (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., and Escherichia coli), which have become the most problematic hospital pathogens.


Architectural switch in plant photosynthetic membranes induced by light stress.
Unavoidable side reactions of photosynthetic energy conversion can damage the water-splitting photosystem II (PSII) holocomplex embedded in the thylakoid membrane system inside chloroplasts. Plant survival is crucially dependent on an efficient molecular repair of damaged PSII realized by a multistep repair cycle. The PSII repair cycle requires a brisk lateral protein traffic between stacked grana thylakoids and unstacked stroma lamellae that is challenged by the tight stacking and low protein mobility in grana. We demonstrated that high light stress induced two main structural changes that work synergistically to improve the accessibility between damaged PSII in grana and its repair machinery in stroma lamellae: lateral shrinkage of grana diameter and increased protein mobility in grana thylakoids. It follows that high light stress triggers an architectural switch of the thylakoid network that is advantageous for swift protein repair. Studies of the thylakoid kinase mutant stn8 and the double mutant stn7/8 demonstrate the central role of protein phosphorylation for the structural alterations. These findings are based on the elaboration of mathematical tools for analyzing confocal laser-scanning microscopic images to study changes in the sophisticated thylakoid architecture in intact protoplasts.


Structural basis for broad detection of genogroup II noroviruses by a monoclonal antibody that binds to a site occluded in the viral particle.
Human noroviruses are genetically and antigenically highly divergent. Monoclonal antibodies raised in mice against one kind of norovirus virus-like particle (VLP), however, were found to have broad recognition. In this study, we present the crystal structure of the antigen-binding fragment (Fab) for one of these broadly reactive monoclonal antibodies, 5B18, in complex with the capsid-protruding domain from a genogroup II genotype 10 (GII.10) norovirus at 3.3-Å resolution and, also, the cryo-electron microscopy structure of the GII.10 VLP at ∼10-Å resolution. The GII.10 VLP structure was more similar in overall architecture to the GV.1 murine norovirus virion than to the prototype GI.1 human norovirus VLP, with the GII.10 protruding domain raised ∼15 Å off the shell domain and rotated ∼40° relative to the GI.1 protruding domain. In the crystal structure, the 5B18 Fab bound to a highly conserved region of the protruding domain. Based on the VLP structure, this region is involved in interactions with other regions of the capsid and is buried in the virus particle. Despite the occluded nature of the recognized epitope in the VLP structure, enzyme-linked immunosorbent assay (ELISA) binding suggested that the 5B18 antibody was able to capture intact VLPs. Together, the results provide evidence that the norovirus particle is capable of extreme conformational flexibility, which may allow for antibody recognition of conserved surfaces that would otherwise be buried on intact particles.


Risk of seizures induced by intracranial research stimulation: analysis of 770 stimulation sessions.
Patients with medically refractory epilepsy often undergo intracranial electroencephalography (iEEG) monitoring to identify a seizure focus and determine their candidacy for surgical intervention. This clinically necessary monitoring period provides an increasingly utilized research opportunity to study human neurophysiology, however ethical concerns demand a thorough appreciation of the associated risks. We measured the incidence of research stimulation-associated seizures in a large multi-institutional dataset in order to determine whether brain stimulation was statistically associated with seizure incidence and identify potential risk factors for stimulation-associated seizures. 188 subjects undergoing iEEG monitoring across ten institutions participated in 770 research stimulation sessions over 3.5 yr. Seizures within 30 min of a stimulation session were included in our retrospective analysis. We analyzed stimulation parameters, seizure incidence, and typical seizure patterns, to assess the likelihood that recorded seizures were stimulation-induced, rather than events that occurred by chance in epilepsy patients prone to seizing. In total, 14 seizures were included in our analysis. All events were single seizures, and no adverse events occurred. The mean amplitude of seizure-associated stimulation did not differ significantly from the mean amplitude delivered in sessions without seizures. In order to determine the likelihood that seizures were stimulation induced, we used three sets of analyses: visual iEEG analysis, statistical frequency, and power analyses. We determined that three of the 14 seizures were likely stimulation-induced, five were possibly stimulation-induced, and six were unlikely stimulation-induced. Overall, we estimate a rate of stimulation-induced seizures between 0.39% and 1.82% of sessions. The rarity of stimulation-associated seizures and the fact that none added morbidity or affected the clinical course of any patient are important findings for understanding the feasibility and safety of intracranial stimulation for research purposes.


UDP-glucose dehydrogenase: structure and function of a potential drug target.
Biosynthesis of the glycosaminoglycan precursor UDP-α-D-glucuronic acid occurs through a 2-fold oxidation of UDP-α-D-glucose that is catalysed by UGDH (UDP-α-D-glucose 6-dehydrogenase). Structure-function relationships for UGDH and proposals for the enzymatic reaction mechanism are reviewed in the present paper, and structure-based sequence comparison is used for subclassification of UGDH family members. The eukaryotic group of enzymes (UGDH-II) utilize an extended C-terminal domain for the formation of complex homohexameric assemblies. The comparably simpler oligomerization behaviour of the prokaryotic group of enzymes (UGDH-I), in which dimeric forms prevail, is traced back to the lack of relevant intersubunit contacts and trimmings within the C-terminal region. The active site of UGDH contains a highly conserved cysteine residue, which plays a key role in covalent catalysis. Elevated glycosaminoglycan formation is implicated in a variety of human diseases, including the progression of tumours. The inhibition of synthesis of UDP-α-D-glucuronic acid using UGDH antagonists might therefore be a useful strategy for therapy.


The role of redox hopping in metal-organic framework electrocatalysis.
The dominant charge transfer mechanism in a vast number of metal-organic frameworks (MOFs) is that of redox hopping, a process best explained through the motion of electrons via self-exchange reactions between redox centers coupled to the motion of counter-balancing ions. Mechanistic studies of redox hopping transport in MOFs reveal characteristics that recall pioneering studies in linear redox polymers. When MOFs are employed as electrocatalysts, consideration must be given to both the catalytic properties - turn-over frequency (TOF) and energetic requirements (overpotential, TON) - and the charge transport properties - rate of charge hopping, measured via an apparent diffusion coefficient (Dapp). Herein, we provide a mathematical framework to provide constraints to MOF catalyst development by relating Dapp, TOF, and film thickness in the context of providing 10 mA cm-2 of catalytic current. Lastly with the mechanistic studies discussed as a foundation, design rules for future MOF electrocatalysts are provided and the challenges to the community to optimize MOF charge transport are laid out.


Auditory neuroscience: Balancing excitation and inhibition during development.
Two recent studies have described how the coupling of excitatory and inhibitory inputs to neurons in the auditory cortex changes during development. This process is driven by experience and, once complete, may limit the plasticity of the cortex in later life.


Nanotechnology researchers' collaboration relationships: a gender analysis of access to scientific information.
Women are underrepresented in science, technology, engineering, and mathematics fields, particularly at higher levels of organizations. This article investigates the impact of this underrepresentation on the processes of interpersonal collaboration in nanotechnology. Analyses are conducted to assess: (I) the comparative tie strength of women's and men's collaborations, (2) whether women and men gain equal access to scientific information through collaborators, (3) which tie characteristics are associated with access to information for women and men, and (4) whether women and men acquire equivalent amounts of information by strengthening ties. Our results show that the overall tie strength is less for women's collaborations and that women acquire less strategic information through collaborators. Women and men rely on different tie characteristics in accessing information, but are equally effective in acquiring additional information resources by strengthening ties. This article demonstrates that the underrepresentation of women in science, technology, engineering, and mathematics has an impact on the interpersonal processes of scientific collaboration, to the disadvantage of women scientists.


Risk of Delayed Human Papillomavirus Vaccination in Inner-City Adolescent Women.
Uptake of human papillomavirus (HPV) vaccine in the United States is slow, and the effectiveness of the vaccine has not been assessed in high-risk adolescent populations. We conducted a longitudinal study of 1139 sexually active, inner-city adolescent women receiving the 3-dose quadrivalent (4vHPV) vaccine. Cervical and anal specimens collected semiannually were tested using an L1-specific polymerase chain reaction assay. Postvaccination incidence of 4vHPV vaccine and nonvaccine HPV types, and risk of cervical cytological abnormalities, were assessed in relation to time to completion of all 3 vaccine doses. Compared to vaccine naive women at enrollment, vaccinated women had significantly lower incidence rate ratios of cervical infection with HPV6/11/16/18 (0.2; 95% confidence interval [CI], .1-.4) and the related types HPV31 and HPV45 (0.4 [95% CI, .2-1.0] and 0.3 [95% CI, .1-.6], respectively), as well as significantly lower incidence rate ratios of anal infection with HPV6/11/16/18 (0.4; 95% CI, .2-.7). Notably, we observed higher risks of cervical HPV6/11/16/18 infection (hazards ratio [HR], 2.9; 95% CI, 1.0-8.0) and associated cytological abnormalities (HR, 4.5; 95% CI, .7-26.0) among women immunized at ≥15 years of age who took ≥12 months (vs <12 months) to complete the 3-dose regimen. Among adolescents immunized at ≥15 years of age, a longer time to complete the 3-dose schedule was associated with an increased risk of anogenital HPV6/11/16/18 infection and an increased incidence of associated cervical cytological abnormalities.


CT for pediatric, acute, minor head trauma: clinician conformity to published guidelines.
In 2001, pediatric radiologists participating in a panel discussion on CT dose reduction suggested that approximately 30% of head CT examinations were performed unnecessarily. With increasing concern regarding radiation exposure to children and imaging costs, this claim warrants objective study. The purpose of this study was to test the null hypothesis that 30% of head CT studies for clinical evaluation of children with acute, minor head trauma do not follow established clinical guidelines. Retrospective review of 182 consecutive patients with acute, minor head trauma from February 2009 to January 2010 at a tertiary care children's hospital emergency department was performed, and clinician adherence to published clinical guidelines for children younger than 2 years and children 2-20 years of age was determined. The binomial test was used for a null hypothesis of 30% unnecessary examinations against the actual percentage of head CTs deemed unnecessary on the basis of established guidelines. Statistical testing was performed for children younger than 2 years and 2-20 years of age. For children younger than 2 years of age, 2 of 78 (2.6%; 95% CI, 0.5%-8.3%) and, for children 2-20 years of age, 12 of 104 (11.5%; CI, 6.4%-18.7%) did not conform to established guidelines. These percentages were significantly less than the hypothesized value of 30% (P < .001). Clinician conformity to published guidelines for use of head CT in acute, minor head trauma is better than suggested by a 2001 informal poll of pediatric radiologists.


Filling the void: controlled donor-acceptor interaction facilitates the formation of an M-M single bond in the zero oxidation state of M (M = Zn, Cd, Hg).
The intriguing question of whether it is possible to form a genuine M0-M0 single bond for the M2 species (M = Zn, Cd, Hg) is addressed here. So far, all the bonds reported in the literature are exclusively MI-MI. Herein, we present viable M2(NHBMe)2 (M = Zn, Cd, Hg; NHBMe = (HCNMe)2B) complexes in which the controlled donor-acceptor interaction leads to an M0-M0 single bond. In these complexes, M2 in the 1∑g ground state with the (nσg+)2(nσu+)2 (n = 7, 10 and 14 for M = Zn, Cd and Hg, respectively) valence electron configuration forms donor-acceptor bonding with singlet 2NHBMe ligands where a combined effect of dominant (+,-) σ-backdonation from the antibonding (nσu+)2 orbital of M2 to the 2NHBMe ligands and a somewhat weaker (+,+) σ-donation from the 2NHBMe ligands to the bonding (n + 1)σg+ orbital leads to the unorthodox bonding situation of forming an M-M single bond in the zero oxidation state by eventually nullifying one effect by another. This is an unprecedented situation in the sense that the NHBMe ligand acts as a strong σ-acceptor and a weaker σ-donor. A comparison with the experimentally reported M2(PhDipp)2 complexes reveals the uniqueness of the NHBMe ligand in exhibiting such a bonding scenario. The M2(NHBMe)2 complex is thermochemically viable with respect to possible dissociation channels at room temperature, except for metal extrusion processes, M2(NHBMe)2 → M + M(NHBMe)2 and M2(NHBMe)2 → M2 + (NHBMe)2. Although the latter two processes are exergonic, they are kinetically protected by a high free energy barrier of 26.5-39.5 kcal mol-1. The experimental characterization of M2(PhDipp)2 despite similar exergonic channels reveals such kinetic stability to be enough for the viability of the M2(NHBMe)2 complexes. Furthermore, the ligand exchange reaction considering M2(PhMe)2 as the starting material also turned out to be feasible. Therefore, the M2(NHBMe)2 complexes are the first cases that feature a neutral M2 moiety with a single M0-M0 covalent bond, where M is a Group 12 metal.


Magnetization-prepared rapid acquisition with gradient echo magnetic resonance imaging signal and texture features for the prediction of mild cognitive impairment to Alzheimer's disease progression.
Early diagnoses of Alzheimer's disease (AD) would confer many benefits. Several biomarkers have been proposed to achieve such a task, where features extracted from magnetic resonance imaging (MRI) have played an important role. However, studies have focused exclusively on morphological characteristics. This study aims to determine whether features relating to the signal and texture of the image could predict mild cognitive impairment (MCI) to AD progression. Clinical, biological, and positron emission tomography information and MRI images of 62 subjects from the AD neuroimaging initiative were used in this study, extracting 4150 features from each MRI. Within this multimodal database, a feature selection algorithm was used to obtain an accurate and small logistic regression model, generated by a methodology that yielded a mean blind test accuracy of 0.79. This model included six features, five of them obtained from the MRI images, and one obtained from genotyping. A risk analysis divided the subjects into low-risk and high-risk groups according to a prognostic index. The groups were statistically different ([Formula: see text]). These results demonstrated that MRI features related to both signal and texture add MCI to AD predictive power, and supported the ongoing notion that multimodal biomarkers outperform single-modality ones.


The sigma factors of Bacillus subtilis.
The specificity of DNA-dependent RNA polymerase for target promotes is largely due to the replaceable sigma subunit that it carries. Multiple sigma proteins, each conferring a unique promoter preference on RNA polymerase, are likely to be present in all bacteria; however, their abundance and diversity have been best characterized in Bacillus subtilis, the bacterium in which multiple sigma factors were first discovered. The 10 sigma factors thus far identified in B. subtilis directly contribute to the bacterium's ability to control gene expression. These proteins are not merely necessary for the expression of those operons whose promoters they recognize; in many instances, their appearance within the cell is sufficient to activate these operons. This review describes the discovery of each of the known B. subtilis sigma factors, their characteristics, the regulons they direct, and the complex restrictions placed on their synthesis and activities. These controls include the anticipated transcriptional regulation that modulates the expression of the sigma factor structural genes but, in the case of several of the B. subtilis sigma factors, go beyond this, adding novel posttranslational restraints on sigma factor activity. Two of the sigma factors (sigma E and sigma K) are, for example, synthesized as inactive precursor proteins. Their activities are kept in check by "pro-protein" sequences which are cleaved from the precursor molecules in response to intercellular cues. Other sigma factors (sigma B, sigma F, and sigma G) are inhibited by "anti-sigma factor" proteins that sequester them into complexes which block their ability to form RNA polymerase holoenzymes. The anti-sigma factors are, in turn, opposed by additional proteins which participate in the sigma factors' release. The devices used to control sigma factor activity in B, subtilis may prove to be as widespread as multiple sigma factors themselves, providing ways of coupling sigma factor activation to environmental or physiological signals that cannot be readily joined to other regulatory mechanisms.


Analysis of the anisotropy decay of trans-parinaric acid in lipid bilayers.
An analysis is presented of the complex anisotropy behavior of trans-parinaric acid in single component DEPC lipid bilayers. It is shown that a model involving two species with distinct lifetime and motional behavior is required, and is adequate, to explain the observed data. In particular, the observed increase in the anisotropy at long times demonstrates the presence of a species with a long fluorescence lifetime that has a high anisotropy. The time dependence of the anisotropy for these two environments is treated using both a purely mathematical sum of exponentials and a constrained fit based on an approximate solution of the anisotropic diffusion problem. In this latter model the anisotropy is described in terms of the second and fourth rank order parameters, (P2) and (P4), and a single dynamical parameter, D1, the perpendicular diffusion coefficient for this uniaxial probe. The parameters of both models are accurately determined from the fits to the data when two environments coexist and an association is made between lifetime components and distinct rotational sites. The values of the parameters obtained demonstrate the "solid-like" and "fluidlike" nature of these two coexisting environments.


Cortical connections to area TE in monkey: hybrid modular and distributed organization.
To investigate the fine anatomical organization of cortical inputs to visual association area TE, 2-3 small injections of retrograde tracers were made in macaque monkeys. Injections were made as a terminal procedure, after optical imaging and electrophysiological recording, and targeted to patches physiologically identified as object-selective. Retrogradely labeled neurons occurred in several unimodal visual areas, the superior temporal sulcus, intraparietal sulcus (IPS), and prefrontal cortex (PFC), consistent with previous studies. Despite the small injection size (<0.5 mm wide), the projection foci in visual areas, but not in IPS or PFC, were spatially widespread (4-6 mm in extent), and predominantly consisted of neurons labeled by only one of the injections. This can be seen as a quasi-modular organization. In addition, within each projection focus, there were scattered neurons projecting to one of the other injections, together with some double-labeled (DL) neurons, in a more distributed pattern. Finally, projection foci included smaller "hotspots," consisting of intermixed neurons, single-labeled by the different injections, and DL neurons. DL neurons are likely the result of axons having extended, spatially separated terminal arbors, as demonstrated by anterograde experiments. These results suggest a complex, hybrid connectivity architecture, with both modular and distributed components.


Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation.
"Humanized" mouse models created by engraftment of immunodeficient mice with human hematolymphoid cells or tissues are an emerging technology with broad appeal across multiple biomedical disciplines. However, investigators wishing to utilize humanized mice with engrafted functional human immune systems are faced with a myriad of variables to consider. In this study, we analyze HSC engraftment methodologies using three immunodeficient mouse strains harboring the IL2rgamma(null) mutation; NOD-scid IL2rgamma(null), NOD-Rag1(null) IL2rgamma(null), and BALB/c-Rag1(null) IL2rgamma(null) mice. Strategies compared engraftment of human HSC derived from umbilical cord blood following intravenous injection into adult mice and intracardiac and intrahepatic injection into newborn mice. We observed that newborn recipients exhibited enhanced engraftment as compared to adult recipients. Irrespective of the protocol or age of recipient, both immunodeficient NOD strains support enhanced hematopoietic cell engraftment as compared to the BALB/c strain. Our data define key parameters for establishing humanized mouse models to study human immunity.


Life beyond severe traumatic injury: an integrative review of the literature.
It is only recently that recognition of the serious and debilitating sequelae of trauma has prompted exploration of outcomes beyond survival, such as disability, health status and quality of life. This paper aims to review the literature describing outcomes following severe traumatic injury to provide clinicians with a greater understanding of the recovery trajectory following severe trauma and highlight the issues faced by those recovering from such injury. Electronic databases, published reference lists and the Internet were searched to identify relevant literature. The heterogeneous nature of published literature in this area prohibited a systematic approach to inclusion of papers in this review. Trauma survivors report significant sequelae that influence functional status, psychological wellbeing, quality of life and return to productivity following severe injury. Key themes that emerge from the review include: current trauma systems which provide inadequate support along the recovery trajectory; rehabilitation referral which is affected by geographical location and provider preferences; a long-term loss of productivity in both society and the workplace; a high incidence of psychological sequelae; a link between poor recovery and increased drug and alcohol consumption; and valued social support which can augment recovery. Future research to evaluate interventions which target the recovery needs of the severely injured patients is recommended. Particular emphasis is required to develop systematic, sustainable and cost-effective follow-up to augment the successes of existing acute trauma services in providing high quality acute resuscitation and definitive trauma management.


Palliative management of lymphangioleiomyomatosis: Using video-assisted thoracoscopic surgery.
Lymphangioleiomyomatosis (LAM) is a rare, progressive systemic disease of unknown etiology, insidious onset, often fatal, and underdiagnosed. It is exclusively found among women. LAM mainly involves the lungs where, as its name suggests, lymphatic (lymph), blood vessel (angio), and airways are surrounded by smooth muscle (leiomyoma) proliferation. It may be associated with tuberous sclerosis with clinical manifestations varying from simple cough to the development of recurrent pneumothoraces, haemoptysis, and pleural effusions. There is currently no treatment or cure. We present a rare case of a 41-year-old female, who presented with recurrent pneumothoraces, whose high-resolution computed tomography findings that were suggestive of multiple bullous lung disease, and the thoracoscopic biopsy revealed features of LAM. She was offered video-assisted thoracoscopic surgery in form of bullectomy and pleurodesis to reduce the volume of abnormal tissue and treated with progesterone hormonal therapy. The present case aims to focus on clinical-radiologic and pathologic findings and the treatment modalities available in developing countries like India where lung transplantation is seldom performed.


Another look at the root of the angiosperms reveals a familiar tale.
Since the advent of molecular phylogenetics more than 25 years ago, a major goal of plant systematists has been to discern the root of the angiosperms. Although most studies indicate that Amborella trichopoda is sister to all remaining extant flowering plants, support for this position has varied with respect to both the sequence data sets and analyses employed. Recently, Goremykin et al. (2013) questioned the "Amborella-sister hypothesis" using a "noise-reduction" approach and reported a topology with Amborella + Nymphaeales (water lilies) sister to all remaining angiosperms. Through a series of analyses of both plastid genomes and mitochondrial genes, we continue to find mostly strong support for the Amborella-sister hypothesis and offer a rebuttal of Goremykin et al. (2013). The major tenet of Goremykin et al. is that the Amborella-sister position is determined by noisy data--that is, characters with high rates of change and lacking true phylogenetic signal. To investigate the signal in these noisy data further, we analyzed the discarded characters from their noise-reduced alignments. We recovered a tree identical to that of the currently accepted angiosperm framework, including the position of Amborella as sister to all other angiosperms, as well as all other major clades. Thus, the signal in the "noisy" data is consistent with that of our complete data sets--arguing against the use of their noise-reduction approach. We also determined that one of the alignments presented by Goremykin et al. yields results at odds with their central claim--their data set actually supports Amborella as sister to all other angiosperms, as do larger plastid data sets we present here that possess more complete taxon sampling both within the monocots and for angiosperms in general. Previous unpartitioned, multilocus analyses of mitochondrial DNA (mtDNA) data have provided the strongest support for Amborella + Nymphaeales as sister to other angiosperms. However, our analysis of third codon positions from mtDNA sequence data also supports the Amborella-sister hypothesis. Finally, we challenge the conclusion of Goremykin et al. that the first flowering plants were aquatic and herbaceous, reasserting that even if Amborella + water lilies, or water lilies alone, are sister to the rest of the angiosperms, the earliest angiosperms were not necessarily aquatic and/or herbaceous.


Early immune reconstitution after potent antiretroviral therapy in HIV-infected children correlates with the increase in thymus volume.
Despite significant rises in total CD4 T cells, the process of immune reconstitution in adults with HIV infection treated with potent antiretroviral treatment results in a rather slow increase in phenotypically naive lymphocytes. In children more than in adults, thymic function may be at least partly restored when disease-induced immunosuppression is attenuated by pharmacological means. Twenty-five vertically infected and antiretroviral-experienced [zidovudine (ZDV)/ZDV plus didanosine (ddl)] children were prospectively followed during 12 months of treatment with lamivudine (3TC), stavudine (d4T) and indinavir (IDV). The plasma HIV viral load and phenotypic and functional cellular immunity-defining parameters were examined. The relationship between the degree of immune reconstitution and thymus volume assessed by nuclear magnetic resonance was also examined. An early and steep increase in CD45RA+62L+ T cells was observed in parallel with a sustained decrease in plasma HIV RNA levels and a significant rise in total CD4 T cells. This increase was significantly greater than that observed in CD4+CD45RO+ T cells. Analysis of the CD4 T cell receptor (TCR) beta repertoire and T helper function showed the ability to reconstitute families almost completely absent at baseline, and a substantial improvement of antigen-specific responses by peripheral blood lymphocytes. The rise in CD4 cells and in CD4+CD45RA+62L+ T cells was statistically associated with changes in thymus size observed over time. These data suggest a relevant contribution of the thymus to reconstitution of the peripheral pool of T cells in vertically HIV-infected children treated with potent antiretroviral regimens.


Assessment of study quality for systematic reviews: a comparison of the Cochrane Collaboration Risk of Bias Tool and the Effective Public Health Practice Project Quality Assessment Tool: methodological research.
The Cochrane Collaboration is strongly encouraging the use of a newly developed tool, the Cochrane Collaboration Risk of Bias Tool (CCRBT), for all review groups. However, the psychometric properties of this tool to date have yet to be described. Thus, the objective of this study was to add information about psychometric properties of the CCRBT including inter-rater reliability and concurrent validity, in comparison with the Effective Public Health Practice Project Quality Assessment Tool (EPHPP). Both tools were used to assess the methodological quality of 20 randomized controlled trials included in our systematic review of the effectiveness of knowledge translation interventions to improve the management of cancer pain. Each study assessment was completed independently by two reviewers using each tool. We analysed the inter-rater reliability of each tool's individual domains, as well as final grade assigned to each study. The EPHPP had fair inter-rater agreement for individual domains and excellent agreement for the final grade. In contrast, the CCRBT had slight inter-rater agreement for individual domains and fair inter-rater agreement for final grade. Of interest, no agreement between the two tools was evident in their final grade assigned to each study. Although both tools were developed to assess 'quality of the evidence', they appear to measure different constructs. Both tools performed quite differently when evaluating the risk of bias or methodological quality of studies in knowledge translation interventions for cancer pain. The newly introduced CCRBT assigned these studies a higher risk of bias. Its psychometric properties need to be more thoroughly validated, in a range of research fields, to understand fully how to interpret results from its application.


Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses.
Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.


Cholesterol prevents interaction of the cell-penetrating peptide transportan with model lipid membranes.
Interaction of the cell-penetrating peptide (CPP) cysteine-transportan (Cys-TP) with model lipid membranes was examined by spin-label electron paramagnetic resonance (EPR). Membranes were labeled with lipophilic spin probes and the influence of Cys-TP on membrane structure was studied. The influence of Cys-TP on membrane permeability was monitored by the reduction of a liposome-trapped water-soluble spin probe. Cys-TP caused lipid ordering in membranes prepared from pure dimyristoylphosphatidylcholine (DMPC) and in DMPC membranes with moderate cholesterol concentration. In addition, Cys-TP caused a large increase in permeation of DMPC membranes. In contrast, with high cholesterol content, at which model lipid membranes are in the so-called liquid-ordered phase, no effect of Cys-TP was observed, either on the membrane structure or on the membrane permeability. The interaction between Cys-TP and the lipid membrane therefore depends on the lipid phase. This could be of great importance for understanding of the CPP-lipid interaction in laterally heterogeneous membranes, while it implies that the CPP-lipid interaction can be different at different points along the membrane.


Can we unlock the potential of IGF-1R inhibition in cancer therapy?
IGF-1R inhibitors arrived in the clinic accompanied by optimism based on preclinical activity of IGF-1R targeting, and recognition that low IGF bioactivity protects from cancer. This was tempered by concerns about toxicity to normal tissue IGF-1R and cross-reactivity with insulin receptor (InsR). In fact, toxicity is not a show-stopper; the key issue is efficacy. While IGF-1R inhibition induces responses as monotherapy in sarcomas and with chemotherapy or targeted agents in common cancers, negative Phase 2/3 trials in unselected patients prompted the cessation of several Pharma programs. Here, we review completed and on-going trials of IGF-1R antibodies, kinase inhibitors and ligand antibodies. We assess candidate biomarkers for patient selection, highlighting the potential predictive value of circulating IGFs/IGFBPs, the need for standardized assays for IGF-1R, and preclinical evidence that variant InsRs mediate resistance to IGF-1R antibodies. We review hypothesis-led and unbiased approaches to evaluate IGF-1R inhibitors with other agents, and stress the need to consider sequencing with chemotherapy. The last few years were a tough time for IGF-1R therapeutics, but also brought progress in understanding IGF biology. Even failed studies include patients who derived benefit; they should be investigated to identify features distinguishing the tumors and host environment of responders from non-responders. We emphasize the importance of incorporating biospecimen collection into trial design, and wording patient consents to allow post hoc analysis of trial material as new data become available. Such information represents the key to unlocking the potential of this approach, to inform the next generation of trials of IGF signalling inhibitors.


Early child care and adolescent functioning at the end of high school: Results from the NICHD Study of Early Child Care and Youth Development.
Relations between early child care and adolescent functioning at the end of high school (EOHS; M age = 18.3 years) were examined in a prospective longitudinal study of 1,214 children. Controlling for extensive measures of family background, early child care was associated with academic standing and behavioral adjustment at the EOHS. More experience in center-type care was linked to higher class rank and admission to more selective colleges, and for females to less risk taking and greater impulse control. Higher quality child care predicted higher academic grades and admission to more selective colleges. Fewer hours in child care was related to admission to more selective colleges. These findings suggest long-term benefits of higher quality child care, center-type care, and lower child-care hours for measures of academic standing at the EOHS. (PsycINFO Database Record


Incarcerated foreign body in the vagina--a metal bangle used as a pessary.
Long-forgotten vaginal pessaries get incarcerated in the vagina and their removal poses problems. A 60-year-old postmenopausal woman presented with foul smelling purulent discharge per vaginum and stress incontinence. Speculum examination revealed foul smelling white discharge per vaginum and a friable vaginal wall which bled on touch. The anterior portion of a metal ring deeply embedded in the vagina was seen. The cervix appeared normal. Attempts of removal by traction under local infiltration failed and resulted in bleeding. Biopsy from the tissue covering the ring reported no evidence of malignancy. She was treated with broad-spectrum antibiotics for 1 week and the metallic ring was removed without any complications under general anaesthesia using electrocautery. It was found to be a metallic bangle with design. It is essential to gently cauterise and release the fibrosis over the incarcerated foreign body to achieve safe removal.


Intensive cognitive-behavioural treatment for women with postnatal obsessive-compulsive disorder: a consecutive case series.
The postnatal period has been identified as a time of increased risk for the development of OCD. Obsessions and compulsions at this time frequently focus on accidental or deliberate harm coming to the infant and may impact on the sufferer's capacities as a parent. Given the similarities in presentation between OCD at this and other times, cognitive-behaviour therapy is likely to be effective, but there is little information on whether or how adaptations of CBT can be made to maximise effectiveness and acceptability for mothers. There are no data on the impact of successful treatment on parenting. Six consecutively referred cases of postnatal OCD were treated using cognitive-behavioural therapy (CBT) intensively delivered over a two week period. All mothers improved on self-report and clinician-rated measures which were sustained at 3-5 month follow-up. Mothers reported significant benefits in terms of their own symptoms and in parenting in general. The intensive mode of delivery appears to be effective and acceptable for this group. Future work should explore whether particular difficulties in terms of parenting are experienced by this group and whether these persist beyond the remission of the maternal disorder.


Weight patterns and perceptions among female university students of Karachi: a cross sectional study.
Body weight and its perception play an important role in the physical and mental well-being of a person. Weight perception is found to be a better predictor of weight management behaviour as compared to actual weight. In Pakistan, studies have been done on the prevalence of weight status but weight perception is still unexplored. The study was done to examine relationships between body weight perception, actual weight status, and weight control behaviour among the female university students of Karachi. A cross sectional study was carried out during Sep-Nov 2009 on female students in four universities of Karachi, Pakistan. Our final sample size included 338 female university students. Height and weight were measured on calibrated scales. A modified BMI criterion for Asian populations was used. Based on measured BMI; the prevalence of underweight, normal weight and overweight females was 27.2%, 51.5% and 21.3% respectively. As a whole, just over one third (33.73%) of the sample misclassified their weight status. Among underweight (n=92), 45.70% thought they were of normal weight. No one who was truly underweight perceived them self as overweight. Among the normal weight (n= 174), 9.8% thought they were underweight and 23.6% considered themselves overweight. Among the overweight (n=72); 18.3% considered themselves normal. Only one female student thought she was underweight despite being truly overweight. Our study shows that among female university students in Karachi, the prevalence of being underweight is comparatively high. There is a significant misperception of weight, with one third of students misclassifying themselves. Underweight females are likely to perceive themselves as normal and be most satisfied with their weight. Health policy makers should implement these findings in future development of health interventions and prevention of depression, social anxiety and eating disorders associated with incorrect weight perception among young females. Studies that employ a longitudinal approach are needed to validate our findings.


Optical diagnostics of slightly rough surfaces.
The relationship between the statistical structure parameters of a rough surface and the associated correlation parameters of a scattered field is used to develop a method for rough-surface diagnostics. The treatment is based on the model of a random phase object with an inhomogeneity phase dispersion sigma(phi0)(2) < 1. The proposed diagnostic methods are applicable to surfaces with a roughness period comparable to the radiation wavelength employed and the surfaces of a thin plane-parallel plate. The sensitivity limit of the methods in measuring the standard deviation of surface-roughness element heights is ~0.003 microm.


Polyols in confectionery: the route to sugar-free, reduced sugar and reduced calorie confectionery.
Polyol-containing confectionery offers considerable advantages over traditional sucrose-based confectionery in terms of reduced energy content and reduced cariogenicity. However, over-consumption of polyol confectionery may lead to gastrointestinal symptoms in some individuals. Rather than consider this as a distinct disadvantage to the consumer, this article discusses how careful consideration of the physico-chemical properties of polyols and advances in product development and formulation can provide suitable polyol-based products for the consumer. Furthermore. food legislation and ingredient pricing issues are just some of the factors that must be taken into account when designing new polyol-containing products if their functional benefits and good product quality are to be delivered to the consumer.


All-solid highly nonlinear singlemode fibers with a tailored dispersion profile.
We investigate a novel approach to obtain highly nonlinear fibers with a tailored group velocity dispersion around a desired wavelength region of interest. Rather than exploiting longitudinal holes to control the average refractive index of the cladding and hence the fiber's waveguide dispersion, as in holey fibers, we propose using an all-solid cladding with a suitably chosen refractive index difference relative to the core. We demonstrate numerically that this solution allows a large freedom in the manipulation of the overall fiber dispersive properties, while enabling, in practice, a much more accurate control of the fiber's structural properties during fabrication. Effectively single mode guidance over a broad wavelength range can be achieved through the use of a second outer cladding forming a W-type index profile. We derive simple design rules for dispersion controlled fibers, based on which an algorithm for the automatic dispersion optimization is proposed, implemented and used to design various nonlinear fibers for all-optical processing and supercontinuum generation. Fabrication of a lead silicate fiber with flattened dispersion at telecoms wavelengths confirms the potential of these new fibers.


Pain Control on Demand Based on Pulsed Radio-Frequency Stimulation of the Dorsal Root Ganglion Using a Batteryless Implantable CMOS SoC.
This paper presents the implementation of a batteryless CMOS SoC with low voltage pulsed radio-frequency (PRF) stimulation. This implantable SoC uses 402 MHz command signals following the medical implanted communication system (MICS) standard and a low frequency (1 MHz) for RF power transmission. A body floating type rectifier achieves 84% voltage conversion ratio. A bi-phasic pulse train of 1.4 V and 500 kHz is delivered by a PRF driver circuit. The PRF parameters include pulse duration, pulse frequency and repetition rate, which are controllable via 402 MHz RF receiver. The minimal required 3 V RF Vin and 2.2 V VDDr is achieved at 18 mm gap. The SoC chip is fabricated in a 0.35 μm CMOS process and mounted on a PCB with a flexible spiral antenna. The packaged PRF SoC was implanted into rats for the animal study. Von Frey was applied to test the mechanical allodynia in a blinded manner. This work has successfully demonstrated that implanted CMOS SoC stimulating DRG with 1.4 V, 500 kHz PRF could significantly reduce spinal nerve ligation (SNL) induced mechanical allodynia for 3-7 days.


Rationality in Joint Action: Maximizing Coefficiency in Coordination.
When people perform simple actions, they often behave efficiently, minimizing the costs of movement for the expected benefit. The present study addressed the question of whether this efficiency scales up to dyads working together to achieve a shared goal: Do people act efficiently as a group (i.e., coefficiently), or do they minimize their own or their partner's individual costs even if this increases the overall cost for the group? We devised a novel, touch-screen-based, sequential object-transfer task to measure how people choose between different paths to coordinate with a partner. Across multiple experiments, we found that participants did not simply minimize their own or their partner's movement costs but made coefficient decisions about paths, which ensured that the aggregate costs of movement for the dyad were minimized. These results suggest that people are able and motivated to make coefficient, collectively rational decisions when acting together.


Outcomes of a 1-year longitudinal integrated medical clerkship in small rural Victorian communities.
Access to medical services for rural communities is poorer than for metropolitan communities in many parts of the world. One of the strategies to improve rural medical workforce has been rural clinical placements for undergraduate medical students. This study explores the workforce outcomes of one model of such placements - the longitudinal integrated clerkship (LIC) - delivered in year 4, the penultimate year of the medical course, as part of the rural programs delivered by a medical school in Victoria, Australia. The LIC involved student supervision under a parallel consulting model with experienced rural generalist doctors for a whole year in small community rural general practices. This study aimed to compare the work locations (regional or more rural), following registration as a medical practitioner, of medical students who had completed 1 year of the LIC, with, first, students who had other types of rural training of comparable duration elsewhere, and second, students who had no rural training. Study participants commenced their medical degree after 2004 and had graduated between 2008 and 2016 and thus were in postgraduate year 1-9 in 2017 when evaluated. Information about the student training location(s), and duration, type and timing of training, was prospectively collected from university administrative systems. The outcome of interest was the main work location in 2017, obtained from the Australian Health Practitioner Regulation Agency's public website. Students who had undertaken the year 4 LIC along with additional rural training in years 3 and/or 5 were more likely than all other groups to be working in smaller regional or rural towns, where workforce need is greatest (relative risk ratio (RRR) 5.62, 95% confidence interval (CI) 2.81-11.20, compared with those having metropolitan training only). Non-LIC training of similar duration in rural areas was also significantly associated, but more weakly, with smaller regional work location (RRR 2.99, 95%CI 1.87-4.77). Students whose only rural training was the year 4 LIC were not significantly associated with smaller regional work location (RRR 1.72, 95%CI 0.59-5.04). Overall, after accounting for both LIC and non-LIC rural training exposure, rural work after graduation was also consistently positively associated with rural background, being an international student and having a return of service obligation under a bonded program as a student. This study demonstrates the value of rural LICs, coupled with additional rural training, in contributing to improving Australia's medical workforce distribution. Whilst other evidence has already demonstrated positive educational outcomes for doctors who participate in rural LIC placements, this is the first known study of work location outcomes. The study provides evidence that expanding this model of rural undergraduate education may lead to a better geographically distributed medical workforce.


Estimation of absorbed radiation doses to skin and S-values for organs at risk due to nasal administration of PET agents using Monte Carlo simulations.
The intranasal (IN) administration of radiopharmaceuticals is of interest in being a viable route for the delivery of radiopharmaceuticals that do not ordinarily cross the blood-brain barrier (BBB). However, to be viable in a patient population, good image quality as well as safety of the administration should be demonstrated. This work provides radiation dosimetry calculations and simulations related to the radiation safety of performing such experiments in a human cohort. We performed Monte Carlo (MC) simulations to estimate radiation dose to the skin inside a cylindrical model of the nasal cavity assuming a homogenous distribution layer of 11 C and 18 F and calculated a geometry conversion factor (FP-C ) which can be used to convert from a planar geometry to a cylindrical geometry using more widely available software tools. We compared radiation doses from our simulated cylindrical geometry with the planar dose estimates employing our geometry conversion factor from VARSKIN 6.1 software and also from an analytical equation. Furthermore, in order to estimate radiation dosimetry to surrounding organs of interest, we performed a voxelized MC simulation of a fixed radioactivity inside the nasal cavity and calculated S-values to organs such as the eyes, thyroid, and brain. MC simulations of contamination scenarios using planar absorbed doses of 15.50 and 8.60 mGy/MBq for 18 F and 11 C, respectively, and 35.70 and 19.80 mGy/MBq per hour for cylindrical geometries, leading to determination of an FP-C of 2.3. Planar absorbed doses (also in units of mGy/MBq) determined by the analytical equation were 16.96 and 8.68 (18 F and 11 C) and using VARSKIN were 16.60 and 9.26 (18 F and 11 C), respectively. Application of FP-C to these results demonstrates values with a maximum difference of 9.41% from the cylindrical geometry MC calculation, demonstrating that when accounting for geometry, more simplistic techniques can be utilized to estimate IN dosimetry. Voxelized MC simulations of radiation dosimetry from a fixed source of 1 MBq of activity confined to the nasal cavity resulted in S-values to the thyroid, eyes, and brain of 1.72 x 10-6 , 1.93 x 10-5 , and 3.51 x 10-6 mGy/MBq·s, respectively, for 18 F and 1.80 × 10-6 , 1.95 × 10-5 , and 3.54 × 10-6 mGy/MBq·s for 11 C. Dosimetry concerns about IN administrations of PET radiotracers should be considered before clinical use. Values presented in the simulations such as the S-values can be further used for assessment of absorbed doses in cases of IN administration, and can be used to develop and adapt specific study protocols. All three presented methods provided similar results when considering the use of a geometry conversion factor for planar to cylindrical geometry, demonstrating that standard tools rather than dedicate MC simulations may be used to perform dose calculations in nasal administrations.


Point-of-care diagnostics for HIV and tuberculosis: landscape, pipeline, and unmet needs.
Early diagnosis and rapid initiation of treatment remains a key strategy to control both HIV and tuberculosis (TB). However, HIV and TB control programs have had completely contrasting successes, especially with the development and deployment of point-of-care (POC) diagnostics. Clinicians, researchers, and public health staff who work at the frontlines of HIV care and control have had access to an outstanding array of POC diagnostics at their disposal, including those used for screening, initial diagnosis, staging, treatment monitoring, and early infant diagnosis. The field has also advanced to consider over-the-counter, self-testing options for HIV and the use of multiplexed platforms that allow for simultaneous detection of infections associated with HIV. In sharp contrast to HIV, suboptimal and delayed diagnosis of TB has perpetuated the epidemic in many high-burden countries. Although the TB diagnostics pipeline is substantially better today than it was even five years ago, absence of a simple POC test continues to be a gaping hole in the pipeline. In this review, we compare the POC diagnostics landscape and pipelines for these two important infectious diseases, and highlight gaps and unmet needs.


Field-Dependent Dehydration and Optimal Ionic Escape Paths for C2N Membranes.
Most analytic theories describing electrostatically driven ion transport through water-filled nanopores assume that the corresponding permeation barriers are bias-independent. While this assumption may hold for sufficiently wide pores under infinitely small bias, transport through subnanometer pores under finite bias is difficult to interpret analytically. Given recent advances in subnanometer pore fabrication and the rapid progress in detailed computer simulations, it is important to identify and understand the specific field-induced phenomena arising during ion transport. Here we consider an atomistic model of electrostatically driven ion permeation through subnanoporous C2N membranes. We analyze probability distributions of ionic escape trajectories and show that the optimal escape path switches between two different configurations depending on the bias magnitude. We identify two distinct mechanisms contributing to field-induced changes in transport-opposing barriers: a weak one arising from field-induced ion dehydration and a strong one due to the field-induced asymmetry of the hydration shells. The simulated current-voltage characteristics are compared with the solution of the 1D Nernst-Planck model. Finally, we show that the deviation of simulated currents from analytic estimates for large fields is consistent with the field-induced barriers and the observed changes in the optimal ion escape path.