Age differences in neural correlates of feedback processing after economic decisions under risk.
This study examines age-related differences in behavioral responses to risk and in the neurophysiological correlates of feedback processing. Our sample was composed of younger, middle-aged, and older adults, who were asked to decide between 2 risky options, in the gain and loss domains, during an EEG recording. Results evidenced group-related differences in early and later stages of feedback processing, indexed by differences in the feedback-related negativity (FRN) and P3 amplitudes. Specifically, in the loss domain, younger adults showed higher FRN amplitudes after non-losses than after losses, whereas middle-aged and older adults had similar FRN amplitudes after both. In the gain domain, younger and middle-aged adults had higher P3 amplitudes after gains than after non-gains, whereas older adults had similar P3 amplitudes after both. Behaviorally, older adults had higher rates of risky decisions than younger adults in the loss domain, a result that was correlated with poorer performance in memory and executive functions. Our results suggest age-related differences in the outcome-related expectations, as well as in the affective relevance attributed to the outcomes, which may underlie the group differences found in risk-aversion.


A putative ECF sigma factor gene, rpol, regulates siderophore production in Rhizobium leguminosarum.
A cloned Rhizobium leguminosarum gene, termed rpoI, when transferred to wild-type strains, caused overproduction of the siderophore vicibactin. An rpoI mutant was defective in Fe uptake but was unaffected in symbiotic N2 fixation. The RpoI gene product was similar in sequence to extra-cytoplasmic sigma factors of RNA polymerase. Transcription of rpoI was reduced in cells grown in medium that was replete with Fe.


Autism and diagnostic substitution: evidence from a study of adults with a history of developmental language disorder.
Rates of diagnosis of autism have risen since 1980, raising the question of whether some children who previously had other diagnoses are now being diagnosed with autism. We applied contemporary diagnostic criteria for autism to adults with a history of developmental language disorder, to discover whether diagnostic substitution has taken place. A total of 38 adults (aged 15-31y; 31 males, seven females) who had participated in studies of developmental language disorder during childhood were given the Autism Diagnostic Observation Schedule--Generic. Their parents completed the Autism Diagnostic Interview--Revised, which relies largely on symptoms present at age 4 to 5 years to diagnose autism. Eight individuals met criteria for autism on both instruments, and a further four met criteria for milder forms of autistic spectrum disorder. Most individuals with autism had been identified with pragmatic impairments in childhood. Some children who would nowadays be diagnosed unambiguously with autistic disorder had been diagnosed with developmental language disorder in the past. This finding has implications for our understanding of the epidemiology of autism.


Disparities in surgery among patients with intractable epilepsy in a universal health system.
To assess the use of epilepsy surgery in patients with medically intractable epilepsy in a publicly funded universal health care system. We performed a population-based retrospective cohort study using linked health care databases for Ontario, Canada, between 2001 and 2010. We identified all patients with medically intractable epilepsy, defined as those with seizures that did not respond to at least 2 adequate trials of seizure medications. We assessed the proportion of patients who had epilepsy surgery within the following 2 years. We further identified the characteristics associated with epilepsy surgery. A total of 10,661 patients were identified with medically intractable epilepsy (mean age 47 years, 51% male); most (74%) did not have other comorbidities. Within 2 years of being defined as medically intractable, only 124 patients (1.2%) underwent epilepsy surgery. Death occurred in 12% of those with medically intractable epilepsy. Those who underwent the procedure were younger and had fewer comorbidities compared to those who did not. In our setting of publicly funded universal health care, more than 10% of patients died within 2 years of developing medically intractable epilepsy. Epilepsy surgery may be an effective treatment for some patients; however, fewer than 2% of patients who may have benefited from epilepsy surgery received it.


Metabolic rate regulates L1 longevity in C. elegans.
Animals have to cope with starvation. The molecular mechanisms by which animals survive long-term starvation, however, are not clearly understood. When they hatch without food, C. elegans arrests development at the first larval stage (L1) and survives more than two weeks. Here we show that the survival span of arrested L1s, which we call L1 longevity, is a starvation response regulated by metabolic rate during starvation. A high rate of metabolism shortens the L1 survival span, whereas a low rate of metabolism lengthens it. The longer worms are starved, the slower they grow once they are fed, suggesting that L1 arrest has metabolic costs. Furthermore, mutants of genes that regulate metabolism show altered L1 longevity. Among them, we found that AMP-dependent protein kinase (AMPK), as a key energy sensor, regulates L1 longevity by regulating this metabolic arrest. Our results suggest that L1 longevity is determined by metabolic rate and that AMPK as a master regulator of metabolism controls this arrest so that the animals survive long-term starvation.


Hospital admission rates and the prevalence of asthma symptoms in 20 local authority districts.
Representative samples of 20-44 year old men living in 20 local authority districts in England were surveyed in 1986 by postal questionnaire and asked about symptoms associated with asthma and treatment for asthma. Regional health authorities provided information on all hospital discharges of men of the same age living in the same districts. Specific information was also provided on discharges where the primary cause of admission was for asthma. Admission rates for asthma were related to the prevalence of night time breathlessness and independently to the all cause admission rate for men of the same age. Admission rates were not significantly related to prescription rates of either corticosteroids or beta 2 agonists for symptomatic men. This lack of association is hard to interpret without further information on variation in the severity of disease. These data show that admission rates for asthma are not dictated solely by health service characteristics, such as availability of beds or the "style" of the physician, but also reflect need. More research is required on how best to reduce the local prevalence and severity of asthma.


Sex differences in the relationship between socioeconomic status and cardiovascular disease: a systematic review and meta-analysis.
Low socioeconomic status (SES) is a known risk factor for cardiovascular disease (CVD) but whether its effects are comparable in women and men is unknown. PubMed MEDLINE was systematically searched. Studies that reported sex-specific estimates, and associated variability, of the relative risk (RR) for coronary heart disease (CHD), stroke or CVD according to a marker of SES (education, occupation, income or area of residence), for women and men were included. RRs were combined with those derived from cohort studies using individual participant data. Data were pooled using random effects meta-analyses with inverse variance weighting. Estimates of the ratio of the RRs (RRR), comparing women with men, were computed. Data from 116 cohorts, over 22 million individuals, and over 1 million CVD events, suggest that lower SES is associated with increased risk of CHD, stroke and CVD in women and men. For CHD, there was a significantly greater excess risk associated with lower educational attainment in women compared with men; comparing lowest with highest levels, the age-adjusted RRR was 1.24 (95% CI 1.09 to 1.41) and the multiple-adjusted RRR was 1.34 (1.09 to 1.63). For stroke, the age-adjusted RRR was 0.93 (0.72 to 1.18), and the multiple-adjusted was RRR 0.79 (0.53 to 1.19). Corresponding results for CVD were 1.18 (1.03 to 1.36), 1.23 (1.03 to 1.48), respectively. Similar results were observed for other markers of SES for all three outcomes. Reduction of socioeconomic inequalities in CHD and CVD outcomes might require different approaches for men and women.


Outbreak-Causing Fungi: Pneumocystis jirovecii.
Pneumocystis jirovecii pneumonia (PCP) is an important cause of morbidity in immunocompromised patients, with a higher mortality in non-HIV than in HIV patients. P. jirovecii is one of the rare transmissible pathogenic fungi and the only one that depends fully on the host to survive and proliferate. Transmissibility among humans is one of the main specificities of P. jirovecii. Hence, the description of multiple outbreaks raises questions regarding preventive care management of the disease, especially in the non-HIV population. Indeed, chemoprophylaxis is well codified in HIV patients but there is a trend for modifications of the recommendations in the non-HIV population. In this review, we aim to discuss the mode of transmission of P. jirovecii, identify published outbreaks of PCP and describe molecular tools available to study these outbreaks. Finally, we discuss public health and infection control implications of PCP outbreaks in hospital setting for in- and outpatients.


An EMG-driven musculoskeletal model for the estimation of biomechanical parameters of wrist flexors.
A musculoskeletal model of wrist flexors comprising musculoskeletal dynamics and limb anatomy was experimentally validated with healthy subjects during maximum voluntary contractions. Electromyography signals recorded from flexors were used as input, while measured torques exerted by the hand were compared to the torques predicted by the model. The root mean square error and the normalized root mean square error calculated during estimation and validation phases were compared. In total, six subject-specific musculoskeletal parameters were estimated, while biomechanical indexes such as the operating range of the flexors, the stiffness of the wrist flexion musculotendon actuators, and the contribution of the muscle fibers to the joint moment were computed. Results are in agreement with previously published data.


Mycobacterium tuberculosis FurA autoregulates its own expression.
The furA-katG region of Mycobacterium tuberculosis, encoding a Fur-like protein and the catalase-peroxidase, is highly conserved among mycobacteria. Both genes are induced upon oxidative stress. In this work we analyzed the M. tuberculosis furA promoter region. DNA fragments were cloned upstream of the luciferase reporter gene, and promoter activity in Mycobacterium smegmatis was measured in both the presence and absence of oxidative stress. The shortest fragment containing an inducible promoter extends 45 bp upstream of furA. In this region, -35 and -10 promoter consensus sequences can be identified, as well as a 23-bp AT-rich sequence that is conserved in the nonpathogenic but closely related M. smegmatis. M. tuberculosis FurA was purified and found to bind upstream of furA by gel shift analysis. A ca. 30-bp DNA sequence, centered on the AT-rich region, was essential for FurA binding and protected by FurA in footprinting analysis. Peroxide treatment of FurA abolished DNA binding. Three different AT-rich sequences mutagenized by site-directed mutagenesis were constructed. In each mutant, both M. tuberculosis FurA binding in vitro and pfurA regulation upon oxidative-stress in M. smegmatis were abolished. Thus, pfurA is an oxidative stress-responsive promoter controlled by the FurA protein.


The biomechanics of human femurs in axial and torsional loading: comparison of finite element analysis, human cadaveric femurs, and synthetic femurs.
To assess the performance of femoral orthopedic implants, they are often attached to cadaveric femurs, and biomechanical testing is performed. To identify areas of high stress, stress shielding, and to facilitate implant redesign, these tests are often accompanied by finite element (FE) models of the bone/implant system. However, cadaveric bone suffers from wide specimen to specimen variability both in terms of bone geometry and mechanical properties, making it virtually impossible for experimental results to be reproduced. An alternative approach is to utilize synthetic femurs of standardized geometry, having material behavior approximating that of human bone, but with very small specimen to specimen variability. This approach allows for repeatable experimental results and a standard geometry for use in accompanying FE models. While the synthetic bones appear to be of appropriate geometry to simulate bone mechanical behavior, it has not, however, been established what bone quality they most resemble, i.e., osteoporotic or osteopenic versus healthy bone. Furthermore, it is also of interest to determine whether FE models of synthetic bones, with appropriate adjustments in input material properties or geometric size, could be used to simulate the mechanical behavior of a wider range of bone quality and size. To shed light on these questions, the axial and torsional stiffness of cadaveric femurs were compared to those measured on synthetic femurs. A FE model, previously validated by the authors to represent the geometry of a synthetic femur, was then used with a range of input material properties and change in geometric size, to establish whether cadaveric results could be simulated. Axial and torsional stiffnesses and rigidities were measured for 25 human cadaveric femurs (simulating poor bone stock) and three synthetic "third generation composite" femurs (3GCF) (simulating normal healthy bone stock) in the midstance orientation. The measured results were compared, under identical loading conditions, to those predicted by a previously validated three-dimensional finite element model of the 3GCF at a variety of Young's modulus values. A smaller FE model of the 3GCF was also created to examine the effects of a simple change in bone size. The 3GCF was found to be significantly stiffer (2.3 times in torsional loading, 1.7 times in axial loading) than the presently utilized cadaveric samples. Nevertheless, the FE model was able to successfully simulate both the behavior of the 3GCF, and a wide range of cadaveric bone data scatter by an appropriate adjustment of Young's modulus or geometric size. The synthetic femur had a significantly higher stiffness than the cadaveric bone samples. The finite element model provided a good estimate of upper and lower bounds for the axial and torsional stiffness of human femurs because it was effective at reproducing the geometric properties of a femur. Cadaveric bone experiments can be used to calibrate FE models' input material properties so that bones of varying quality can be simulated.


Rotational Laxity Control by the Anterolateral Ligament and the Lateral Meniscus Is Dependent on Knee Flexion Angle: A Cadaveric Biomechanical Study.
Injury to the anterolateral ligament (ALL) has been reported to contribute to high-grade anterolateral laxity after anterior cruciate ligament (ACL) injury. Failure to address ALL injury has been suggested as a cause of persistent rotational laxity after ACL reconstruction. Lateral meniscus posterior root (LMPR) tears have also been shown to cause increased internal rotation of the knee. The purpose of this study was to determine the functional relationship between the ALL and LMPR in the control of internal rotation of the ACL-deficient knee. Specifically: (1) We asked if there was a difference in internal rotation among: the intact knee; the ACL-deficient knee; the ACL/ALL-deficient knee; the ACL/LMPR-deficient knee; and the ACL/ALL/LMPR-deficient knee. (2) We also asked if there was a difference in anterior translation among these conditions. Sixteen fresh frozen cadaveric knee specimens (eight men, mean age 79 years) were potted into a hip simulator (femur) and a 6 degree-of-freedom load cell (tibia). Rigid optical trackers were inserted into the proximal femur and distal tibia, allowing for the motion of the tibia with respect to the femur to be tracked during biomechanical tests. A series of points on the femur and tibia were digitized to create bone coordinate systems that were used to calculate internal rotation and anterior translation. Biomechanical testing involved applying a 5-Nm internal rotation moment to the tibia from full extension to 90° of flexion. Anterior translation was performed by applying a 90-N anterior load using a tensiometer. Both tests were performed in 15° increments tested sequentially in the following conditions: (1) intact; and (2) ACL injury (ACL-). The specimens were then randomized to either have the ALL sectioned (3) first (M+/ALL-); or (4) the LMPR sectioned first (M-/ALL+) followed by the other structure (M-/ALL-). A one-way analysis of variance was performed for each sectioning condition at each angle of knee flexion (α = 0.05). At 0° of flexion there was an effect of tissue sectioning such that internal rotation of the M-/ALL- condition was greater than ACL- by 1.24° (p = 0.03; 95% confidence interval [CI], 0.16-2.70) and the intact condition by 2.5° (p = 0.01; 95% CI, 0.69-3.91). In addition, the mean (SD) internal rotations for the M+/ALL- (9.99° [5.39°]) and M-/ALL+ (12.05° [5.34°]) were greater by 0.87° (p = 0.04; 95% CI, 0.13-3.83) and by 2.15°, respectively, compared with the intact knee. At 45° the internal rotation for the ACL- (19.15° [9.49°]), M+/ALL- (23.70° [7.00°]), and M-/ALL- (18.80° [8.27°]) conditions was different than the intact (12.78° [9.23°]) condition by 6.37° (p = 0.02; 95% CI, 1.37-11.41), 8.47° (p < 0.01; 95% CI, 3.94-13.00), and 6.02° (p = 0.01; 95% CI, 1.73-10.31), respectively. At 75° there was a 10.11° difference (p < 0.01; 95% CI, 5.20-15.01) in internal rotation between the intact (13.96° [5.34°]) and the M+/ALL- (23.22° [4.46°]) conditions. There was also a 4.08° difference (p = 0.01; 95% CI, 1.14-7.01) between the intact and M-/ALL- (18.05° [7.31°]) conditions. Internal rotation differences of 6.17° and 5.43° were observed between ACL- (16.28° [6.44°]) and M+/ALL- (p < 0.01; 95% CI, 2.45-9.89) as well as between M+/ALL- and M-/ALL- (p = 0.01; 95% CI, -8.17 to -1.63). Throughout the range of flexion, there was no difference in anterior translation with progressive section of the ACL, meniscus, or ALL. The ALL and LMPR both play a role in aiding the ACL in controlling internal rotation laxity in vitro; however, these effects seem to be dependent on flexion angle. The ALL has a greater role in controlling internal rotation at flexion angles > 30o. The LMPR appears to have more of an effect on controlling rotation closer to extension. Injury to the ALL and/or LMPR may contribute to high-grade anterolateral laxity after ACL injury. The LMPR and the ALL, along with the iliotibial tract, appear to act in concert as secondary stabilizers of anterolateral rotation and could be considered as the "anterolateral corner" of the knee.


Avian gut-associated lymphoid tissues and intestinal immune responses to Eimeria parasites.
Coccidiosis, an intestinal infection caused by intracellular protozoan parasites belonging to several different species of Eimeria, seriously impairs the growth and feed utilization of livestock and poultry. Host immune responses to coccidial infection are complex. Animals infected with Eimeria spp. produce parasite-specific antibodies in both the circulation and mucosal secretions. However, it appears that antibody-mediated responses play a minor role in protection against coccidiosis. Furthermore, there is increasing evidence that cell-mediated immunity plays a major role in resistance to infection. T lymphocytes appear to respond to coccidial infection through both cytokine production and a direct cytotoxic attack on infected cells. The exact mechanisms by which T cells eliminate the parasites, however, remain unclear. Although limited information is available on the intestinal immune system of chickens, gut lymphoid tissues have evolved specialized features that reflect their role as the first line of defense at mucosal surfaces, including both immunoregulatory cells and effector cells. This review summarizes our current understanding of the avian intestinal immune system and mucosal immune responses to Eimeria spp., providing an overview of the complex cellular and molecular events involved in intestinal immune responses to enteric pathogens.


Estimated Effect of Inactivated Poliovirus Vaccine Campaigns, Nigeria and Pakistan, January 2014-April 2016.
In 2014, inactivated poliovirus vaccine (IPV) campaigns were implemented in Nigeria and Pakistan after clinical trials showed that IPV boosts intestinal immunity in children previously given oral poliovirus vaccine (OPV). We estimated the effect of these campaigns by using surveillance data collected during January 2014-April 2016. In Nigeria, campaigns with IPV and trivalent OPV (tOPV) substantially reduced the incidence of poliomyelitis caused by circulating serotype-2 vaccine-derived poliovirus (incidence rate ratio [IRR] 0.17 for 90 days after vs. 90 days before campaigns, 95% CI 0.04-0.78) and the prevalence of virus in environmental samples (prevalence ratio [PR] 0.16, 95% CI 0.02-1.33). Campaigns with tOPV alone resulted in similar reductions (IRR 0.59, 95% CI 0.18-1.97; PR 0.45, 95% CI 0.21-0.95). In Pakistan, the effect of IPV+tOPV campaigns on wild-type poliovirus was not significant. Results suggest that administration of IPV alongside OPV can decrease poliovirus transmission if high vaccine coverage is achieved.


Controllable, Sequential, and Stereoselective C-H Allylic Alkylation of Alkenes.
The direct conversion of C-H bonds into new C-C bonds represents a powerful approach to generate complex molecules from simple starting materials. However, a general and controllable method for the sequential conversion of a methyl group into a fully substituted carbon center remains a challenge. We report a new method for the selective and sequential replacement of three C-H bonds at the allylic position of propylene and other simple terminal alkenes with different carbon groups derived from Grignard reagents. A copper catalyst and electron-rich biaryl phosphine ligand facilitate the formation of allylic alkylation products in high branch selectivity. We also present conditions for the generation of enantioenriched allylic alkylation products in the presence of catalytic copper and a chiral phosphine ligand. With this approach, diverse and complex products with substituted carbon centers can be generated from simple and abundant feedstock chemicals.


Predicting the outcome in elderly patients of hospital admission for acute care in Paris, France: construction and initial validation of a simplex index.
To develop a simple index able to identify at an early stage those elderly patients at high risk of requiring discharge to a residential or nursing home after admission to hospital for acute care. For these patients, early discharge planning might lead to a more effective management and reduce the length of hospitalisation. This was a prospective study conducted in two teaching hospitals in Paris, France. A total of 510 consecutive patients was included. They were aged 75 years or more and had been admitted to acute medical care units through the emergency department. Demographic data, social support, physical disability, mental disability, and pathologic status were assessed shortly after admission (within 24-48 hours). Outcome of hospitalisation was defined as discharge to home or residential/nursing home. The index, developed by multiple logistic regression, included six variables: the wish of patients' principal career about their returning home after acute hospitalisation, presence of a chronic condition, ability to perform toileting, ability to know the name of the hospital or the city, their age, and their living arrangements. The sensitivity of the index in identifying patients at high risk of requiring discharge to a residential/nursing home was 74.4%, the specificity 63.8% the positive predictive value was 57.8%, and the negative predictive value was 80.6%. The simple index, using data available very early in the course of hospitalisation, provides an accurate prediction of the hospitalisation outcome. The performance of the index should be tested in other populations and the practical benefits of risk screening should be assessed in a controlled trial to evaluate whether the intervention is useful and without any adverse effects.


Immunohistochemical expression of Bcl-2, p53 and caspase-9 in hypothalamus magnocellular centers of nNOS knockout mice following water deprivation.
We studied the interactions between apoptosis regulator proteins (Bcl-2, p53 and caspase-9) and neuronal nitric oxide in vasopressinergic magnocellular centers of the hypothalamus using neuronal nitric oxide synthase (nNOS) gene knockout mice. nNOS gene deletion resulted in accumulation of Bcl-2, p53 and caspase-9 in the paraventricular (PVN) and supraoptic (SON) nuclei in controls. Dehydration increased the levels of all three apoptosis regulator proteins studied in nuclei of wild type mice. In the hypothalamus magnocellular centers of nNOS knockout mice, however, expression of Bcl-2, p53 and caspase-9 was unchanged after dehydration. The number of magnocellular neurons did not change in the SON and PVN of nNOS deficient mice compared to wild type, and after dehydration, cell death was not observed in either nucleus of wild type or knockout mice despite activation of apoptosis regulator protein expression. Thus, we demonstrated that gene disruption of nNOS prevents activation of Bcl-2, p53 and caspase-9 expression during water deprivation, and that nNOS deficiency did not affect survival of magnocellular neurons of the hypothalamus.


Association between blood manganese level during pregnancy and birth size: The Japan environment and children's study (JECS).
Manganese (Mn) is both an essential element and a potential toxicant. Although a few studies have suggested a nonlinear relationship between the maternal whole blood Mn level at delivery and infant birth weight, little is known about the effects of Mn levels during pregnancy on fetal growth, particularly with regard to sex-specific differences. In this nationwide birth cohort study, we examined the association of maternal blood Mn level during pregnancy with infant birth weight, length, and head circumference in 16,473 mother-infant pairs. Pregnant women living in 15 regions across Japan were recruited between January 2011 and March 2014. The analysis of birth size (8,484 males and 7,989 females) was conducted using a nonlinear spline, followed by the use of quadratic regression or linear regression models. The analysis of small-for-gestational-age (SGA) (6,962 males and 6,528 females born vaginally) was conducted using multivariate logistic regression. Additionally, subgroup analysis was conducted according to the timing of blood sampling. The median maternal blood Mn level during pregnancy (i.e., 2nd and 3rd trimesters) was 16.2 µg/L (range, 4.3-44.5 µg/L). A positive linear association between the log blood Mn level and head circumference was observed in both male and female infants. However, a nonlinear relationship between the log blood Mn level and birth weight was observed only in male infants, such that the birth weight increased up to a blood Mn level of 18.6 µg/L. In the subgroup analysis stratified by the timing of maternal blood sampling, this nonlinear relationship was obvious only when sampling was performed in the 3rd trimester. Male infants in the lowest blood Mn level quartile (≤ 13.2 µg/L) faced an increased risk of SGA (odds ratio [95% confidence interval] = 1.35 [1.04-1.74]), as did those in the highest blood Mn level quartile (≥ 21.0 µg/L) when sampling was performed during the 3rd trimester (odds ratio [95% confidence interval] = 1.62 [1.10 to 2.39]), compared to those in the third blood Mn level quartile (the category including 18.6 µg/L). No association of blood Mn level with birth weight was observed among female infants, and blood Mn level was not associated with birth length in either male or female infants. A low blood Mn level during pregnancy or a high blood Mn level during the 3rd trimester was associated with a lower birth weight and increased risk of SGA in male infants, but not in female infants. A low blood Mn level was found to correlate slightly with a small head circumference among infants of both sexes.


Metabolomics: an emerging post-genomic tool for nutrition.
The post-genomic era has been driven by the development of technologies that allow the function of cells and whole organisms to be explored at the molecular level. Metabolomics is concerned with the measurement of global sets of low-molecular-weight metabolites. Metabolite profiles of body fluids or tissues can be regarded as important indicators of physiological or pathological states. Such profiles may provide a more comprehensive view of cellular control mechanisms in man and animals, and raise the possibility of identifying surrogate markers of disease. Metabolomic approaches use analytical techniques such as NMR spectroscopy and MS to measure populations of low-molecular-weight metabolites in biological samples. Advanced statistical and bioinformatic tools are then employed to maximise the recovery of information and interpret the large datasets that are generated. Metabolomics has already been used to study toxicological mechanisms and disease processes and offers enormous potential as a means of investigating the complex relationship between nutrition and metabolism. Examples include the metabolism of dietary substrates, drug-induced disturbances of lipid metabolites in type 2 diabetes mellitus and the therapeutic effects of vitamin supplementation in the treatment of chronic metabolic disorders.


U.S. natural resources and climate change: concepts and approaches for management adaptation.
Public lands and waters in the United States traditionally have been managed using frameworks and objectives that were established under an implicit assumption of stable climatic conditions. However, projected climatic changes render this assumption invalid. Here, we summarize general principles for management adaptations that have emerged from a major literature review. These general principles cover many topics including: (1) how to assess climate impacts to ecosystem processes that are key to management goals; (2) using management practices to support ecosystem resilience; (3) converting barriers that may inhibit management responses into opportunities for successful implementation; and (4) promoting flexible decision making that takes into account challenges of scale and thresholds. To date, the literature on management adaptations to climate change has mostly focused on strategies for bolstering the resilience of ecosystems to persist in their current states. Yet in the longer term, it is anticipated that climate change will push certain ecosystems and species beyond their capacity to recover. When managing to support resilience becomes infeasible, adaptation may require more than simply changing management practices--it may require changing management goals and managing transitions to new ecosystem states. After transitions have occurred, management will again support resilience--this time for a new ecosystem state. Thus, successful management of natural resources in the context of climate change will require recognition on the part of managers and decisions makers of the need to cycle between "managing for resilience" and "managing for change."


Regional aspects of long-term public sector psychiatric care in the Eastern Cape.
The objective of this research was to determine regional aspects (such as clinical, geographic and socio-demographic) influencing the use of public sector long-term psychiatric services in the Eastern Cape. This is important in improving service delivery, to assist policy developers with evidence-based research and in providing equitable and efficient resource utilisation. A situational analysis of Tower Psychiatric Hospital and Psychosocial Rehabilitation Centre (TPHPRC) in the Eastern Cape was conducted. Patient administrative data were utilised to determine geographic origin, date and age at admission, gender and diagnosis as of December 2015. The number of admissions from each region for the years 2010-2015 was also extracted from these data. As of December 2015, there were a total of 390 patients at TPHPRC. Of these, 87% were male patients. The average age at admission for male and female patients was 36 years and 44 years, respectively. Of the patients, 53% originated from the western regions and 57% of female patients presented with a dual diagnosis. The highest number of admissions was in 2015, with the majority originating from Port Elizabeth. Despite higher access to public psychiatric care in the western region, the majority of patients originated from there. Contributing factors to this include diagnoses, insufficient bed numbers and the absence of admission criteria and referral pathways. It is recommended that the provincial Department of Health set up a task team to determine a standardised working framework for all public sector psychiatric institutions. This should be informed by national policies, legislation and provincial norms and indicators.


Systemic delivery of DNA or siRNA mediated by linear polyethylenimine (L-PEI) does not induce an inflammatory response.
The success of nucleic acid therapies depends upon delivery vehicle's ability to selectively and efficiently deliver therapeutic nucleic acids to target organ with minimal toxicity. The cationic polymer polyethylenimine (PEI) has been widely used for nucleic acid delivery due to its versatility and efficiency. In particular, the last generation of linear PEI (L-PEI) is being more efficient in vivo than the first generation of branched PEI. This led to several clinical trials including phase II bladder cancer therapy and human immunodeficiency virus immunotherapy. When moving towards to the clinic, it is crucial to identify potential side-effects induced by the delivery vehicle. For this purpose we have analyzed the production of pro-inflammatory cytokines [tumor necrosis factor-alpha, interferon (IFN)-gamma, interleukin (IL)-6, IL-12/IL-23, IFN-beta and IL-1beta] and hepatic enzyme levels (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase) in the blood serum of mice after systemic injection of DNA or siRNAs delivered with L-PEI. Our data show no major production of pro-inflammatory cytokines or hepatic enzymes after injection of DNA or oligonucleotides active for RNA interference (siRNAs or sticky siRNAs) complexed with L-PEI. Only a slight induction of IFN-gamma was measured after DNA delivery, which is probably induced by the CpG mediated response. Taken together our data highlight that linear polyethylenimine is a delivery reagent of choice for nucleic acid therapeutics.


Features of effective medical knowledge resources to support point of care learning: a focus group study.
Health care professionals access various information sources to quickly answer questions that arise in clinical practice. The features that favorably influence the selection and use of knowledge resources remain unclear. We sought to better understand how clinicians select among the various knowledge resources available to them, and from this to derive a model for an effective knowledge resource. We conducted 11 focus groups at an academic medical center and outlying community sites. We included a purposive sample of 50 primary care and subspecialist internal medicine and family medicine physicians. We transcribed focus group discussions and analyzed these using a constant comparative approach to inductively identify features that influence the selection of knowledge resources. We identified nine features that influence users' selection of knowledge resources, namely efficiency (with sub-features of comprehensiveness, searchability, and brevity), integration with clinical workflow, credibility, user familiarity, capacity to identify a human expert, reflection of local care processes, optimization for the clinical question (e.g., diagnosis, treatment options, drug side effect), currency, and ability to support patient education. No single existing resource exemplifies all of these features. The influential features identified in this study will inform the development of knowledge resources, and could serve as a framework for future research in this field.


Pertussis control strategies: A consistent approach for New Zealand. Synopsis of Ministry of Health Workshop, April 2015.
In the past decade, pertussis has made a global resurgence, driving reconsideration of national immunisation schedules and vaccine usage. A workshop held by the Ministry of Health in 2015 discussed New Zealand's pertussis disease control strategies. Data were presented from current research into vaccine safety during pregnancy and the effectiveness of the immunisation schedule in preventing pertussis throughout childhood. The greatest burden of disease and mortality remains in infants under 1 year of age, especially infants too young to be immunised, those of Māori and Pacific ethnicity, and those living in deprivation. The workshop considered strategies including the timing of the scheduled vaccines, maternal immunisation, improving immunisation coverage, vaccination timeliness and service delivery to reduce inequalities and overall disease burden. It concluded that the current infant schedule appears to be working well to protect older infants from severe pertussis. Significant gains for reducing severe disease in vulnerable young infants could be made with improvements in maternal vaccine uptake. Other strategic directions include attention to schedule adherence and timeliness of vaccine delivery, and more effective communication approaches for healthcare professionals and the public.


Open-Label Allopregnanolone Treatment of Men with Fragile X-Associated Tremor/Ataxia Syndrome.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and ataxia and neuropsychological evaluations. Brain activity consisted of event-related potential N400 word repetition effect during a semantic memory processing task. Structural MRI outcomes comprised volumes of the hippocampus, amygdala, and fluid-attenuated inversion recovery hyperintensities, and microstructural integrity of the corpus callosum. The results of the study showed that allopregnanolone infusions were well tolerated in all subjects. Before treatment, the patients disclosed impairment in executive function, verbal fluency and learning, and progressive deterioration of all MRI measurements. After treatment, the patients demonstrated improvement in executive functioning, episodic memory and learning, and increased N400 repetition effect amplitude. Although MRI changes were not significant as a group, both improved and deteriorated MRI measurements occurred in individual patients in contrast to uniform deterioration before the treatment. Significant correlations between baseline MRI measurements and changes in neuropsychological test scores indicated the effects of allopregnanolone on improving executive function, learning, and memory for patients with relatively preserved hippocampus and corpus callosum, while reducing psychological symptoms for patients with small hippocampi and amygdalae. The findings show the promise of allopregnanolone in improving cognitive functioning in patients with FXTAS and in partially alleviating some aspects of neurodegeneration. Further studies are needed to verify the efficacy of allopregnanolone for treating FXTAS.


Early or later prophylactic INSURE in preterm infants of less than 30 weeks' gestation.
We aimed to determine whether an early prophylactic INSURE strategy combined with early nasal continuous positive airway pressure (nCPAP) treatment could decrease the subsequent need for mechanical ventilation (MV) compared to the administration of surfactant prophylaxis later, at the 15th minute after birth, combined with early nCPAP. Infants born at <30 weeks' gestation were randomized to receive surfactant prophylaxis immediately or at the 15th minute after birth. All infants received 100 mg/kg poractant alpha, were ventilated with a T-piece resuscitator and were extubated to nCPAP if they had sufficient respiratory drive. Forty infants were analyzed in each group. Ten (25%) infants in the early prophylactic INSURE group, and 13 (32.5%) infants in the later prophylactic INSURE group could not be extubated after surfactant administration in the delivery room. Among the infants who were initially extubated to nCPAP after surfactant administration, 6 in the early prophylactic INSURE group and 4 in the later prophylactic INSURE group needed intubation for MV within the first 3 days of life (20% vs. 16.7%; P=0.73). The duration of total respiratory support (CPAP plus MV) of infants who were intubated within the first 3 days of life was shorter in the early prophylactic INSURE group than in the later prophylactic INSURE group (median: 96 h vs. 309 h; P=0.038). The incidence of all neonatal morbidities and mortality and the duration of hospitalization were similar between the groups. Our study did not demonstrate superiority of early surfactant prophylaxis combined with early nCPAP to the later administration of prophylactic surfactant with early nCPAP; however, it did detect an absolute difference in the primary outcome: need for MV within the first 3 days of life.


EPLIN is a crucial regulator for extrusion of RasV12-transformed cells.
At the initial stage of carcinogenesis, a mutation occurs in a single cell within a normal epithelial layer. We have previously shown that RasV12-transformed cells are apically extruded from the epithelium when surrounded by normal cells. However, the molecular mechanisms underlying this phenomenon remain elusive. Here, we demonstrate that Cav-1-containing microdomains and EPLIN (also known as LIMA1) are accumulated in RasV12-transformed cells that are surrounded by normal cells. We also show that knockdown of Cav-1 or EPLIN suppresses apical extrusion of RasV12-transformed cells, suggesting their positive role in the elimination of transformed cells from epithelia. EPLIN functions upstream of Cav-1 and affects its enrichment in RasV12-transformed cells that are surrounded by normal cells. Furthermore, EPLIN regulates non-cell-autonomous activation of myosin-II and protein kinase A (PKA) in RasV12-transformed cells. In addition, EPLIN substantially affects the accumulation of filamin A, a vital player in epithelial defense against cancer (EDAC), in the neighboring normal cells, and vice versa. These results indicate that EPLIN is a crucial regulator of the interaction between normal and transformed epithelial cells.


Transcriptome Analysis of the Response to NaCl in Suaeda maritima Provides an Insight into Salt Tolerance Mechanisms in Halophytes.
Although salt tolerance is a feature representative of halophytes, most studies on this topic in plants have been conducted on glycophytes. Transcriptome profiles are also available for only a limited number of halophytes. Hence, the present study was conducted to understand the molecular basis of salt tolerance through the transcriptome profiling of the halophyte Suaeda maritima, which is an emerging plant model for research on salt tolerance. Illumina sequencing revealed 72,588 clustered transcripts, including 27,434 that were annotated using BLASTX. Salt application resulted in the 2-fold or greater upregulation of 647 genes and downregulation of 735 genes. Of these, 391 proteins were homologous to proteins in the COGs (cluster of orthologous groups) database, and the majorities were grouped into the poorly characterized category. Approximately 50% of the genes assigned to MapMan pathways showed homology to S. maritima. The majority of such genes represented transcription factors. Several genes also contributed to cell wall and carbohydrate metabolism, ion relation, redox responses and G protein, phosphoinositide and hormone signaling. Real-time PCR was used to validate the results of the deep sequencing for the most of the genes. This study demonstrates the expression of protein kinase C, the target of diacylglycerol in phosphoinositide signaling, for the first time in plants. This study further reveals that the biochemical and molecular responses occurring at several levels are associated with salt tolerance in S. maritima. At the structural level, adaptations to high salinity levels include the remodeling of cell walls and the modification of membrane lipids. At the cellular level, the accumulation of glycinebetaine and the sequestration and exclusion of Na+ appear to be important. Moreover, this study also shows that the processes related to salt tolerance might be highly complex, as reflected by the salt-induced enhancement of transcription factor expression, including hormone-responsive factors, and that this process might be initially triggered by G protein and phosphoinositide signaling.


Stability and dynamics of membrane-spanning DNA nanopores.
Recently developed DNA-based analogues of membrane proteins have advanced synthetic biology. A fundamental question is how hydrophilic nanostructures reside in the hydrophobic environment of the membrane. Here, we use multiscale molecular dynamics (MD) simulations to explore the structure, stability and dynamics of an archetypical DNA nanotube inserted via a ring of membrane anchors into a phospholipid bilayer. Coarse-grained MD reveals that the lipids reorganize locally to interact closely with the membrane-spanning section of the DNA tube. Steered simulations along the bilayer normal establish the metastable nature of the inserted pore, yielding a force profile with barriers for membrane exit due to the membrane anchors. Atomistic, equilibrium simulations at two salt concentrations confirm the close packing of lipid around of the stably inserted DNA pore and its cation selectivity, while revealing localized structural fluctuations. The wide-ranging and detailed insight informs the design of next-generation DNA pores for synthetic biology or biomedicine.


Indoor Culturable Fungal Load and Associated Factors among Public Primary School Classrooms in Gondar City, Northwest Ethiopia, 2018: A Cross-sectional Study.
Fungi are heavy threats to public health in indoor environments, particularly in residential buildings, offices, and schools where people spend a lot of time indoors. This study was conducted to investigate the load of culturable fungi and associated factors in a school indoor environment. Institutional based cross-sectional study was conducted in eight public primary school classrooms in Gondar City from March to April 2018. Settle plate technique was used to determine the culturable fungal load. Log transformed linear regression analysis was employed. The beta-coefficient with a 95% confidence interval was used to determine the degree and direction of the association with a p-value less than 0.05. The highest and the lowest mean culturable fungal loads recorded were 1140.29 CFU/m3 and 211.25 CFU/m3, respectively. Aspergillus, Mucor, Penicillium, Candida, Microsporum, Trichophyton, Rhizopus, Alternaria and Fusarium species were isolated. Age of buildings (β= -0.122, 95%CI -0.238,-0.007), area of classroom (β= 0.639, 95% CI 0.285, 0.993), temperature (β= -0.189, 95% CI -0.325,-0.047), humidity (β= -0.023, 95% CI -0.043, -0.002) and PM10 (β= -0.01, 95% CI -0.015,-0.005) were associated with culturable fungal load. High culturable fungal load was found in school classrooms in Gondar City. Age of buildings, area of classrooms, temperature, humidity, and PM10 were predictors of the culturable fungal load. Therefore, proficient corrective methods are needed to combat the problem of indoor air quality in a school indoor environment by controlling factors contributing to growth of fungi.


Clinical characteristics, process of care and outcomes among Mexican, Hispanic and non-Hispanic white patients presenting with non-ST elevation acute coronary syndromes: data from RENASICA and CRUSADE registries.
Data regarding management characteristics of non-ST elevation acute coronary syndromes (NSTE ACS) in Mexican, Hispanic and Non- Hispanic white patients are scarce. We sought to describe the clinical characteristics, process of care, and outcomes of Mexicans, Hispanics and non-Hispanic whites presenting with NSTE ACS at Mexican and US hospitals. We compared baseline characteristics, resource use, clinical practice guidelines (CPGs) compliance and in-hospital mortality among 3 453 Mexicans, 3 936 Hispanics and 90, 280 non-Hispanic whites with NSTE ACS from the RENASICA and CRUSADE registries. Mexicans were younger with a different cardiovascular risk profile, fewer incidences of hypertension (p<0.001), hyperlipidemia (p<0.001), renal failure (p<0.001) and prior revascularization (p<0.001) but were more likely to be smoking compared with Hispanics and non-Hispanic white populations. Mexicans and Hispanics had a higher incidence of diabetes (p<0.001). At clinical presentation Mexican patients were more likely to have ST depression (p<0.001) but less likely to have left ventricular dysfunction (p<0.001) and troponin stratification (p<0.001). Regarding CPGs compliance, aspirin was used in 90% of patients in all groups, but clopidogrel or unfractionated or low-molecular weight heparin in 50% of patients or less. Mexican patients were less likely to receive glycoprotein IIb/IIIa inhibitors and revascularization. In spite of clinical differences and therapeutic trends, cardiovascular mortality was similar among all groups (Mexicans 4%, Hispanics 4% and non-Hispanic white 5%). In all groups of patients, a poor CPGs compliance was observed. In a post-hoc analysis, Mexican patients with NSTE ACS had a different cardiovascular risk factor profile and clinical presentation, and less intensive in - hospital treatment than Hispanic and non-Hispanic white patients. However, these differences do not appear to affect in - hospital mortality.


Species- and stage-specific differences in trace element tissue concentrations in amphibians: implications for the disposal of coal-combustion wastes.
Information on species- and stage-specific patterns of contaminant accumulation is generally lacking for amphibians, yet such information could provide valuable knowledge on how amphibians interact with contaminants. We assessed concentrations of As, Cd, Cu, Ni, Pb, Se, Sr, and Zn in whole bodies of larval, recently metamorphosed, and adult life stages in Bufo terrestris and Rana sphenocephala from a site that currently receives coal combustion waste (CCW) discharge, a site where CCW was formerly discharged that has undergone natural attenuation for 30 years, and a nearby reference site. For the majority of elements (As, Cd, Cu, Ni, Pb, Zn), concentrations were highest in larvae, but Se and Sr concentrations remained elevated in later life stages, likely because these elements are S and Ca analogs, respectively, and are thus retained throughout structural changes during metamorphosis. Element concentrations were generally higher in B. terrestris than in R. sphenocephala. Concentrations of As, Se, and Sr were up to 11-35 times higher in metamorphs emigrating from CCW-polluted wetlands compared to unpolluted wetlands, suggesting metamorphosed amphibians can transport trace elements from aquatic disposal basins to nearby uncontaminated terrestrial habitats. In addition, anurans utilizing naturally revegetated sites up to 30 years after CCW disposal ceases are exposed to trace elements, although to a lesser degree than sites where CCW is currently discharged.


Noninvasive physiologic monitoring of high-risk surgical patients.
To study the feasibility of multicomponent noninvasive monitoring, consisting of a new bioimpedance method for estimating cardiac output together with routine pulse oximetry and transcutaneous oximetry, and to compare physiologic data obtained noninvasively with hemodynamic and oxygen transport data obtained by standard invasive pulmonary artery thermodilution catheter to evaluate circulatory function in high-risk surgical patients. Prospective descriptive analysis of the time course of physiologic patterns in surgical patients. University-run county hospital. Seventy-one consecutively monitored, high-risk critically ill surgical patients in their perioperative period. Simultaneous measurements by invasive and noninvasive methods to describe and compare the temporal physiologic patterns of survivors and nonsurvivors. The new impedance cardiac output estimations closely approximated those of the thermodilution method (r = 0.82, P < .001). Episodes of hypotension, tachycardia, low cardiac index, arterial hemoglobin desaturation, low transcutaneous oximetry, reduced oxygen delivery, and low oxygen consumption occurred with both groups but were more pronounced in the nonsurvivors than in the survivors. Noninvasive monitoring provided information similar to that of the thermodilution method. Both approaches indicated low flow and poor tissue perfusion (oxygenation) that was worse in the nonsurvivors. The multicomponent noninvasive monitoring provides continuous online, real-time displays of physiologic data that allow immediate recognition of circulatory dysfunction as well as the means to titrate therapy to appropriate predetermined therapeutic goals. The noninvasive systems are easy to apply, safe, inexpensive, reasonably accurate, and cost-effective.


Repair of Double Head Pectoralis Major Tendon Avulsion into its Native Footprint Using Bi-cortical EndoButtons and Tendon Sliding Technique.
Injuries to the pectoralis major muscle are relatively infrequent. The mechanism of injury is usually an eccentric shortening of the pectoralis major under heavy load, such as when performing a bench press exercise. We report a case that presented to us with a history of sudden pain in the left pectoral region while doing heavy bench press exercise. The patient sustained a type III D pectoralis muscle -tendon avulsion. Surgical repair was done through a bi-cortical tendon sliding technique using two cortical buttons. In this article we describe our modifications to the previously described surgical technique for the pectoralis major tendon repair using the EndoButton and tension - slide technique, aiming to overcome the possible complications.


Validity of the Participation and Environment Measure for Children and Youth (PEM-CY) for Health Impact Assessment (HIA) in sustainable development projects.
Participation in home, school, and community activities is an important indicator of child health and well-being. Evaluating environmental influences on children's participation can inform efforts to develop sustainable built environments, but few validated measures exist. To examine the concurrent validity and utility of the Participation and Environment Measure for Children and Youth (PEM-CY) for Health Impact Assessment in non-urban sustainable development projects affecting children with disabilities. Eighty-nine parents of children and youth with disabilities who identified as residing in a small town or rural community were sampled. Sixty-six caregivers completed the PEM-CY online, and 23 caregivers completed the PEM-CY and CHIEF-CP paper forms. Spearman correlational analyses were conducted to establish the concurrent validity of the PEM-CY environment sections against the CHIEF-CP. Group comparisons by child's age, number of functional limitations, and annual household income were used to examine differences in summary and item-level responses on the PEM-CY community section. Moderate to strong associations were found between CHIEF-CP Total Product and Magnitude Scores and all PEM-CY Environment Summary Scores. CHIEF-CP Physical/Structural and Policies Subscale Scores were most consistently associated with PEM-CY Environment Summary Scores. Group differences by household income were found for participation frequency and number of supports, including perceived availability and adequacy of money and information about programs and services, even when controlling child's age and number of functional limitations. Study results lend support to the use of the PEM-CY in HIA to reliably assess for environmental impact on children's participation. Implications for using the PEM-CY to inform decision-making in non-urban sustainable development projects affecting families of children and youth with disabilities are discussed.


Deep venous thrombosis prophylaxis for knee replacement: warfarin and pneumatic compression.
A prospective study of the prevalence of proximal deep venous thrombosis in total knee replacement patients who had prophylaxis for thrombosis with a combination of low-dose warfarin and intermittent pneumatic compression was done. Two hundred and ninety-seven patients who underwent 377 consecutive total knee replacements were studied. All patients were treated with low-dose warfarin and intermittent pneumatic compression using thigh-high sleeves. Surveillance for proximal thrombosis was done by duplex ultrasonography. Proximal thrombosis was detected in 19 patients, for a prevalence of 5%. There were 3 patients who had a major bleeding complication, for a prevalence of 0.9% for the 337 procedures performed. Although there was no concurrent control group of patients treated with another means of prophylaxis to compare with these patients, the low prevalence of proximal thrombosis and the low risk of major bleeding complications that was found compares well with recent reports on the effectiveness and safety of low-molecular-weight heparin.


An international qualitative study exploring patients' experiences of cutaneous leishmaniasis: study set-up and protocol.
Lack of investments in drug development, lack of standardisation of clinical trials and the complexity of disease presentations contribute to the current lack of effective, safe and adapted treatments for cutaneous leishmaniasis (CL). One aspect concerns outcomes affecting patients' quality of life (QoL): these are hardly assessed in trials, despite potential functional and/or aesthetic impairment caused by CL, which typically affects disadvantaged and vulnerable people living in rural areas. Here, we describe the approach used to bring perspectives of patients with CL into designing and assessing treatments. This international qualitative study uses interviews with patients to explore their experiences with CL to (1) elicit outcomes and eligibility criteria for clinical trials important to them and (2) to better understand their needs and views about the disease and their requirements and expectations from treatment. Here, we describe the set-up of this collaborative study and the protocol. Data collection is ongoing.The protocol includes study design, preparation, conduct and analysis of individual interviews with approximately 80 patients in seven countries (Burkina Faso, Brazil, two sites in Colombia, Iran, Morocco, Peru and Tunisia) where CL is prevalent. Principal investigators and sites were selected through an open call, and two workshops were organised for protocol development and training in conduct and analysis of qualitative health research. Patient recruitment aims at covering a maximum variation of experiences. Transcripts will be analysed to identify outcomes and eligibility criteria as well as further topics that are expected to emerge from the interviews, such as direct and indirect costs related to CL, its psychological impact, preferred modes of drug administration and traditional treatments. The study received ethical approval by the responsible committees of each of the participating institutions. Findings will be disseminated through publication in peer-reviewed journals, scientific meetings and to participants and their communities.


A Parallel Proximal Algorithm for Anisotropic Total Variation Minimization.
Total variation (TV) is a one of the most popular regularizers for stabilizing the solution of ill-posed inverse problems. This paper proposes a novel proximal-gradient algorithm for minimizing TV regularized least-squares cost functionals. Unlike traditional methods that require nested iterations for computing the proximal step of TV, our algorithm approximates the latter with several simple proximals that have closed form solutions. We theoretically prove that the proposed parallel proximal method achieves the TV solution with arbitrarily high precision at a global rate of converge that is equivalent to the fast proximal-gradient methods. The results in this paper have the potential to enhance the applicability of TV for solving very large-scale imaging inverse problems.


Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease.
Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.


The spatial sensitivity of the spectral diversity-biodiversity relationship: an experimental test in a prairie grassland.
Remote sensing has been used to detect plant biodiversity in a range of ecosystems based on the varying spectral properties of different species or functional groups. However, the most appropriate spatial resolution necessary to detect diversity remains unclear. At coarse resolution, differences among spectral patterns may be too weak to detect. In contrast, at fine resolution, redundant information may be introduced. To explore the effect of spatial resolution, we studied the scale dependence of spectral diversity in a prairie ecosystem experiment at Cedar Creek Ecosystem Science Reserve, Minnesota, USA. Our study involved a scaling exercise comparing synthetic pixels resampled from high-resolution images within manipulated diversity treatments. Hyperspectral data were collected using several instruments on both ground and airborne platforms. We used the coefficient of variation (CV) of spectral reflectance in space as the indicator of spectral diversity and then compared CV at different scales ranging from 1 mm2 to 1 m2 to conventional biodiversity metrics, including species richness, Shannon's index, Simpson's index, phylogenetic species variation, and phylogenetic species evenness. In this study, higher species richness plots generally had higher CV. CV showed higher correlations with Shannon's index and Simpson's index than did species richness alone, indicating evenness contributed to the spectral diversity. Correlations with species richness and Simpson's index were generally higher than with phylogenetic species variation and evenness measured at comparable spatial scales, indicating weaker relationships between spectral diversity and phylogenetic diversity metrics than with species diversity metrics. High resolution imaging spectrometer data (1 mm2 pixels) showed the highest sensitivity to diversity level. With decreasing spatial resolution, the difference in CV between diversity levels decreased and greatly reduced the optical detectability of biodiversity. The optimal pixel size for distinguishing α diversity in these prairie plots appeared to be around 1 mm to 10 cm, a spatial scale similar to the size of an individual herbaceous plant. These results indicate a strong scale-dependence of the spectral diversity-biodiversity relationships, with spectral diversity best able to detect a combination of species richness and evenness, and more weakly detecting phylogenetic diversity. These findings can be used to guide airborne studies of biodiversity and develop more effective large-scale biodiversity sampling methods.


Strobilurin biosynthesis in Basidiomycete fungi.
Strobilurins from fungi are the inspiration for the creation of the β-methoxyacrylate class of agricultural fungicides. However, molecular details of the biosynthesis of strobilurins have remained cryptic. Here we report the sequence of genomes of two fungi that produce strobilurins and show that each contains a biosynthetic gene cluster, which encodes a highly reducing polyketide synthase with very unusual C-terminal hydrolase and methyltransferase domains. Expression of stpks1 in Aspergillus oryzae leads to the production of prestrobilurin A when the fermentation is supplemented with a benzoyl coenzyme A (CoA) analogue. This enables the discovery of a previously unobserved route to benzoyl CoA. Reconstruction of the gene cluster in A. oryzae leads to the formation of prestrobilurin A, and addition of the gene str9 encoding an FAD-dependent oxygenase leads to the key oxidative rearrangement responsible for the creation of the β-methoxyacrylate toxophore. Finally, two methyltransferases are required to complete the synthesis.


Bacteria Etiological Agents Causing Lower Respiratory Tract Infections and Their Resistance Patterns.
Lower respiratory tract infections (LTRIs) are among the most common infectious diseases with potential life-threatening complications. The study consisted of 426 patients with suspected LTRIs from mid and far western region of Nepal between September 2011 and July 2014. The specimens were collected and processed according to the standard microbiological methods at the Central Laboratory of Microbiology of Nepalgunj Medical College, Nepal. Among the isolated Gram-positive organisms, Streptococcus pneumonia (n = 30, 51.7%) was the most predominant pathogen, followed by Staphylococcus aureus (n = 28, 48.3%). Among the isolated Gram-negative organisms, Pseudomonas aeruginosa (n = 71, 35.32%) was the most predominant pathogen, followed by Haemophilus influenzae (n = 68, 33.83%), Klebsiella pneumonia (n = 36, 17.19%), and Escherichia coli (n = 26, 12.94%). The pattern of resistance varied regarding the bacteria species, and there were multi-resistant isolates. Also, a significant difference (P value less than 0.05) was observed between males and females for each type of bacterial species. Among 259 isolates, 86 (33.20%) were from children aged 1-10 years, which were statistically significant (P valuse less than 0.05) compared to the other age groups. P. aeruginosa and H. influenzae (Gram-negative) and S. pnemoniae (Gram-positive) were the most common bacterial isolates recovered from LTRIs. Age group of 1-10 years old was at a higher risk. Many isolates showed appreciable levels of antibiotic resistance due to antibiotic abuse. There is a need to increase surveillance and develop better strategies to curb the increasing prevalence of LRTI in this region of Nepal.


Effect of pH on chitosan hydrogel polymer network structure.
Chitosan is a molecule that can form water-filled 3D polymer networks with a wide range of applications. A new coarse-grained model for chitosan hydrogel was developed to explore its pH-dependent self-assembly behavior and mechanical properties. Our results indicate that the underlying polymer physical crosslinking pattern induced by solution pH has a significant effect on hydrogel elastic moduli. With this model, we obtain pH-dependent structural and mechanical property changes in agreement with experimental observations, and provide a molecular mechanism behind the changes in polymer crosslinking patterns.


Improved discriminability of spatiotemporal neural patterns in rat motor cortical areas as directional choice learning progresses.
Animals learn to choose a proper action among alternatives to improve their odds of success in food foraging and other activities critical for survival. Through trial-and-error, they learn correct associations between their choices and external stimuli. While a neural network that underlies such learning process has been identified at a high level, it is still unclear how individual neurons and a neural ensemble adapt as learning progresses. In this study, we monitored the activity of single units in the rat medial and lateral agranular (AGm and AGl, respectively) areas as rats learned to make a left or right side lever press in response to a left or right side light cue. We noticed that rat movement parameters during the performance of the directional choice task quickly became stereotyped during the first 2-3 days or sessions. But learning the directional choice problem took weeks to occur. Accompanying rats' behavioral performance adaptation, we observed neural modulation by directional choice in recorded single units. Our analysis shows that ensemble mean firing rates in the cue-on period did not change significantly as learning progressed, and the ensemble mean rate difference between left and right side choices did not show a clear trend of change either. However, the spatiotemporal firing patterns of the neural ensemble exhibited improved discriminability between the two directional choices through learning. These results suggest a spatiotemporal neural coding scheme in a motor cortical neural ensemble that may be responsible for and contributing to learning the directional choice task.


Evolution of organogenesis and the origin of altriciality in mammals.
Mammals feature not only great phenotypic disparity, but also diverse growth and life history patterns, especially in maturity level at birth, ranging from altriciality to precocity. Gestation length, morphology at birth, and other markers of life history are fundamental to our understanding of mammalian evolution. Based on the first synthesis of embryological data and the study of new ontogenetic series, we reconstructed estimates of the ancestral chronology of organogenesis and life-history modes in placental mammals. We found that the ancestor of marsupial and placental mammals was placental-like at birth but had a long, marsupial-like infancy. We hypothesize that mammalian viviparity might have evolved in association with the extension of growth after birth, enabled through lactation, and that mammalian altriciality is inherited from the earliest amniotes. The precocial lifestyle of extant sauropsids and that of many placental mammals were acquired secondarily. We base our conclusions on the best estimates and provide a comprehensive discussion on the methods used and the limitations of our dataset. We provide the most comprehensive embryological dataset ever published, "rescue" old literature sources, and apply available methods and illustrate thus an approach on how to investigate comparatively organogenesis in macroevolution.


[Allergic march in children, from rhinitis to asthma: management, indication of immunotherapy].
Allergic rhinitis (AR) is a common IgE dependent disorder. AR is maybe one of the steps of the allergic march, which starts with atopic dermatitis and food allergy and includes atopic asthma. AR and asthma are frequently associated. AR is frequently under-diagnosed and undertreated although it affects quality of life and school performance. Management of AR depends on its severity and will associate environmental control (best guided by environmental investigation and skin testing of specific IgE antibodies), pharmacotherapy (with antihistamines and intranasal corticosteroids as first line drugs). At present allergen immunotherapy is considered in patients with severe AR, insufficiently controlled by pharmacotherapy and who demonstrate specific IgE antibodies to relevant allergens. Sublingual immunotherapy is well tolerated. Only immunotherapy with the right allergens has the potential to alter the natural history of the allergic march, by preventing the development of new allergen sensitizations and reducing the risk for the subsequent development of asthma. This fact might extend the indications of specific allergen immunotherapy. Patients (and parents) education is of utmost importance in the management of allergic disorders.


Understanding the patterns and trends of sodium intake, potassium intake, and sodium to potassium ratio and their effect on hypertension in China.
Recent studies have shown inconsistent effects of sodium reduction, potassium intake, and the ratio of sodium to potassium (Na/K ratio) on hypertension and other cardiovascular diseases. Major gaps exist in knowledge regarding these issues in China. We analyzed the patterns and trends of dietary sodium intake, potassium intake, and the Na/K ratio and their relations with incident hypertension in China. The China Health and Nutrition Survey cohort includes 16,869 adults aged 20-60 y from 1991 to 2009. Three consecutive 24-h dietary recalls and condiment and food weights provided detailed dietary data. Multinomial logistic regression models determined trends and patterns of sodium and potassium intake and the Na/K ratio. Models for survival-time data estimated the hazard of incident hypertension. Sodium intake is decreasing but remains double the Institute of Medicine recommendations. Most sodium comes from added condiments. Adults in the central provinces have the highest sodium intake and the most rapid increase in hypertension. Potassium intake has increased slightly but is below half of the recommended amount. The Na/K ratio is significantly higher than the recommended amounts. Recent measurements of high sodium intake, low potassium intake, and high Na/K ratio have strong independent dose-response associations with incident hypertension. Reducing sodium in processed foods, the major public health strategy in Western countries, may be less effective in China, where salt intake remains high. Replacing sodium with potassium in salt to control and prevent hypertension in China should be considered along with other public health and clinical prevention options.


Proteomic identification of germline proteins in Caenorhabditis elegans.
Sexual reproduction involves fusion of 2 haploid gametes to form diploid offspring with genetic contributions from both parents. Gamete formation represents a unique developmental program involving the action of numerous germline-specific proteins. In an attempt to identify novel proteins involved in reproduction and embryonic development, we have carried out a proteomic characterization of the process in Caenorhabditis elegans. To identify candidate proteins, we used 2D gel electrophoresis (2DGE) to compare protein abundance in nucleus-enriched extracts from wild-type C. elegans, and in extracts from mutant worms with greatly reduced gonads (glp-4(bn2) worms reared at 25°C); 84 proteins whose abundance correlated with germline presence were identified. To validate candidates, we used feeding RNAi to deplete candidate proteins, and looked for reduction in fertility and/or germline cytological defects. Of 20 candidates so screened for involvement in fertility, depletion of 13 (65%) caused a significant reduction in fertility, and 6 (30%) resulted in sterility (<5 % of wild-type fertility). Five of the 13 proteins with demonstrated roles in fertility have not previously been implicated in germline function. The high frequency of defects observed after RNAi depletion of candidate proteins suggests that this approach is effective at identifying germline proteins, thus contributing to our understanding of this complex organ.


The movement protein (NSm) of Tomato spotted wilt virus is the avirulence determinant in the tomato Sw-5 gene-based resistance.
The avirulence determinant triggering the resistance conferred by the tomato gene Sw-5 against Tomato spotted wilt virus (TSWV) is still unresolved. Sequence comparison showed two substitutions (C118Y and T120N) in the movement protein NSm present only in TSWV resistance-breaking (RB) isolates. In this work, transient expression of NSm of three TSWV isolates [RB1 (T120N), RB2 (C118Y) and non-resistance-breaking (NRB)] in Nicotiana benthamiana expressing Sw-5 showed a hypersensitive response (HR) only with NRB. Exchange of the movement protein of Alfalfa mosaic virus (AMV) with NSm supported cell-to-cell and systemic transport of the chimeric AMV RNAs into N. tabacum with or without Sw-5, except for the constructs with NBR when Sw-5 was expressed, although RB2 showed reduced cell-to-cell transport. Mutational analysis revealed that N120 was sufficient to avoid the HR, but the substitution V130I was required for systemic transport. Finally, co-inoculation of RB and NRB AMV chimeric constructs showed different prevalence of RB or NBR depending on the presence or absence of Sw-5. These results indicate that NSm is the avirulence determinant for Sw-5 resistance, and mutations C118Y and T120N are responsible for resistance breakdown and have a fitness penalty in the context of the heterologous AMV system.


Problematic internet use and psychiatric co-morbidity in a population of Japanese adult psychiatric patients.
Many studies reported the high prevalence of problematic internet use (PIU) among adolescents (13-50%), and PIU was associated with various psychiatric symptoms. In contrast, only a few studies investigated the prevalence among the adult population (6%). This study aimed to investigate the prevalence of PIU and psychiatric co-morbidity among adult psychiatric patients. Three hundred thirty-three adult psychiatric patients were recruited over a 3-month period. Two hundred thirty-one of them completed the survey (response rate: 69.4%, 231/333; Male/Female/Transgender: 90/139/2; mean age = 42.2). We divided participants into "normal internet users" and "problematic internet users" using a combination of Young's Internet Addiction Test (IAT) and the Compulsive Internet Use Scale (CIUS). Demographic data and comorbid psychiatric symptoms were compared between the two groups using self-rating scales measuring insomnia (Athens Insomnia Scale, AIS), depression (Beck Depression Inventory, BDI), anxiety (State-trait Anxiety Inventory, STAI), attention deficit hyperactivity disorder (ADHD) (Adult ADHD Self-report Scale, ASRS), autism (Autism Spectrum Quotient, AQ), obsessive-compulsive disorder (OCD) (Obsessive-Compulsive Inventory, OCI), social anxiety disorder (SAD) (Liebowitz Social Anxiety Scale, LSAS), alcohol abuse, and impulsivity (Barratt Impulsive Scale, BIS). Among 231 respondents, 58 (25.1%) were defined as problematic internet users, as they scored high on the IAT (40 or more) or CIUS (21 or more). The age of problematic internet users was significantly lower than that of normal internet users (p < 0.001, Mann-Whitney U test). The problematic internet users scored significantly higher on scales measuring sleep problems (AIS, 8.8 for problematic internet users vs 6.3 for normal internet users, p < 0.001), depression (BDI, 27.4 vs 18.3, p < 0.001), trait anxiety (STAI, 61.8 vs 53.9, p < 0.001), ADHD (ASRS, part A 3.1 vs 1.8 and part B 3.5 vs 1.8, p < 0.001), autism (AQ, 25.9 vs 21.6, p < 0.001), OCD (OCI, 63.2 vs 36.3, p < 0.001), SAD (LSAS, 71.4 vs 54.0, p < 0.001), and impulsivity (BIS, 67.4 vs 63.5, p = 0.004). The prevalence of PIU among adult psychiatric patients is relatively high. As previous studies reported in the general population, lower age and psychiatric comorbidity were associated with PIU among adult psychiatric patients. More research is needed to determine any causal relations between PIU and psychopathological illnesses.


Resistant hypertension, patient characteristics, and risk of stroke.
Little is known about the prognosis of resistant hypertension (RH) in Asian population. This study aimed to evaluate the impacts of RH in Taiwanese patients with hypertension, and to ascertain whether patient characteristics influence the association of RH with adverse outcomes. Patients aged ≥45 years with hypertension were identified from the National Health Insurance Research Database. Medical records of 111,986 patients were reviewed in this study, and 16,402 (14.6%) patients were recognized as having RH (continuously concomitant use of ≥3 anti-hypertensive medications, including a diuretic, for ≥2 years). Risk of major adverse cardiovascular events (MACE, a composite of all-cause mortality, acute coronary syndrome, and stroke [included both fatal and nonfatal events]) in patients with RH and non-RH was analyzed. A total of 11,856 patients experienced MACE in the follow-up period (average 7.1±3.0 years). There was a higher proportion of females in the RH group, they were older than the non-RH (63.1 vs. 60.5 years) patients, and had a higher prevalence of cardiovascular co-morbidities. Overall, patients with RH had higher risks of MACE (adjusted HR 1.17; 95%CI 1.09-1.26; p<0.001). Significantly elevated risks of stroke (10,211 events; adjusted HR 1.17; 95%CI 1.08-1.27; p<0.001), especially ischemic stroke (6,235 events; adjusted HR 1.34; 95%CI 1.20-1.48; p<0.001), but not all-cause mortality (4,594 events; adjusted HR 1.06; 95%CI 0.95-1.19; p = 0.312) or acute coronary syndrome (2,145 events; adjusted HR 1.17; 95%CI 0.99-1.39; p = 0.070) were noted in patients with RH compared to those with non-RH. Subgroup analysis showed that RH increased the risks of stroke in female and elderly patients. However, no significant influence was noted in young or male patients. Patients with RH were associated with higher risks of MACE and stroke, especially ischemic stroke. The risks were greater in female and elderly patients than in male or young patients.


Efficacy of the African weaver ant Oecophylla longinoda (Hymenoptera: Formicidae) in the control of Helopeltis spp. (Hemiptera: Miridae) and Pseudotheraptus wayi (Hemiptera: Coreidae) in cashew crop in Tanzania.
Cashew, Anacardium occidentale, is an economically important cash crop for more than 300 000 rural households in Tanzania. Its production is, however, severely constrained by infestation by sap-sucking insects such as Helopeltis anacardii, H. schoutedeni and Pseudotheraptus wayi. The African weaver ant, Oecophylla longinoda, is an effective biocontrol agent of hemipteran pests in coconuts in Tanzania, but its efficacy in the control of Helopeltis spp. and P. wayi in Tanzanian cashew has not been investigated so far. The aim of this study was therefore to evaluate the efficacy of O. longinoda in the management of these insect pests in the cashew crop at different sites of the Coast region of Tanzania. Colonisation levels of O. longinoda, expressed as weaver ant trails, varied from 57.1 to 60.6% and from 58.3 to 67.5% in 2010 and 2011 respectively. The mean number of leaf nests per tree varied from five to eight nests in 2010 and from five to nine nests in 2011. There was a negative correlation between numbers of nests and pest damage. Oecophylla longinoda-colonised cashew trees had the lowest shoot damage by Helopeltis spp. of 4.8 and 7.5% in 2010 and 2011, respectively, as opposed to uncolonised cashew trees with 36 and 30% in 2010 and 2011 respectively. Similarly, nut damage by P. wayi was lowest in O. longinoda-colonised trees, with only 2.4 and 6.2% in 2010 and 2011 as opposed to uncolonised trees with 26 and 21%. Oecophylla longinoda is an effective biocontrol agent of the sap-sucking pests of cashew in the Coast region of Tanzania and should be considered as an important component of IPM.


Both a visual and a semiquantitative analysis for differentiating benign from malignant chondrogenic bone tumors using Tc-99m (V) DMSA scintigraphy: a prospective study.
The aims of this prospective study were to assess the relationship between tumor aggressiveness and Tc-99m (V) dimercaptosuccinic acid (DMSA) uptake in chondrogenic bone tumors and the value of Tc-99m (V) DMSA scintigraphy for differentiating benign from malignant tumors. Twenty-four patients with chondrogenic tumors (19 benign and five malignant) underwent Tc-99m DMSA (V) scintigraphy. Radiopharmaceutical uptake was classified using a three-point scale to allow a visual-only analysis, and a tumor-to-background contrast (TBC) was computed using regions of interest to provide a semiquantitative analysis. Spearman's correlation coefficient was used to assess the correlation between tumor aggressiveness and TBC. The difference in TBC between benign and malignant tumors was analyzed with the Mann-Whitney U-test. An appropriate cutoff value of TBC was chosen for the diagnosis of malignancy of a tumor using receiver operating characteristic analysis. Six benign tumors showed negative uptake (uptake score 0), whereas 13 benign tumors showed positive uptake (n=10 uptake score 1; n=3 uptake score 2). All chondrosarcomas showed positive uptake (n=2 uptake score 1; n=3 uptake score 2). A significant correlation was found between tumor aggressiveness and TBC. A significant difference was seen in TBC between benign and malignant tumors. With the chosen cutoff value of TBC equal to 0.611, the sensitivity was 80.0%, specificity was 78.9%, the positive predictive value was 50.0%, and the negative predictive value was 93.8%. Tc-99m (V) DMSA scintigraphy may have the potential to improve diagnostic methods for detecting chondrosarcomas using visual and/or semiquantitative analyses.


AZT (zidovudine) may act postintegrationally to inhibit generation of HIV-1 progeny virus in chronically infected cells.
The reverse transcriptase enzyme of HIV-1 is known to be error-prone. We were interested in the possibility of isolating a variant HIV-1 strain that might be capable of replication in the presence of AZT, thought to act by antagonizing reverse transcriptase activity. Toward this end, chronically infected H-9 cells were exposed to various concentrations of AZT for at least 500 days. No mutant has yet arisen from such cultures, which continued to produce high levels of each of the viral proteins p24, p17, gp41, and gp51/66 in the presence of the drug. Notwithstanding such expression of viral antigens, culture fluids from these various AZT-treated cultures were not capable of infecting otherwise susceptible target cells. Electron microscopic observations of AZT-treated chronically infected H-9 cells indicated a lower production of viral structures, in comparison with control cultures. Furthermore, those particles seen at the plasma membrane of AZT-treated cells often appeared to be envelope-deficient. These data suggest that AZT may be able to interfere in some way with proper assembly and/or packaging of infectious progeny HIV-1 at the cell membrane, although other modes of action for a postintegrational effect of AZT cannot be excluded.


Early findings of small-animal MRI and small-animal computed tomography correlate with histological changes in a rat model of rheumatoid arthritis.
With the use of a commonly utilized animal model of rheumatoid arthritis, the central goal of this work was to determine how well the small-animal imaging tools, small-animal MRI (microMRI) and small-animal X-ray computed tomography (microCT), can detect very early histological changes that occur immediately after induction of the disease. Arthritis was induced in rats by injecting complete Freund's adjuvant into the tail. Right hind paws of living rats were evaluated with 4.7 T microMRI with T1-weighted spin echo and inversion recovery sequences. Paw specimens were also evaluated with microCT and by histological examination (n = 29). MicroMR images were scored for the presence of joint effusion, soft tissue swelling, bone marrow changes, and bone erosions. MicroCT measured bone mineral density (BMD). Histology scores were obtained from representative slides from the same rats. The correlation between BMD, MRI and histology was analyzed using linear regression analysis and analysis of covariance. MRI abnormalities were detected on day 5 after induction as joint effusion and soft tissue swelling, followed by bone marrow changes on day 6 and bone erosion on day 8. BMD measured by microCT decreased, the decrease becoming significant on day 7 (P < 0.019). Soft tissue swelling, joint effusion, and bone erosion scores on microMRI correlated with histology (r2 approximately 0.7). Bone marrow changes were seen more clearly with microMRI than by histological examination. Bone loss could be detected earlier by microCT than on histological sections. In conclusion, microMRI and microCT can be used to evaluate early disease changes within 1 week of induction in the adjuvant-induced arthritis model, and have the ability to detect certain manifestations of disease earlier than histological analysis. The use of small-animal imaging techniques potentially allows earlier diagnosis, improved subject stratification, earlier drug implementation, and therefore improved drug trials in animal models of rheumatoid arthritis.


Quantum Rifling: Protecting a Qubit from Measurement Back Action.
Quantum mechanics postulates that measuring the qubit's wave function results in its collapse, with the recorded discrete outcome designating the particular eigenstate that the qubit collapsed into. We show that this picture breaks down when the qubit is strongly driven during measurement. More specifically, for a fast evolving qubit the measurement returns the time-averaged expectation value of the measurement operator, erasing information about the initial state of the qubit while completely suppressing the measurement backaction. We call this regime quantum rifling, as the fast spinning of the Bloch vector protects it from deflection into either of its eigenstates. We study this phenomenon with two superconducting qubits coupled to the same probe field and demonstrate that quantum rifling allows us to measure either one of the qubits on demand while protecting the state of the other from measurement backaction. Our results allow for the implementation of selective readout multiplexing of several qubits, contributing to the efficient scaling up of quantum processors for future quantum technologies.


A multi-scale model of hepcidin promoter regulation reveals factors controlling systemic iron homeostasis.
Systemic iron homeostasis involves a negative feedback circuit in which the expression level of the peptide hormone hepcidin depends on and controls the iron blood levels. Hepcidin expression is regulated by the BMP6/SMAD and IL6/STAT signaling cascades. Deregulation of either pathway causes iron-related diseases such as hemochromatosis or anemia of inflammation. We quantitatively analyzed how BMP6 and IL6 control hepcidin expression. Transcription factor (TF) phosphorylation and reporter gene expression were measured under co-stimulation conditions, and the promoter was perturbed by mutagenesis. Using mathematical modeling, we systematically analyzed potential mechanisms of cooperative and competitive promoter regulation by the transcription factors, and experimentally validated the model predictions. Our results reveal that hepcidin cross-regulation primarily occurs by combinatorial transcription factor binding to the promoter, whereas signaling crosstalk is insignificant. We find that the presence of two BMP-responsive elements enhances the steepness of the promoter response towards the iron-sensing BMP signaling axis, which promotes iron homeostasis in vivo. IL6 co-stimulation reduces the promoter sensitivity towards the BMP signal, because the SMAD and STAT transcription factors compete for recruiting RNA polymerase to the transcription start site. This may explain why inflammatory signals disturb iron homeostasis in anemia of inflammation. Taken together, our results reveal why the iron homeostasis circuit is sensitive to perturbations implicated in disease.


A Systematic Review of Interventions for Multilingual Preschoolers With Speech and Language Difficulties.
Purpose There is a shortage of information on evidence-based interventions for supporting young multilingual children. The purpose of this review was to identify interventions that have been evaluated with preschool-age multilingual children with a speech and/or language disorder or who are at risk of poor speech, language, literacy, and/or educational outcomes. Method This review considered speech, language, and early literacy interventions evaluated with preschool-age multilingual children with a speech and/or language disorder or who have been identified as being at risk of language difficulties (PROSPERO ID: 165892). The following electronic databases were searched: EBSCO (CINAHL Plus, ERIC, PsycINFO, Medline, Education) and Linguistics, Language, and Behavior Abstracts. Data were extracted describing article, participant, methodological, and intervention variables, and effect sizes. The Council for Exceptional Children's (CEC) standards for evidence-based practice were used to examine the quality of studies. Results Fifty-six relevant studies were identified in 52 articles and these studies described 4,551 participants who had speech sound disorder (six articles), developmental language disorder (11 articles), or were considered to be at risk (36 articles). The interventions targeted speech production (seven studies), language (45 studies), and early literacy (11 studies) skills. Most studies reported positive effects. Only 15 studies met all quality indicators specified by the CEC (2014) and these described 18 interventions targeting language and literacy skills. The only intervention with sufficient evidence to be considered an evidence-based practice was Nuestros Niños [Our Children] for children's early literacy and phonological awareness skills. Conclusions A number of high-quality studies exist that describe speech, language and/or literacy interventions for preschool-age multilingual children with a speech and/or language disorder, or who have been identified as being at risk of language difficulties. However, there remains limited evidence for specific interventions as to their ability to inform evidence-based practices. Supplemental Material https://doi.org/10.23641/asha.16632649.


Compositional analysis with atomic column spatial resolution by 5th-order aberration-corrected scanning transmission electron microscopy.
We show in this article that it is possible to obtain elemental compositional maps and profiles with atomic-column resolution across an InxGa1-xAs multilayer structure from 5th-order aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) images. The compositional profiles obtained from the analysis of HAADF-STEM images describe accurately the distribution of In in the studied multilayer in good agreement with Muraki's segregation model [Muraki, K., Fukatsu, S., Shiraki, Y. & Ito, R. (1992). Surface segregation of In atoms during molecular beam epitaxy and its influence on the energy levels in InGaAs/GaAs quantums wells. Appl Phys Lett 61, 557-559].