4D CT sorting based on patient internal anatomy.
Respiratory motion during free-breathing computed tomography (CT) scan may cause significant errors in target definition for tumors in the thorax and upper abdomen. A four-dimensional (4D) CT technique has been widely used for treatment simulation of thoracic and abdominal cancer radiotherapy. The current 4D CT techniques require retrospective sorting of the reconstructed CT slices oversampled at the same couch position. Most sorting methods depend on external surrogates of respiratory motion recorded by extra instruments. However, respiratory signals obtained from these external surrogates may not always accurately represent the internal target motion, especially when irregular breathing patterns occur. We have proposed a new sorting method based on multiple internal anatomical features for multi-slice CT scan acquired in the cine mode. Four features are analyzed in this study, including the air content, lung area, lung density and body area. We use a measure called spatial coherence to select the optimal internal feature at each couch position and to generate the respiratory signals for 4D CT sorting. The proposed method has been evaluated for ten cancer patients (eight with thoracic cancer and two with abdominal cancer). For nine patients, the respiratory signals generated from the combined internal features are well correlated to those from external surrogates recorded by the real-time position management (RPM) system (average correlation: 0.95+/-0.02), which is better than any individual internal measures at 95% confidence level. For these nine patients, the 4D CT images sorted by the combined internal features are almost identical to those sorted by the RPM signal. For one patient with an irregular breathing pattern, the respiratory signals given by the combined internal features do not correlate well with those from RPM (correlation: 0.68+/-0.42). In this case, the 4D CT image sorted by our method presents fewer artifacts than that from the RPM signal. Our 4D CT internal sorting method eliminates the need of externally recorded surrogates of respiratory motion. It is an automatic, accurate, robust, cost efficient and yet simple method and therefore can be readily implemented in clinical settings.


[Architectonics of cell subpopulations of peripheral blood in patients with autoimmune myocarditis: clinical and pathogenetic aspects].
To compare the most significant architectonic parameters of peripheral blood cell subpopulations in patients with different variants of an autoimmune myocarditis (AIM) course and their clinical value in therapeutic practice. Blood cell subpopulations were studied with flow cytometry in 99 blood samples from patients having different AIM variants and myocardiosclerosis as well as in 40 healthy donors. Severe (malignant) AIM was characterized by growing indices of T-/B lymphocyte activation, expression of activation markers on the cells of both differentiation lines, disproportions in composition of subpopulations of the immunoregulatory cells, parallel rise in specific weight of dendritic cells, reduced intensity of apoptosis of autoreactive T-lymphocytes. In benign AIM marked immunopathology was not found. This group can be considered as a separate variant of AIM course necessitating an individual approach to planning pathogenetically sound therapeutic and rehabilitation measures. The study of activation markers expression on peripheral blood cells is superior to the study of endomyocardial biopsies providing a non-invasive method of immunodiagnosis.


Spatial pattern of grazing affects influence of herbivores on spatial heterogeneity of plants and soils.
With our enhanced understanding of the factors that determine biodiversity and assemblage structure has come increasing acknowledgment that the use of an appropriate disturbance regime to maintain spatial heterogeneity is an effective conservation technique. A herbivore's behavior affects its disturbance regime (size and intensity); this, in turn, may modify the associated spatial heterogeneity of plants and soil properties. We examined whether the pattern of spatial disturbance created by the Siberian marmot (Marmota sibirica) affects the spatial heterogeneity of vegetation and soils at a colony scale on the Mongolian steppe. We expected that the difference in management between two types of area (protection against hunting marmots vs. hunting allowed) would result in different behavioral patterns; therefore, we estimated the patterns of spatial disturbance separately in protected and unprotected areas. We then surveyed plant communities and soil nutrients in these areas to assess their spatial heterogeneity. We found that disturbance of both vegetation and soil was more concentrated near marmot burrows in the unprotected area than in the protected area. In addition, the degrees of spatial heterogeneity of vegetation and soil NO(3)-N were greater in the unprotected area than in the protected area, where disturbance was more widely distributed. These results indicate that the spatial pattern of disturbance by herbivores affects the spatial heterogeneity of vegetation and soil properties through changes in the disturbance regime. Our findings also suggest that the intensity of disturbance is more important than its size in determining community structure in Mongolian grasslands.


How does obstructive sleep apnoea evolve in syndromic craniosynostosis? A prospective cohort study.
To describe the course of obstructive sleep apnoea syndrome (OSAS) in children with syndromic craniosynostosis. Prospective cohort study. Dutch Craniofacial Centre from January 2007 to January 2012. A total of 97 children with syndromic craniosynostosis underwent level III sleep study. Patients generally undergo cranial vault remodelling during their first year of life, but OSAS treatment only on indication. Obstructive apnoea-hypopnoea index, the central apnoea index and haemoglobin oxygenation-desaturation index derived from consecutive sleep studies. The overall prevalence of OSAS in syndromic craniosynostosis was 68% as defined by level III sleep study. Twenty-three patients were treated for OSAS. Longitudinal profiles were computed for 80 untreated patients using 241 sleep studies. A mixed effects model showed higher values for the patients with midface hypoplasia as compared to those without midface hypoplasia (Omnibus likelihood ratio test=7.9). In paired measurements, the obstructive apnoea-hypopnoea index (Z=-3.4) significantly decreased over time, especially in the first years of life (Z=-3.3), but not in patients with midface hypoplasia (Z=-1.5). No patient developed severe OSAS during follow-up if it was not yet diagnosed during the first sleep study. OSAS is highly prevalent in syndromic craniosynostosis. There is some natural improvement, mainly during the first 3 years of life and least in children with Apert or Crouzon/Pfeiffer syndrome. In the absence of other co-morbid risk factors, it is highly unlikely that if severe OSAS is not present early in life it will develop during childhood. Ongoing clinical surveillance is of great importance and continuous monitoring for the development of other co-morbid risk factors for OSAS should be warranted.


Gum chewing while walking increases fat oxidation and energy expenditure.
[Purpose] Although gum chewing while walking has been reported to increase walking speed and heart rate, its effect on energy expenditure remains unclear. The purpose of the present study was to investigate the effects of gum chewing while walking on fat oxidation, energy expenditure, and different walking parameters. [Participants and Methods] This randomized crossover study included 10 males and 5 females who walked for 15 min at their own pace while chewing 2 pieces of gum in the gum trial or while eating 2 tablets in the control trial. A wearable metabolic system, heart rate monitor, and pedometer measured fat oxidation, energy expenditure, heart rate, step count, and walking distance. Walking speed and stride length were also calculated. [Results] The energy expenditure, fat oxidation and heart rate were significantly higher during the gum trial than during the control trial. Significant increases were observed in the step count, walking distance, and walking speed but not in the stride length. [Conclusion] Our results suggest that gum chewing affects sympathetic nervous system activity and walking rhythm with a consequent improvement in the health-related effects of walking, which in turn helps to maintain weight. These findings may play a role in preventing the gradual age-related weight gain that predisposes to obesity.


Inflationary cosmology: exploring the universe from the smallest to the largest scales.
Understanding the behavior of the universe at large depends critically on insights about the smallest units of matter and their fundamental interactions. Inflationary cosmology is a highly successful framework for exploring these interconnections between particle physics and gravitation. Inflation makes several predictions about the present state of the universe-such as its overall shape, large-scale smoothness, and smaller scale structure-which are being tested to unprecedented accuracy by a new generation of astronomical measurements. The agreement between these predictions and the latest observations is extremely promising. Meanwhile, physicists are busy trying to understand inflation's ultimate implications for the nature of matter, energy, and spacetime.


Embryonic expression patterns of the neural cell adhesion molecule gene are regulated by homeodomain binding sites.
During development of the vertebrate nervous system, the neural cell adhesion molecule (N-CAM) is expressed in a defined spatiotemporal pattern. We have proposed that the expression of N-CAM is controlled, in part, by proteins encoded by homeobox genes. This hypothesis has been supported by previous in vitro experiments showing that products of homeobox genes can both bind to and transactivate the N-CAM promoter via two homeodomain binding sites, HBS-I and HBS-II. We have now tested the hypothesis that the N-CAM gene is a target of homeodomain proteins in vivo by using transgenic mice containing native and mutated N-CAM promoter constructs linked to a beta-galactosidase reporter gene. Segments of the 5' flanking region of the mouse N-CAM gene were sufficient to direct expression of the reporter gene in the central nervous system in a pattern consistent with that of the endogenous N-CAM gene. For example, at embryonic day (E) 11, beta-galactosidase staining was found in postmitotic neurons in dorsolateral and ventrolateral regions of the spinal cord; at E14.5, staining was seen in these neurons throughout the spinal cord. In contrast, mice carrying an N-CAM promoter-reporter construct with mutations in both homeodomain binding sites (HBS-I and HBS-II) showed altered expression patterns in the spinal cord. At E11, beta-galactosidase expression was seen in the ventrolateral spinal cord, but was absent in the dorsolateral areas, and at E 14.5, beta-galactosidase expression was no longer detected in any cells of the cord. Homeodomain binding sites found in the N-CAM promoter thus appear to be important in determining specific expression patterns of N-CAM along the dorsoventral axis in the developing spinal cord. These experiments suggest that the N-CAM gene is an in vivo target of homeobox gene products in vertebrates.


Dereplication of macrocyclic trichothecenes from extracts of filamentous fungi through UV and NMR profiles.
Macrocyclic trichothecenes (MTs), which have potent cytotoxicity, have been isolated from many different fungal species. These compounds were evaluated clinically by the US National Cancer Institute in the 1970s and 1980s. However, they have yet to be advanced into viable drugs because of severe side effects. Our team is investigating a diverse library of filamentous fungi for new anticancer leads. To avoid reisolating MTs through bioactivity-directed fractionation studies, a protocol for their facile dereplication was developed. The method uses readily available photodiode array detectors to identify one of two types of characteristic UV spectra for these compounds. In addition, diagnostic signals can be observed in the (1)H-NMR spectra, particularly for the epoxide and conjugated diene moieties, even at the level of a crude extract. Using these techniques in a complementary manner, MTs can be dereplicated rapidly.


Effects of space exposure on optical filters.
Optical transmittance characteristics of nine optical filters were remeasured after nearly 6 years in space aboard the NASA Long-Duration Exposure Facility. Three different filter types were included. In general, transmittance decreased for most filters. The center frequency and bandpass of a narrow-band filter under an aluminum cover were unchanged, while narrow-band filters exposed directly to the space environment tended to show a shift in center frequency and increased bandwidth. A pair of infraredreflecting mirrors exhibited reduced transmittance in the visible, with a mirror under an aluminum cover less degraded than a mirror exposed to space. The bandpass was unchanged for both of these mirrors. Neutral density filters showed a slight increase in transmittance for an uncovered filter; essentially no change for the filter under the aluminum cover.


Molecular architecture of native HIV-1 gp120 trimers.
The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Using cryo-electron tomography combined with three-dimensional image classification and averaging, we report the three-dimensional structures of trimeric Env displayed on native HIV-1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV-1 gp120 trimer in unliganded and CD4-bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV-1 gp120 relevant to antibody neutralization and attachment to target cells.


Impact of sleep in respiratory failure.
Sleep has a physiological influence on respiration, which can have major adverse effects on gas exchange in patients with respiratory insufficiency. These effects relate largely to a reduction in various stimulant inputs to the brainstem respiratory centre. Conditions that may be associated with sleep-related respiratory insufficiency range from pulmonary disorders (such as chronic obstructive pulmonary disease (COPD)), to central respiratory insufficiency (such as central alveolar hypoventilation), neurological and neuromuscular disorders (such as polio and muscular dystrophy), and thoracic cage disorders (such as kyphoscoliosis). All these conditions have in common the finding of hypoxaemia and hypercapnia, which become more pronounced during sleep. The relative hypoventilation, which is common to each condition, is due to varying combinations of an inadequate respiratory drive and an increase in the work of breathing. Management of respiratory insufficiency during sleep should be directed first at optimizing the underlying disorder, then at correcting hypoxaemia with controlled low-flow supplemental oxygen. Pharmacological therapy may be effective in some instances, but the choice of agent varies with the underlying disorder. Assisted ventilation is an important part of the management of advanced cases, and the recent development of intermittent positive pressure ventilation by nasal mask (NIPPV) has been an important advance in this area. Use of NIPPV during the night is associated with beneficial effects during the day, particularly improved awake gas exchange and respiratory muscle strength, in addition to less dyspnoea and improved quality of life. Electrophrenic pacing of the diaphragm is helpful in highly selected cases, particularly patients with central respiratory insufficiency and high quadriplegia, but is frequently complicated by the development of obstructive sleep apnoea.


Any qualified provider: a qualitative case study of one community NHS Trust's response.
To examine how those managing and providing community-based musculoskeletal (MSK) services have experienced recent policy allowing patients to choose any provider that meets certain quality standards from the National Health Service (NHS), private or voluntary sector. Intrinsic case study combining qualitative analysis of interviews and field notes. An NHS Community Trust (the main providers of community health services in the NHS) in England, 2013-2014. NHS Community Trust employees involved in delivering MSK services, including clinical staff and managerial staff in senior and mid-range positions. Managers (n=4) and clinicians (n=4) working within MSK services understood and experienced the Any Qualified Provider (AQP) policy as involving: (1) a perceived trade-off between quality and cost in its implementation; (2) deskilling of MSK clinicians and erosion of professional values; and (3) a shift away from interprofessional collaboration and dialogue. These ways of making sense of AQP policy were associated with dissatisfaction with market-based health reforms. AQP policy is poorly understood. Clinicians and managers perceive AQP as synonymous with competition and privatisation. From the perspective of clinicians providing MSK services, AQP, and related health policy reforms, tend, paradoxically, to drive down quality standards, supporting reconfiguration of services in which the complex, holistic nature of specialised MSK care may become marginalised by policy concerns about efficiency and cost. Our analysis indicates that the potential of AQP policy to increase quality of care is, at best, equivocal, and that any consideration of how AQP impacts on practice can only be understood by reference to a wider range of health policy reforms.


Religious Social Support, Discrimination, and Psychiatric Disorders among Black Adolescents.
Discrimination is a common experience for Black youth that can jeopardize their mental health. However, research suggests that various dimensions of religion have positive effects on youths' mental health and well-being. Additionally, exposure to discrimination may vary by youths' socio-demographic factors, such as gender and ethnicity. Numerous studies identify the protective effects of emotional and tangible religious social support on the mental health of Black adults reporting discrimination. Conversely, fewer studies address the influence of emotional and tangible religious social support on mental health for Black adolescents experiencing discrimination, while also accounting for socio-demographic heterogeneity among Black adolescents. Historically, religion has played an instrumental role in the diverse narratives of the Black Diaspora in the United States. It is important to account for its potential protective effects for Black youth. Examining these factors using a compensatory risk and resilience model, our study finds that Black adolescents who experience discrimination are also more likely to meet criteria for a psychiatric disorder. Additionally, those who report experiencing religious social support are less likely to meet criteria for a psychiatric disorder. These findings were not moderated by the sociodemographic factors of race or ethnicity. To date, this investigation is one of the first to examine the effect of different types of religious social support in the presence of discrimination on psychiatric illness among African American and Caribbean Black adolescents.


A new in vivo screening paradigm to accelerate antimalarial drug discovery.
The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task.


The evolution of siderophore production as a competitive trait.
Microbes have the potential to be highly cooperative organisms. The archetype of microbial cooperation is often considered to be the secretion of siderophores, molecules scavenging iron, where cooperation is threatened by "cheater" genotypes that use siderophores without making them. Here, we show that this view neglects a key piece of biology: siderophores are imported by specific receptors that constrain their use by competing strains. We study the effect of this specificity in an ecoevolutionary model, in which we vary siderophore sharing among strains, and compare fully shared siderophores with private siderophores. We show that privatizing siderophores fundamentally alters their evolution. Rather than a canonical cooperative good, siderophores become a competitive trait used to pillage iron from other strains. We also study the physiological regulation of siderophores using in silico long-term evolution. Although shared siderophores evolve to be downregulated in the presence of a competitor, as expected for a cooperative trait, privatized siderophores evolve to be upregulated. We evaluate these predictions using published experimental work, which suggests that some siderophores are upregulated in response to competition akin to competitive traits like antibiotics. Although siderophores can act as a cooperative good for single genotypes, we argue that their role in competition is fundamental to understanding their biology.


Exploring food contents in scientific literature with FoodMine.
Thanks to the many chemical and nutritional components it carries, diet critically affects human health. However, the currently available comprehensive databases on food composition cover only a tiny fraction of the total number of chemicals present in our food, focusing on the nutritional components essential for our health. Indeed, thousands of other molecules, many of which have well documented health implications, remain untracked. To explore the body of knowledge available on food composition, we built FoodMine, an algorithm that uses natural language processing to identify papers from PubMed that potentially report on the chemical composition of garlic and cocoa. After extracting from each paper information on the reported quantities of chemicals, we find that the scientific literature carries extensive information on the detailed chemical components of food that is currently not integrated in databases. Finally, we use unsupervised machine learning to create chemical embeddings, finding that the chemicals identified by FoodMine tend to have direct health relevance, reflecting the scientific community's focus on health-related chemicals in our food.


Post Genome-Wide Gene-Environment Interaction Study Using Random Survival Forest: Insulin Resistance, Lifestyle Factors, and Colorectal Cancer Risk.
Molecular and genetic pathways of insulin resistance (IR) connecting colorectal cancer and obesity factors in postmenopausal women remain inconclusive. We examined the IR pathways on both genetic and phenotypic perspectives at the genome-wide level. We further constructed colorectal cancer risk profiles with the most predictive IR SNPs and lifestyle factors. In our earlier genome-wide association gene-environmental interaction study, we used data from a large cohort of postmenopausal women in the Women's Health Initiative Database for Genotypes and Phenotypes Study and identified 58 SNPs in relation to IR phenotypes. In this study, we evaluated the identified IR SNPs and selected 34 lifestyles for their association with colorectal cancer risk in a total of 11,078 women (including 736 women with colorectal cancer) using a 2-stage multimodal random survival forest analysis. In overall and subgroup (defined via body mass index, exercise, and dietary-fat intake) analyses, we identified 2 SNPs (LINC00460 rs1725459 and MTRR rs722025) and lifetime cumulative exposure to estrogen (oral contraceptive use) and cigarette smoking as the most common and strongest predictive markers for colorectal cancer risk across the analyses. The combinations of genetic and lifestyle factors had much greater impact on colorectal cancer risk than any individual risk factors, and a possible synergism existed to increase colorectal cancer risk in a gene-behavior dose-dependent manner. Our findings may inform research on the role of IR in the etiology of colorectal cancer and contribute to more accurate prediction of colorectal cancer risk, suggesting potential intervention strategies for women with specific genotypes and lifestyles to reduce their colorectal cancer risk.


Volitional walking via upper limb muscle-controlled stimulation of the lumbar locomotor center in man.
Gait disturbance in individuals with spinal cord lesion is attributed to the interruption of descending pathways to the spinal locomotor center, whereas neural circuits below and above the lesion maintain their functional capability. An artificial neural connection (ANC), which bridges supraspinal centers and locomotor networks in the lumbar spinal cord beyond the lesion site, may restore the functional impairment. To achieve an ANC that sends descending voluntary commands to the lumbar locomotor center and bypasses the thoracic spinal cord, upper limb muscle activity was converted to magnetic stimuli delivered noninvasively over the lumbar vertebra. Healthy participants were able to initiate and terminate walking-like behavior and to control the step cycle through an ANC controlled by volitional upper limb muscle activity. The walking-like behavior stopped just after the ANC was disconnected from the participants even when the participant continued to swing arms. Furthermore, additional simultaneous peripheral electrical stimulation to the foot via the ANC enhanced this walking-like behavior. Kinematics of the induced behaviors were identical to those observed in voluntary walking. These results demonstrate that the ANC induces volitionally controlled, walking-like behavior of the legs. This paradigm may be able to compensate for the dysfunction of descending pathways by sending commands to the preserved locomotor center at the lumbar spinal cord and may enable individuals with paraplegia to regain volitionally controlled walking.


Progress of aging in human diploid cells transformed with a tsA mutant of simian virus 40.
Normal human diploid cells, TIG-1, ceased to proliferate at about the 62 population doubling level (PDL). Transformed clones isolated from TIG-1 cells infected with wtSV40 and those with tsA900 SV40 cultured at 34 degrees C were subcultured up to about 80 PDL. When the culture temperature of tsA SV40-transformed cells was shifted from 34 to 39.5 degrees C at 51 PDL, the growth curve of these transformed cells changed to that of normal young cells. When shifted to 39.5 degrees C after 62 PDL, cells immediately reached the end of their proliferative lifespan even under such favourable conditions for growth as low cell density in fresh medium. Growth of wtSV40-transformed cells did not change markedly at either temperature. These findings suggest that the clock of aging progresses in transformed cells as in normal cells, around 62 PDL being the senescent state in both cases, and that T-antigen of the tsA mutant of SV40 supports the extension of the lifespan of human cells only at the permissive temperature.


The effects of manipulating phospholipase C on guard cell ABA-signalling.
Studies using stably transformed tobacco plants containing very low levels of PI-PLC in their guard cells show that this enzyme plays a role in the events associated with the inhibition of stomatal opening by ABA, but not in the cellular reactions that are responsible for ABA-induced stomatal closure. However, Commelina communis guard cells microinjected with the InsP3 antagonist, heparin, fail to close on addition of ABA. There are three possible explanations for this apparent data mismatch. The differences may be indicative of species-specific signalling pathways, the presence of a PI-PLC isoform(s) that is not down-regulated in these transgenic lines and/or they may reflect differences between short-term (acute) administration of an inhibitor and long-term (chronic) effects of gene manipulation. It is possible that the guard cell is a robust signalling system that is able to adapt or compensate for the chronic loss of PI-PLC, but which is unable to adjust quickly to acute loss of this component. It would be interesting to investigate this possibility further using either transient manipulation of gene expression or through the use of an inducible promoter.


Size Matters: Normalization of QRS Duration to Left Ventricular Dimension Improves Prediction of Long-Term Cardiac Resynchronization Therapy Outcome.
In patients with left bundle branch block (LBBB), QRS duration (QRSd) depends on left ventricular (LV) dimension. Previously, we demonstrated that normalizing QRSd to LV dimension, to adjust for variations in LV size, improved prediction of hemodynamic response to cardiac resynchronization therapy (CRT). In addition, sex-specific differences in CRT outcome have been attributed to normalized QRSd. The present study evaluates the effect of normalization of QRSd to LV dimension on prediction of survival after CRT implantation. In this 2-center study, we studied 250 heart failure patients with LV ejection fraction ≤35% and QRSd ≥120 ms who underwent cardiac magnetic resonance imaging before CRT implantation. LV end-diastolic volumes were used for QRSd normalization (ie, QRSd/LV end-diastolic volumes). The primary end point was a combined end point of death, LV assist device, or heart transplantation. During a median follow-up of 3.9 years, 79 (32%) patients reached the primary end point. Using univariable Cox regression, unadjusted QRSd was unrelated to CRT outcome ( P=0.116). In contrast, normalized QRSd was a strong predictor of survival (hazard ratio, 0.81 per 0.1 ms/mL; P=0.008). Women demonstrated higher normalized QRSd than men (0.62±0.17 versus 0.55±0.17 ms/mL; P=0.003) and showed better survival after CRT (hazard ratio, 0.52; P=0.018). A multivariable prognostic model included normalized QRSd together with age, atrial fibrillation, renal function, and heart failure cause, whereas sex, diabetes mellitus, strict left bundle branch block morphology, and LV end-diastolic volumes were expelled from the model. Normalization of QRSd to LV dimension improves prediction of survival after CRT implantation. In addition, sex-specific differences in CRT outcome might be attributed to the higher QRSd/LV end-diastolic volumes ratio that was found in selected women, indicating more conduction delay.


Ex-situ catalytic pyrolysis of wastewater sewage sludge - A micro-pyrolysis study.
Concerns over increasing amounts of sewage sludge and unsustainability of current disposal methods have led to development of alternative routes for sludge management. The large amount of organics in sewage sludge makes it potential feedstock for energy or fuel production via thermochemical pathways. In this study, ex-situ catalytic pyrolysis using HZSM-5 catalyst was explored for the production of olefinic and aromatic hydrocarbons and nutrient-rich char from sewage sludge. The optimal pyrolysis and catalysis temperatures were found to be 500°C and 600°C, respectively. Carbon yields of hydrocarbons from sewage sludge were higher than for lignocellulose; yield differences were attributed to the high extractives content in the sludge. Full recovery of most inorganic elements were found in the char, which suggests that catalyst deactivation maybe alleviated through ex-situ catalytic pyrolysis. Most of the nitrogen was retained in the char while 31.80% was released as ammonia, which suggests a potential for nitrogen recycling.


A Delphi survey of leadership attributes necessary for national nurse leaders' participation in health policy development: an East African perspective.
Nurses' involvement in health policy development ensures that health services are: safe, effective, available and inexpensive. Nursing history reveals several legendary nurse leaders who have influenced policy and the course of nursing and health care. In the recent times there have been concerns regarding the availability of effective leaders physically, symbolically and functionally at clinical, organizational and national levels, who can effectively influence health policy. Exerting influence in the policy arena requires that nurse leaders acquire attributes that enable them to be effective in policy development activity. This paper reports part of a larger study whose purpose included: "build consensus on leadership attributes necessary for nurse leaders' participation in health policy development in East Africa". A Delphi survey was utilized and included the following criteria: expert panelists, three iterative rounds, qualitative and quantitative analysis, and building consensus. The study included purposively selected sample of national nurse leaders (expert panelists) from the three East African countries of Kenya, Tanzania and Uganda. The study was conducted in three iterative rounds. Seventy eight (78) expert panelists were invited to participate in the study and 37 (47%) participated in the first round of these; 24 (64.8%) participated in the second round and all invited in the third round 24 (100%) participated. Data collection was done using questionnaires and collected qualitative and quantitative data. Data analysis was done utilizing the principles of qualitative analysis in the first round and descriptive statistics in the second and third rounds. The study achieved consensus on the essential leadership attributes for nurse leaders' participation in health policy and include being able to: influence; communicate effectively; build relationships; feel empowered and demonstrate professional credibility. For nursing to participate in influencing the health policy and the health of the population, it will need to develop nurses with leadership attributes who are able to inspire change and influence the policy development process within the context where it exists. The leadership attributes identified in this study can be utilized to develop programmes geared to support nurses' participation in health policy activity.


Immunohistochemical localization, biochemical characterization, and biological activity of neurotensin in the frog adrenal gland.
The primary structure of neurotensin has been recently determined for the frog Rana ridibunda (Endocrinology 139: 4140-4146, 1998). In the present study, we have investigated the distribution and biochemical characterization of neurotensin-like immunoreactivity in the frog adrenal gland, using an antiserum directed against the conserved C-terminal region of the peptide. Neurotensin-like immunoreactivity was detected in two populations of nerve fibers: numerous varicose fibers coursing between adrenal cells, and a few processes located in the walls of blood vessels irrigating the gland. Reversed-phase HPLC analysis of frog adrenal gland extracts revealed the existence of a major peak of neurotensin-like immunoreactivity that exhibited the same retention time as synthetic frog neurotensin. The possible involvement of neurotensin in the regulation of steroid secretion was studied in vitro using perifused frog adrenal slices. For concentrations ranging from 10(-10) to 10(-5) M, synthetic frog neurotensin increased corticosterone and aldosterone production in a dose-dependent manner (EC50 = 1.2 x 10(-9) M and 5.8 x 10(-10) M, respectively). Repeated administration of neurotensin induced a reproducible stimulation of steroid output without any tachyphylaxis. Prolonged administration (3 h) of frog neurotensin caused a transient increase in corticosterone and aldosterone secretion followed by a decline of corticosteroid secretion. Neurotensin also produced a significant stimulation of corticosteroid secretion from dispersed frog adrenal cells. This study demonstrates that neurotensin is located in nerve processes innervating the adrenal gland of amphibians. The results also show that synthetic frog neurotensin exerts a direct stimulatory effect on corticosteroid output. Taken together, these data support the view that neurotensin, released by nerve fibers, may act as a local regulator of corticosteroid secretion.


Diabetes and Cause-Specific Mortality in Mexico City.
Most large, prospective studies of the effects of diabetes on mortality have focused on high-income countries where patients have access to reasonably good medical care and can receive treatments to establish and maintain good glycemic control. In those countries, diabetes less than doubles the rate of death from any cause. Few large, prospective studies have been conducted in middle-income countries where obesity and diabetes have become common and glycemic control may be poor. From 1998 through 2004, we recruited approximately 50,000 men and 100,000 women 35 years of age or older into a prospective study in Mexico City, Mexico. We recorded the presence or absence of previously diagnosed diabetes, obtained and stored blood samples, and tracked 12-year disease-specific deaths through January 1, 2014. We accepted diabetes as the underlying cause of death only for deaths that were due to acute diabetic crises. We estimated rate ratios for death among participants who had diabetes at recruitment versus those who did not have diabetes at recruitment; data from participants who had chronic diseases other than diabetes were excluded from the main analysis. At the time of recruitment, obesity was common and the prevalence of diabetes rose steeply with age (3% at 35 to 39 years of age and >20% by 60 years of age). Participants who had diabetes had poor glycemic control (mean [±SD] glycated hemoglobin level, 9.0±2.4%), and the rates of use of other vasoprotective medications were low (e.g., 30% of participants with diabetes were receiving antihypertensive medication at recruitment and 1% were receiving lipid-lowering medication). Previously diagnosed diabetes was associated with rate ratios for death from any cause of 5.4 (95% confidence interval [CI], 5.0 to 6.0) at 35 to 59 years of age, 3.1 (95% CI, 2.9 to 3.3) at 60 to 74 years of age, and 1.9 (95% CI, 1.8 to 2.1) at 75 to 84 years of age. Between 35 and 74 years of age, the excess mortality associated with previously diagnosed diabetes accounted for one third of all deaths; the largest absolute excess risks of death were from renal disease (rate ratio, 20.1; 95% CI, 17.2 to 23.4), cardiac disease (rate ratio, 3.7; 95% CI, 3.2 to 4.2), infection (rate ratio, 4.7; 95% CI, 4.0 to 5.5), acute diabetic crises (8% of all deaths among participants who had previously diagnosed diabetes), and other vascular disease (mainly stroke). Little association was observed between diabetes and mortality from cirrhosis, cancer, or chronic obstructive pulmonary disease. In this study in Mexico, a middle-income country with high levels of obesity, diabetes was common, glycemic control was poor, and diabetes was associated with a far worse prognosis than that seen in high-income countries; it accounted for at least one third of all deaths between 35 and 74 years of age. (Funded by the Wellcome Trust and others.).


The influence of gender and place of residence on cardiovascular diseases and their risk factors. The Isfahan cohort study.
To determine the impact of gender and place of residence on cardiovascular disease (CVD) events and related risk factors. In a prospective cohort study, 6323 participants free of CVD (3255 women), with age of more than 35 years from 3 cities (Isfahan, Najafabad, and Arak) and their rural districts in central Iran were followed-up from 2001 to 2007. This study was carried out at the Cardiovascular Research Institute of Isfahan University of Medical Sciences, Isfahan, Iran. Endpoints were defined as fatal- and nonfatal myocardial infarction, sudden cardiac death, unstable angina and stroke that constituted CVD events. Subjects in the rural area had significantly better risk factor profile in terms of most CVD risk factors in both genders, but it was reverse for low density lipoprotein (LDL)-cholesterol in both genders, and smoking in men. Except for smoking, men had an overall better risk factor profile compared to women. The age and risk factors adjusted hazard ratio of living in rural area was 0.71 (95% confidence interval [CI]: 0.51-0.99) for men, and 0.63 (95% CI: 0.44-0.91) for women. The age of CVD occurrence was similar in men and women, and in rural and urban areas. Hypertension was the strongest predictor of these events except for rural men showing that high LDL-cholesterol was the strongest risk factor. The findings in this study documented differences in CVD risk factors affecting the occurrence of CVD events according to gender and place of residence. Such differences should be taken into account in future preventive public health strategies for CVD prevention.


Development of a Cultural Awareness Scale for Occupational Therapy Students in Latin America: A Qualitative Delphi Study.
Cultural awareness is a key issue in healthcare worldwide. Valid and reliable assessments are needed to assess cultural awareness for occupational therapy students. The purpose of this study was to develop a scale to assess cultural awareness for Latin American occupational therapy students. A Delphi design was implemented considering four rounds with experts from four countries. A 30-item scale in Spanish was developed to assess three categories of items: personal, therapeutic strategies and persons' cultures. The experts highlighted local features for professional practice as a key aspect of the scale. Local differences in practice were considered with the profession's traditions and prevailing knowledge across the scale. A participatory strategy and an international group of experts enriched the cultural relevance. A subsequent study of statistical reliability is required (the scale is not presented in an extended version here). Further research should consider the application of the scale and strategies to improve cultural awareness across the curricula. Copyright © 2016 John Wiley & Sons, Ltd.


Resection of benign sciatic notch dumbbell-shaped tumors.
The operative management of combined intrapelvic and extrapelvic sciatic notch dumbbell-shaped tumors is challenging. The relatively rare occurrence of these tumors and the varied extent of disease have made it difficult for surgeons to establish definitive surgical indications or predict favorable neurological outcomes based on preoperative imaging data. In the past 3 years, the authors treated five patients presenting with radiating leg pain as a result of benign sciatic notch dumbbell-shaped tumors. These tumors in three patients with unilateral leg symptoms were considered unresectable by other neurosurgeons because of presumed direct intrinsic neural involvement. After high-resolution magnetic resonance (MR) imaging demonstrated that the extensive tumors were separate from the sciatic nerve and the lumbosacral plexus, however, these patients underwent a combined one-stage transabdominal and posterior transgluteal complete resection. Normal neurological status was maintained postoperatively in these three patients, and after more than 1 year of postoperative follow up, there were no tumor recurrences. In two patients with bilateral symptoms and extensive tumor burden, serial MR images showed that innumerable tumors directly involved the entire cross-sectional area of the sciatic nerves and extended longitudinally to the lumbosacral plexuses. Tumor debulking or resection in these patients would have resulted in neurological deficits and would not have addressed their neuropathic pain, and therefore no surgery was performed. These two patients were treated pharmacologically and advised to monitor their tumor status over the course of their lifetimes in case of malignant transformation of the tumor. A combined one-stage transabdominal and transgluteal approach allows safe resection of selected benign but extensive sciatic notch tumors. High-resolution MR imaging is a useful tool in the management of these tumors because it allows the surgeon to visualize the anatomical relationships of the tumor to the sciatic nerve. The authors believe that as this imaging technology advances, it will provide surgeons with a method to predict definitively which sciatic notch tumors displace rather than directly involve the sciatic nerve, and therefore indicate which tumors can be resected safely and completely.


Polymorphisms and methylation of the reduced folate carrier in osteosarcoma.
High-dose methotrexate is a standard component in the treatment of osteogenic sarcoma. Impaired methotrexate uptake associated with decreased reduced folate carrier expression is a common mechanism of methotrexate resistance in osteogenic sarcoma samples. We investigated whether promoter methylation and polymorphisms in the 3' untranslated region are involved in regulating reduced folate carrier expression. In a cohort of 66 osteogenic sarcoma specimens, quantitative methylation-specific polymerase chain reaction and single-strand conformation polymorphism were performed. We found detectable levels of promoter methylation in 84.3% of samples. When related to the reduced folate carrier mRNA levels, a trend was observed that reduced folate carrier expression is lower in samples (median, 0.7) with greater than 10% DNA methylation as compared with those (median, 2.3) with less than 10% DNA methylation. The heterozygous polymorphisms of 2582 T/G and 2617C/T in the 3' untranslated region showed reduced folate carrier expression (median, 0.9) as compared with the wild-type 2582T and 2617C (median, 4.2). The data suggest promoter methylation and polymorphisms in the 3' untranslated region of the reduced folate carrier may be involved in its transcriptional regulation in osteogenic sarcoma. Further study is required to confirm this finding.


Characterization of Fatty Acid Composition in Bone Marrow Fluid From Postmenopausal Women: Modification After Hip Fracture.
Bone marrow adipose tissue (BMAT) is associated with low bone mass, although the functional consequences for skeletal maintenance of increased BMAT are currently unclear. BMAT might have a role in systemic energy metabolism, and could be an energy source as well as an endocrine organ for neighboring bone cells, releasing cytokines, adipokines and free fatty acids into the bone marrow microenvironment. The aim of the present report was to compare the fatty acid composition in the bone marrow supernatant fluid (BMSF) and blood plasma of postmenopausal women women (65-80 years old). BMSF was obtained after spinning the aspirated bone marrow samples; donors were classified as control, osteopenic or osteoporotic after dual-energy X-ray absorptiometry. Total lipids from human bone marrow fluid and plasma were extracted, converted to the corresponding methyl esters, and finally analyzed by a gas chromatographer coupled with a mass spectrometer. Results showed that fatty acid composition in BMSF was dynamic and distinct from blood plasma, implying significance in the locally produced lipids. The fatty acid composition in the BMSF was enriched in saturated fatty acid and decreased in unsaturated fatty acids as compared to blood plasma, but this relationship switched in women who suffered a hip fracture. On the other hand, there was no relationship between BMSF and bone mineral density. In conclusion, lipid composition of BMSF is distinct from the circulatory compartment, most likely reflecting the energy needs of the marrow compartment. J. Cell. Biochem. 117: 2370-2376, 2016. © 2016 Wiley Periodicals, Inc.


Mapping the antigenic and genetic evolution of influenza virus.
The antigenic evolution of influenza A (H3N2) virus was quantified and visualized from its introduction into humans in 1968 to 2003. Although there was remarkable correspondence between antigenic and genetic evolution, significant differences were observed: Antigenic evolution was more punctuated than genetic evolution, and genetic change sometimes had a disproportionately large antigenic effect. The method readily allows monitoring of antigenic differences among vaccine and circulating strains and thus estimation of the effects of vaccination. Further, this approach offers a route to predicting the relative success of emerging strains, which could be achieved by quantifying the combined effects of population level immune escape and viral fitness on strain evolution.


Impact of Learning to Read in a Mixed Approach on Neural Tuning to Words in Beginning Readers.
The impact of learning to read in a mixed approach using both the global and phonics teaching methods on the emergence of left hemisphere neural specialization for word recognition is yet unknown in children. Taking advantage of a natural school context with such a mixed approach, we tested 42 first graders behaviorally and with Fast Periodic Visual Stimulation using electroencephalographic recordings (FPVS-EEG) to measure selective neural responses to letter strings. Letter strings were inserted periodically (1/5) in pseudofonts in 40 s sequences displayed at 6 Hz and were either words globally taught at school, that could therefore be processed by visual whole-word form recognition (global method), or control words/pseudowords eliciting grapheme-phoneme (GP) mappings (phonics method). Results show that selective responses (F/5, 1.2 Hz) were left lateralized for control stimuli that triggered GP mappings but bilateral for globally taught words. It implies that neural mechanisms recruited during visual word processing are influenced by the nature of the mapping between written and spoken word forms. GP mappings induce left hemisphere discrimination responses, and visual recognition of whole-word forms induce bilateral responses, probably because the right hemisphere is relatively more involved in holistic visual object recognition. Splitting the group as a function of the mastery of GP mappings into "good" and "poor" readers strongly suggests that good readers actually processed all stimuli (including global words) predominantly with their left hemisphere, while poor readers showed bilateral responses for global words. These results show that in a mixed approach of teaching to read, global method instruction may induce neural processes that differ from those specialized for reading in the left hemisphere. Furthermore, given their difficulties in automatizing GP mappings, poor readers are especially prone to rely on this alternative visual strategy. A preprint of this paper has been released on Biorxiv (van de Walle de Ghelcke et al., 2018).


Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review.
To assess the use of extracorporeal cardiopulmonary resuscitation (ECPR), compared with manual or mechanical cardiopulmonary resuscitation (CPR), for out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) in adults and children. The PRISMA guidelines were followed. We searched Medline, Embase, and Evidence-Based Medicine Reviews for randomized clinical trials and observational studies published before May 22, 2018. The population included adult and pediatric patients with OHCA and IHCA of any origin. Two investigators reviewed studies for relevance, extracted data, and assessed risk of bias using the ROBINS-I tool. Outcomes included short-term and long-term survival and favorable neurological outcome. We included 25 observational studies, of which 15 studies were in adult OHCA, 7 studies were in adult IHCA, and 3 studies were in pediatric IHCA. There were no studies in pediatric OHCA. No randomized trials were included. Results from individual studies were largely inconsistent, although several studies in adult and pediatric IHCA were in favor of ECPR. The risk of bias for individual studies was overall assessed to be critical, with confounding being the primary source of bias. The overall quality of evidence was assessed to be very low. Heterogeneity across studies precluded any meaningful meta-analyses. There is inconclusive evidence to either support or refute the use of ECPR for OHCA and IHCA in adults and children. The quality of evidence across studies is very low.


Actinides and decay products in selected produce and bioindicators in the vicinity of a uranium plant.
Cypress needles collected at the edge of the Malvési uranium facility (SW France) exhibit enhanced activities of actinides and some decay products (uranium, americium, plutonium, (230)Th, (226)Ra) compared to a remote site. These enhanced activities resulted from the release of U via smokestacks and passive release from former artificial ponds located inside the nuclear site. Enhanced activities are also observed in selected produce (wheat, lettuce, fruits) sampled from the edge of the site. However, excess actinides measured in wheat grains in 2007 are inconsistent with the activities and the uranium ratio measured in the soils. This result suggests that the studied annual crops were contaminated mainly through the short-term release of airborne actinides, and that other transfer pathways, such as, uptake through the roots or adhesion of soil particles, were negligible.


Modulation of long-term potentiation-like cortical plasticity in the healthy brain with low frequency-pulsed electromagnetic fields.
Non-depolarizing magnetic fields, like low frequency-pulsed electromagnetic fields (LF-PEMFs) have shown the ability to modulate living structures, principally by influencing synaptic activity and ion channels on cellular membranes. Recently, the CTU Mega 20 device was presented as a molecular accelerator, using energy up to 200 J and providing high-power (2 Tesla) pulsating fields with a water-repulsive (diamagnetic) action and tissue biostimulation. We tested the hypothesis that LF-PEMFs could modulate long-term corticospinal excitability in healthy brains by applying CTU Mega 20®. Ten healthy subjects without known neurological and/or psychiatric diseases entered the study. A randomized double-blind sham-controlled crossover design was employed, recording TMS parameters (amplitude variation of the motor evoked potential as index of cortical excitability perturbations of the motor system) before (pre) and after (post + 0, + 15, + 30 min) a single CTU Mega 20 session on the corresponding primary right-hand motor area, using a real (magnetic field = 2 Tesla; intensity = 90 J; impulse frequency = 7 Hz; duration = 15 min) or sham device. A two-way repeated measures ANOVA with TIME (pre, post + 0, + 15, + 30 min) and TREATMENT (real vs. sham stimulation) as within-subjects factor was applied. A significant TIME × TREATMENT interaction was found (p < 0.001). Post hoc comparisons showed a significant effect of TIME, with significant differences at + 0, + 15 and + 30 min compared to baseline after real stimulation (all p < 0.05) but not after sham stimulation (all p < 0.05) and significant effects of TREATMENT, with significant differences at + 0, + 15 and + 30 min for real stimulation compared to sham stimulation (all p < 0.005). No significant depolarizing effects were detected throughout the (real) stimulation. Our proof-of-concept study in healthy subjects supports the idea that non-ionizing LF-PEMFs induced by the CTU Mega 20 diamagnetic acceleration system could represent a new approach for brain neuromodulation. Further studies to optimize protocol parameters for different neurological and psychiatric conditions are warranted. Trial Registration The present work has been retrospectively registered as clinical trial on ClinicalTrials.gov NCT03537469 and publicly released on May 24, 2018.


Influenza vaccination for healthcare workers who care for people aged 60 or older living in long-term care institutions.
Healthcare workers' influenza rates are unknown but may be similar to those of the general public. Healthcare workers may transmit influenza to patients. To identify all randomised controlled trials (RCTs) and non-RCTs assessing the effects of vaccinating healthcare workers on the incidence of laboratory-proven influenza, pneumonia, death from pneumonia and admission to hospital for respiratory illness in those aged 60 years or older resident in long-term care institutions (LTCIs). We searched CENTRAL 2013, Issue 2, MEDLINE (1966 to March week 3, 2013), EMBASE (1974 to March 2013), Biological Abstracts (1969 to March 2013), Science Citation Index-Expanded (1974 to March 2013) and Web of Science (2006 to March 2013). Randomised controlled trials (RCTs) and non-RCTs of influenza vaccination of healthcare workers caring for individuals aged 60 years or older in LTCIs and the incidence of laboratory-proven influenza and its complications (lower respiratory tract infection, or hospitalisation or death due to lower respiratory tract infection) in individuals aged 60 years or older in LTCIs. Two authors independently extracted data and assessed risk of bias. We identified four cluster-RCTs (C-RCTs) (n = 7558) and one cohort study (n = 12,742) of influenza vaccination for HCWs caring for individuals ≥ 60 years in LTCFs. Three RCTs (5896 participants) provided outcome data that met our criteria. These three studies were comparable in study populations, intervention and outcome measures. The studies did not report adverse events. The principal sources of bias in the studies related to attrition and blinding. The pooled risk difference (RD) from the three cluster-RCTs for laboratory-proven influenza was 0 (95% confidence interval (CI) -0.03 to 0.03) and for hospitalisation was RD 0 (95% CI -0.02 to 0.02). The estimated risk of death due to lower respiratory tract infection was also imprecise (RD -0.02, 95% CI -0.06 to 0.02) in individuals aged 60 years or older in LTCIs. Adjusted analyses which took into account the cluster design did not differ substantively from the pooled analysis with unadjusted data. The results for specific outcomes: laboratory-proven influenza or its complications (lower respiratory tract infection, or hospitalisation or death due to lower respiratory tract illness) did not identify a benefit of healthcare worker vaccination on these key outcomes. This review did not find information on co-interventions with healthcare worker vaccination: hand-washing, face masks, early detection of laboratory-proven influenza, quarantine, avoiding admissions, antivirals and asking healthcare workers with influenza or influenza-like-illness (ILI) not to work. This review does not provide reasonable evidence to support the vaccination of healthcare workers to prevent influenza in those aged 60 years or older resident in LTCIs. High-quality RCTs are required to avoid the risks of bias in methodology and conduct identified by this review and to test further these interventions in combination.


Measuring broader wellbeing in mental health services: validity of the German language OxCAP-MH capability instrument.
The OxCAP-MH capabilities questionnaire was developed and validated in the UK for outcome measurement in mental health clinical studies. Its broader wellbeing construct or validity in routine mental health services so far has not been assessed. The objectives were to investigate the extent the OxCAP-MH measures broader wellbeing compared to the EQ-5D-5L and to test psychometric properties of the German language OxCAP-MH in routine mental health services in Austria. Study sample consisted of patients in socio-psychiatric services (n = 159) assessed at baseline and 6-month follow-up. Underlying factors associated with quality-of-life/wellbeing concepts measured by the OxCAP-MH and EQ-5D-5L were identified in exploratory factor analysis (EFA). Responsiveness was assessed using anchor questionnaires and standardised response mean (SRM). For discriminant validity, subgroups of respondents were compared using t test and one-way ANOVA. Test-retest analysis was assessed for a period of maximum 30 days from the baseline assessment with intra-class correlation coefficient (ICC). EFA identified a two-factor structure. All EQ-5D-5L items and seven OxCAP-MH items loaded on one factor and nine remaining OxCAP-MH items loaded on a separate factor. Responsiveness was found for patients who improved in anchor questionnaire scores with large or moderate SRM statistics. OxCAP-MH discriminated between various groups in univariable and multivariable analyses. Reliability of the German language OxCAP-MH was confirmed by ICC of 0.80. Besides providing evidence that the OxCAP-MH measures broader wellbeing constructs beyond traditional health-related quality of life, the study also confirms the validity of the instrument for implementation in routine evaluation of mental health services.


Genetic evidence that Drosophila frizzled controls planar cell polarity and Armadillo signaling by a common mechanism.
The frizzled (fz) gene in Drosophila controls two distinct signaling pathways: it directs the planar cell polarization (PCP) of epithelia and it regulates cell fate decisions through Armadillo (Arm) by acting as a receptor for the Wnt protein Wingless (Wg). With the exception of dishevelled (dsh), the genes functioning in these two pathways are distinct. We have taken a genetic approach, based on a series of new and existing fz alleles, for identifying individual amino acids required for PCP or Arm signaling. For each allele, we have attempted to quantify the strength of signaling by phenotypic measurements. For PCP signaling, the defect was measured by counting the number of cells secreting multiple hairs in the wing. We then examined each allele for its ability to participate in Arm signaling by the rescue of fz mutant embryos with maternally provided fz function. For both PCP and Arm signaling we observed a broad range of phenotypes, but for every allele there is a strong correlation between its phenotypic strength in each pathway. Therefore, even though the PCP and Arm signaling pathways are genetically distinct, the set of signaling-defective fz alleles affected both pathways to a similar extent. This suggests that fz controls these two different signaling activities by a common mechanism. In addition, this screen yielded a set of missense mutations that identify amino acids specifically required for fz signaling function.


Clinical and toxicological consequences of the inductive potential of ethanol.
Variability in drug metabolism is an important factor that accounts for individual responsiveness to xenobiotics. Enzyme induction which leads to a more rapid elimination of foreign compounds and to a more extensive formation of potentially active metabolites significantly contributes to large interindividual variability in drug effects. Ethanol is consumed worldwide in tremendous amounts and is an effective inducer of hepatic drug metabolism, especially involving pathways accomplished by the CYP2E1 isoform of the cytochrome P-450 (CYP) superfamily. Therefore, whenever xenobiotics that are substrates of CYP2E1, such as chlorzoxazone, paracetamol (acetaminophen), halothane, enflurane, methoxyflurane, sevoflurane and many organic solvents (e.g. aniline, trichloroethylene), are taken by an individual who is also chronically consuming ethanol, the accelerated metabolism of these agents and their clinical impact (e.g. decrease in drug activity) and toxicological impact (accumulation of active metabolites) have to be considered. Consequently, in the assessment of drug disposition and action the history of ethanol intake should be carefully evaluated.


Contractile and elastic ankle joint muscular properties in young and older adults.
The purpose of this study was to investigate age-related differences in contractile and elastic properties of both dorsi- (DF) and plantarflexor (PF) muscles controlling the ankle joint in young and older adults. Experimental data were collected while twelve young and twelve older male and female participants performed maximal effort isometric and isovelocity contractions on a dynamometer. Equations were fit to the data to give torque-angle (Tθ) and torque-angular velocity (Tω) relations. Muscle series-elasticity was measured during ramped dynamometer contractions using ultrasonography to measure aponeurosis extension as a function of torque; second order polynomials were used to characterize the torque-extension (TΔL) relation. The results showed no age differences in DF maximal torque and none for female PF; however, older males had smaller maximal PF torques compared to young males. In both muscle groups and genders, older adults had decreased concentric force capabilities. Both DF and PF TΔL relations were more nonlinear in the older adults. Older PF, but not DF muscles, were stiffer compared to young. A simple antagonism model suggested age-related differences in Tθ and Tω relations would be magnified if antagonistic torque contributions were included. This assessment of static, dynamic, and elastic joint properties affords a comprehensive view of age-related modifications in muscle function. Although many clinical studies use maximal isometric strength as a marker of functional ability, the results demonstrate that there are also significant age-related modifications in ankle muscle dynamic and elastic properties.


Measurement training and feedback system for implementation of evidence-based treatment for adolescent externalizing problems: protocol for a randomized trial of pragmatic clinician training.
Innovations in clinical training and support that enhance fidelity to evidence-based treatment (EBT) for adolescent behavior problems are sorely needed. This study will develop an online training system to address this gap: Measurement Training and Feedback System for Implementation (MTFS-I). Using procedures intended to be practical and sustainable, MTFS-I is designed to increase two aspects of therapist behavior that are fundamental to boosting EBT fidelity: therapist self-monitoring of EBT delivery, and therapist utilization of core techniques of EBTs in treatment sessions. This version of MTFS-I focuses on two empirically supported treatment approaches for adolescent conduct and substance use problems: family therapy and cognitive behavioral therapy (CBT). MTFS-I expands on conventional measurement feedback systems for client outcomes by adding training in observational coding to promote EBT self-monitoring and focusing on implementation of EBT treatment techniques. It has two primary components. (1) The training component, delivered weekly in two connected parts, involves self-monitored learning modules containing brief clinical descriptions of core EBT techniques and mock session coding exercises based on 5-8 min video segments that illustrate delivery of core techniques. (2) The feedback component summarizes aggregated therapist-reported data on EBT techniques used with their active caseloads. MTFS-I is hosted online and requires approximately 20 min per week to complete for each treatment approach. This randomized trial will first collect data on existing delivery of family therapy and CBT techniques for youth in outpatient behavioral health sites (Baseline phase). It will then randomize site clinicians to two study conditions (Implementation phase): Training Only versus Training + Feedback + Consultation. Therapists will choose whether to train in family therapy, CBT, or both. Study aims will compare clinician performance across study phase and between study conditions on MTFS-I uptake, reliability and accuracy in EBT self-monitoring, and utilization of EBT techniques in treatment sessions (based on observer coding of audiotapes). Study contributions to implementation science and considerations of MTFS-I sustainability are discussed. ClinicalTrials.gov, NCT03722654. Registered on 29 October 2018.


Oral Dysbiosis in Pancreatic Cancer and Liver Cirrhosis: A Review of the Literature.
The human body is naturally colonized by a huge number of different commensal microbial species, in a relatively stable equilibrium. When this microbial community undergoes dysbiosis at any part of the body, it interacts with the innate immune system and results in a poor health status, locally or systemically. Research studies show that bacteria are capable of significantly influencing specific cells of the immune system, resulting in many diseases, including a neoplastic response. Amongst the multiple different types of diseases, pancreatic cancer and liver cirrhosis were significantly considered in this paper, as they are major fatal diseases. Recently, these two diseases were shown to be associated with increased or decreased numbers of certain oral bacterial species. These findings open the way for a broader perception and more specific investigative studies, to better understand the possible future treatment and prevention. This review aims to describe the correlation between oral dysbiosis and both pancreatic cancer and liver cirrhotic diseases, as well as demonstrating the possible diagnostic and treatment modalities, relying on the oral microbiota, itself, as prospective, simple, applicable non-invasive approaches to patients, by focusing on the state of the art. PubMed was electronically searched, using the following key words: "oral microbiota" and "pancreatic cancer" (PC), "liver cirrhosis", "systemic involvement", and "inflammatory mediators". Oral dysbiosis is a common problem related to poor oral or systemic health conditions. Oral pathogens can disseminate to distant body organs via the local, oral blood circulation, or pass through the gastrointestinal tract and enter into the systemic circulation. Once oral pathogens reach an organ, they modify the immune response and stimulate the release of the inflammatory mediators, this results in a disease. Recent studies have reported a correlation between oral dysbiosis and the increased risk of pancreatic and liver diseases and provided evidence of the presence of oral pathogens in diseased organs. The profound impact that microbial communities have on human health, provides a wide domain towards precisely investigating and clearly understanding the mechanism of many diseases, including cancer. Oral microbiota is an essential contributor to health status and imbalance in this community was correlated to oral and systemic diseases. The presence of elevated numbers of certain oral bacteria, particularly P. gingivalis, as well as elevated levels of blood serum antibodies, against this bacterial species, was associated with a higher risk of pancreatic cancer and liver cirrhosis incidence. Attempts are increasingly directed towards investigating the composition of oral microbiome as a simple diagnostic approach in multiple diseases, including pancreatic and liver pathosis. Moreover, treatment efforts are concerned in the recruitment of microbiota, for remedial purposes of the aforementioned and other different diseases. Further investigation is required to confirm and clarify the role of oral microbiota in enhancing pancreatic and liver diseases. Improving the treatment modalities requires an exertion of more effort, especially, concerning the microbiome engineering and oral microbiota transplantation.


Repression of anti-proliferative factor Tob1 in osteoarthritic cartilage.
Osteoarthritis is the most common degenerative disorder of the modern world. However, many basic cellular features and molecular processes of the disease are poorly understood. In the present study we used oligonucleotide-based microarray analysis of genes of known or assumed relevance to the cellular phenotype to screen for relevant differences in gene expression between normal and osteoarthritic chondrocytes. Custom made oligonucleotide DNA arrays were used to screen for differentially expressed genes in normal (n = 9) and osteoarthritic (n = 10) cartilage samples. Real-time polymerase chain reaction (PCR) with gene-specific primers was used for quantification. Primary human adult articular chondrocytes and chondrosarcoma cell line HCS-2/8 were used to study changes in gene expression levels after stimulation with interleukin-1beta and bone morphogenetic protein, as well as the dependence on cell differentiation. In situ hybridization with a gene-specific probe was applied to detect mRNA expression levels in fetal growth plate cartilage. Overall, more than 200 significantly regulated genes were detected between normal and osteoarthritic cartilage (P < 0.01). One of the significantly repressed genes, Tob1, encodes a protein belonging to a family involved in silencing cells in terms of proliferation and functional activity. The repression of Tob1 was confirmed by quantitative PCR and correlated to markers of chondrocyte activity and proliferation in vivo. Tob1 expression was also detected at a decreased level in isolated chondrocytes and in the chondrosarcoma cell line HCS-2/8. Again, in these cells it was negatively correlated with proliferative activity and positively with cellular differentiation. Altogether, the downregulation of the expression of Tob1 in osteoarthritic chondrocytes might be an important aspect of the cellular processes taking place during osteoarthritic cartilage degeneration. Activation, the reinitiation of proliferative activity and the loss of a stable phenotype are three major changes in osteoarthritic chondrocytes that are highly significantly correlated with the repression of Tob1 expression.


Selective influence of Sox2 on POU transcription factor binding in embryonic and neural stem cells.
Embryonic stem cell (ESC) identity is orchestrated by co-operativity between the transcription factors (TFs) Sox2 and the class V POU-TF Oct4 at composite Sox/Oct motifs. Neural stem cells (NSCs) lack Oct4 but express Sox2 and class III POU-TFs Oct6, Brn1 and Brn2. This raises the question of how Sox2 interacts with POU-TFs to transcriptionally specify ESCs versus NSCs. Here, we show that Oct4 alone binds the Sox/Oct motif and the octamer-containing palindromic MORE equally well. Sox2 binding selectively increases the affinity of Oct4 for the Sox/Oct motif. In contrast, Oct6 binds preferentially to MORE and is unaffected by Sox2. ChIP-Seq in NSCs shows the MORE to be the most enriched motif for class III POU-TFs, including MORE subtypes, and that the Sox/Oct motif is not enriched. These results suggest that in NSCs, co-operativity between Sox2 and class III POU-TFs may not occur and that POU-TF-driven transcription uses predominantly the MORE cis architecture. Thus, distinct interactions between Sox2 and POU-TF subclasses distinguish pluripotent ESCs from multipotent NSCs, providing molecular insight into how Oct4 alone can convert NSCs to pluripotency.


Exploration of Factors Related to Depressive Symptomatology in Family Members of Military Veterans With Traumatic Brain Injury.
Traumatic brain injury (TBI) is a family affair, affecting those with the injury and their families. Psychological distress, often measured as depression or depressive symptoms, is highly prevalent among family members. Predictors of depression in family members of civilians with TBI have been examined, but predictors of depression in family members of military veterans have received very little research attention and are poorly understood. To address the knowledge gap, this study explored factors related to depressive symptoms in family members of veterans in the United States, using an ecological framework. Baseline data from 83 family members were used. Family members with higher caregiver burden, presence of a veteran with posttraumatic stress disorder (PTSD), and greater financial difficulty experienced significantly more depressive symptoms. Findings suggest that efforts to support family members and decrease their depression should aim to reduce caregiver burden and financial difficulty, and help family members cope with veteran PTSD and TBI. Family-focused interventions are needed.


Molecular dynamics of a food carcinogen-DNA adduct in a replicative DNA polymerase suggest hindered nucleotide incorporation and extension.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant of the carcinogenic heterocyclic aromatic amines in the human diet, and the major mutagenic effect of dietary PhIP is G-->T transversions. The major PhIP-derived DNA adduct is to C8 of guanine. We have investigated this adduct in a PhIP-induced mutational hotspot 5'-GGGA-3' of the Apc tumor suppressor gene, frequently mutated in mammalian colon tumors. We have carried out a molecular dynamics study to elucidate on a structural level nucleotide incorporation and extension opposite this major adduct during replication. The PhIP adduct was modeled into the ternary complex closed conformation of DNA polymerase RB69, at incorporation and extension positions, with normal cytosine or mismatched partner adenine. RB69 polymerase is a member of the B family as are most replicative eukaryotic DNA polymerases such as DNA polymerase alpha. These systems were subjected to molecular dynamics simulations with AMBER. Our results show that the adduct can reside on the major groove side of the modified DNA template opposite an incoming dCTP or dATP. In the case of the normal partner, disturbance to the active site is observed at the incorporation step, but there is less perturbance in the extension simulation. In the case of the mismatched partner, a less disturbed active site is observed during the incorporation step, but extension appears to be more difficult. Disturbances include adverse impacts on Watson-Crick hydrogen bonding in the nascent base pair, on the distance between the alpha-phosphate of the incoming dNTP and the primer terminus 3'-OH, and on critical protein interactions with the dNTP. However, in all of these cases, a near reaction ready distance (within 3.5 angstroms) between the 3'-terminal oxygen of the primer and the Palpha of the incoming nucleotide triphosphate is sampled occasionally (0.4-23.5% of the time). Thus, error-free bypass or the induction of a G-->T transversion mutation could occur at times and contribute to an extent to the mutagenic effect of PhIP. Polymerase stalling would be the more common outcome and in vivo could lead to switch to an error-prone bypass polymerase.


Chunked Bounding Volume Hierarchies for Fast Digital Prototyping Using Volumetric Meshes.
We present a novel approach to using Bounding Volume Hierarchies (BVHs) for collision detection of volumetric meshes for digital prototyping based on accurate simulation. In general, volumetric meshes contain more primitives than surface meshes, which in turn means larger BVHs. To manage these larger BVHs, we propose an algorithm for splitting meshes into smaller chunks with a limited-size BVH each. Limited-height BVHs make guided, all-pairs testing of two chunked meshes well-suited for GPU implementation. This is because the dynamically generated work during BVH traversal becomes bounded. Chunking is simple to implement compared to dynamic load balancing methods and can result in an overall two orders of magnitude speedup on GPUs. This indicates that dynamic load balancing may not be a well suited scheme for the GPU. The overall application timings showed that data transfers were not the bottleneck. Instead, the conversion to and from OpenCL friendly data structures was causing serious performance impediments. Still, a simple OpenMP acceleration of the conversion allowed the GPU solution to beat the CPU solution by 20 percent. We demonstrate our results using rigid and deformable body scenes of varying complexities on a variety of GPUs.


The DnaX-binding subunits delta' and psi are bound to gamma and not tau in the DNA polymerase III holoenzyme.
The DnaX complex subassembly of the DNA polymerase III holoenzyme is comprised of the DnaX proteins tau and gamma and the auxiliary subunits delta, delta', chi, and psi, which together load the beta processivity factor onto primed DNA in an ATP-dependent reaction. delta' and psi bind directly to DnaX whereas delta and chi bind to delta' and psi, respectively (Onrust, R., Finkelstein, J., Naktinis, V., Turner, J., Fang, L., and O'Donnell, M. (1995) J. Biol. Chem. 270, 13348-13357). Until now, it has been unclear which DnaX protein, tau or gamma, in holoenzyme binds the auxiliary subunits delta, delta', chi,and psi. Treatment of purified holoenzyme with the homobifunctional cross-linker bis(sulfosuccinimidyl)suberate produces covalently cross-linked gamma-delta' and gamma-psi complexes identified by Western blot analysis. Immunodetection of cross-linked species with anti-delta' and anti-psi antibodies revealed that no tau-delta' or tau-psi cross-links had formed, suggesting that the delta' and psi subunits reside only on gamma within holoenzyme.


Metabolic network fluxes in heterotrophic Arabidopsis cells: stability of the flux distribution under different oxygenation conditions.
Steady-state labeling experiments with [1-(13)C]Glc were used to measure multiple metabolic fluxes through the pathways of central metabolism in a heterotrophic cell suspension culture of Arabidopsis (Arabidopsis thaliana). The protocol was based on in silico modeling to establish the optimal labeled precursor, validation of the isotopic and metabolic steady state, extensive nuclear magnetic resonance analysis of the redistribution of label into soluble metabolites, starch, and protein, and a comprehensive set of biomass measurements. Following a simple modification of the cell culture procedure, cells were grown at two oxygen concentrations, and flux maps of central metabolism were constructed on the basis of replicated experiments and rigorous statistical analysis. Increased growth rate at the higher O(2) concentration was associated with an increase in fluxes throughout the network, and this was achieved without any significant change in relative fluxes despite differences in the metabolite profile of organic acids, amino acids, and carbohydrates. The balance between biosynthesis and respiration within the tricarboxylic acid cycle was unchanged, with 38% +/- 5% of carbon entering used for biosynthesis under standard O(2) conditions and 33% +/- 2% under elevated O(2). These results add to the emerging picture of the stability of the central metabolic network and its capacity to respond to physiological perturbations with the minimum of rearrangement. The lack of correlation between the change in metabolite profile, which implied significant disruption of the metabolic network following the alteration in the oxygen supply, and the unchanging flux distribution highlights a potential difficulty in the interpretation of metabolomic data.


Effect of Body Mass Index on the Outcome of In-Vitro Fertilization/Intracytoplasmic Sperm Injection in Women.
Obesity, a known epidemic, is a leading cause of various reproductive disorders. Association of body mass index (BMI) with pregnancy outcomes, either ovarian or endometrial, is controversial and least elucidated. This study aimed to analyze the effect of BMI on in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcome in women using self-oocytes, embryos prepared from donor oocytes (DE), or vitrified/frozen embryos (VE) obtained from both the SE and DE groups. A 9-month retrospective study was conducted on women undergoing IVF/ICSI. The women were grouped according to the World Health Organization classification of BMI (<18.50, 18.50-24.99, 25.00-29.99, and ≥30.00 kg/m2). They were further subcategorized as SE, DE, and VE groups. Ongoing pregnancy rate (OPR) was recorded as primary, whereas pregnancy rate (PR), clinical PR (CPR), implantation rate (IR), and clinical abortion rate (CAR) were secondary endpoints. Age, number of mature eggs, usable embryos, and embryos transferred were also measured. The data were statistically analyzed using chi-square and analysis of variance. P-value <0.05 was considered statistically significant. OPR was statistically insignificant across all the groups. Secondary outcomes were statistically insignificant in all the groups except in VE, where IR (P = 0.008) and CAR (P = 0.0002) were statically significant. Other parameters were statistically insignificant among all the groups. However, in the SE and VE groups, the mean age was statistically significant (SE, P = 0.0001; VE, P = 0.0191). This study showed marginal/no effect of BMI on oocyte quality/endometrial receptivity and, subsequently, on the pregnancy outcome. However, well-designed, larger prospective studies are needed to clarify the role of BMI in pregnancy outcome in women undergoing IVF/ICSI.


Particulated Juvenile Articular Cartilage Allograft for Treatment of Chondral Defects of the Knee: Short-Term Survivorship with Functional Outcomes.
While basic science research confirms the robust biological profile of juvenile chondrocytes, the clinical outcomes after particulated juvenile cartilage allograft transplantation are not well established. A retrospective analysis of active duty servicemembers undergoing surgical treatment with particulated juvenile articular cartilage allograft transplantation for chondral defects of the knee from two military treatment facilities was completed. Demographic variables, operative details, activity limitations, and medical discharges were obtained. A total of 29 patients with 36 treated chondral defects were isolated at an average follow-up of 16.2 months. The cohort was comprised of male service members in the Army with mean age of 33.1 years. Location of chondral lesion included the patellofemoral articulation (patella 39%, trochlea 31%, bipolar lesions 8%) and condyles (31%). Offloading or realignment osteotomy procedures were performed in 7 patients (23%). Of all patients, 14 servicemembers (48%) underwent knee-related medical discharge, and one patient underwent conversion to total knee arthroplasty. In this small patient cohort, particulated juvenile cartilage allograft transplantation for chondral defects of the knee did not reliably restore military servicemembers to full military function. At least one in two patients had persisting knee pain after chondral restoration procedure. (Journal of Surgical Orthopaedic Advances 30(1):010-013, 2021).


CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes.
The genetic interrogation and reprogramming of cells requires methods for robust and precise targeting of genes for expression or repression. The CRISPR-associated catalytically inactive dCas9 protein offers a general platform for RNA-guided DNA targeting. Here, we show that fusion of dCas9 to effector domains with distinct regulatory functions enables stable and efficient transcriptional repression or activation in human and yeast cells, with the site of delivery determined solely by a coexpressed short guide (sg)RNA. Coupling of dCas9 to a transcriptional repressor domain can robustly silence expression of multiple endogenous genes. RNA-seq analysis indicates that CRISPR interference (CRISPRi)-mediated transcriptional repression is highly specific. Our results establish that the CRISPR system can be used as a modular and flexible DNA-binding platform for the recruitment of proteins to a target DNA sequence, revealing the potential of CRISPRi as a general tool for the precise regulation of gene expression in eukaryotic cells.


Plasma histamine in patients with chronic renal failure and nephrotic syndrome.
Plasma histamine concentrations were measured using a commercially available monoclonal antibody radioimmunoassay in 38 patients with nephrotic syndrome, end stage renal failure, those receiving haemodialysis, and those receiving continuous ambulatory peritoneal dialysis to determine whether histamine may mediate damage to glomerular capillaries and arterial endothelium. Plasma histamine concentrations were significantly increased in all four patient groups when compared with those of controls and were the highest in two patients with pruritus. Raised plasma histamine concentrations in such patients are consistent with the hypothesis that histamine may contribute to the damage to glomerular capillaries and to arterial endothelium. These effects may be relevant to the pathogenesis of glomerular disease and atherosclerosis. Histamine may also contribute to the pathogenesis of pruritus in patients with chronic renal failure.


CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO-1)-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease.
The cysteine protease interleukin-1beta converting enzyme (ICE) is implicated as an effector of apoptosis in mammalian cells. Proteolytic activity of ICE can be blocked in vitro by the cytokine response modifier A (crmA), a serpin-like protease inhibitor encoded by cowpox virus. Here we show that CD2 enhancer-driven expression of crmA in T lymphocytes of transgenic mice (CD2-crmA mice) reduces CD95 (Fas/APO-1)-transduced apoptosis in vitro to the level seen in CD95-deficient mutant lpr mice, but does not protect against gamma-radiation or corticosteroid-induced cell death. Unlike lpr mice, CD2-crmA transgenic mice developed neither T cell hyperplasia nor serum autoantibodies. These results provide evidence that the phenotype of lpr mice is not simply due to failure of CD95 to trigger T cell apoptosis mediated by ICE.


[Nutritional status surveillance of children in a health district in southern Brazil].
To investigate the nutritional status of children referred by a primary care center to the Nutritional Surveillance Program (Prá-Crescer), and to follow up children at risk in a health district of Porto Alegre. A retrospective cohort study was conducted with 674 children, aged between 6 and 59 months, referred to the Prá-Crescer Program. Height-for-age, weight-for-height and weight-for-age indices were used to evaluate nutritional status. The cutoff points were the 3rd and 10th percentiles of the NCHS standards. The nutritional status of 391 children at nutritional risk was followed up for 12 months. The chi-square test was used to analyze associations between variables. Fifty-eight percent of the children had nutritional deficit. Of these, 38.1% were undernourished (< P3), and 61.9% were at nutritional risk (between P3 and P10). Height-for-age deficit was the most frequent, and the age group mostly affected was 12 to 24 months. Among those at nutritional risk, 50.1% completed the follow-up, 33.5% did not start follow-up, and 16.4% were lost to follow-up. 41.3 % recovered nutritional health, 10.2% showed some improvement, without correcting their anthropometric deficits. 39.8% did not show any improvement, and 8.7% had worsening of their deficits. Recovery of nutritional health occurred, on average, within 7.5 months. This study showed the importance of following up children at nutritional risk and indicates that some aspects should be improved in surveillance programs. Such improvements may reduce the number of children lost to follow-up.


Unintentional injuries in children with disabilities: a systematic review and meta-analysis.
Children with disabilities are thought to have an increased risk of unintentional injuries, but quantitative syntheses of findings from previous studies have not been done. We conducted a systematic review and meta-analysis to assess whether pre-existing disability can increase the risk of unintentional injuries among children when they are compared to children without disability. We searched 13 electronic databases to identify original research published between 1 January 1990 and 28 February 2013. We included those studies that reported on unintentional injuries among children with pre-existing disabilities compared with children without disabilities. We conducted quality assessments and then calculated pooled odds ratios of injury using random-effects models. Fifteen eligible studies were included from 24,898 references initially identified, and there was a total sample of 83,286 children with disabilities drawn from the eligible studies. When compared with children without disabilities, the pooled OR of injury was 1.86 (95 % CI 1.65-2.10) in children with disabilities. The pooled ORs of injury were 1.28, 1.75, and 1.86 in the 0-4 years, 5-9 years, and ≥10 years of age subgroups, respectively. Compared with children without disabilities, the pooled OR was 1.75 (95 % CI 1.26-2.43) among those with International Classification of Functioning (ICF) limitations. When disability was defined as physical disabilities, the pooled OR was 2.39 (95 % CI 1.43-4.00), and among those with cognitive disabilities, the pooled OR was 1.77 (95 % CI 1.49-2.11). There was significant heterogeneity in the included studies. Compared with peers without disabilities, children with disabilities are at a significantly higher risk of injury. Teens with disabilities may be an important subgroup for future injury prevention efforts. More data are needed from low- and middle-income countries.


Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants.
Until recently our approach to analyzing human genetic diseases has been to accurately phenotype patients and sequence the genes known to be associated with those phenotypes; for example, in thalassemia, the globin loci are analyzed. Sequencing has become increasingly accessible, and thus a larger panel of genes can be analyzed and whole exome and/or whole genome sequencing can be used when no variants are found in the candidate genes. By using such approaches in patients with unexplained anemias, we have discovered that a broad range of hitherto unrelated human red cell disorders are caused by variants in KLF1, a master regulator of erythropoiesis, which were previously considered to be extremely rare causes of human genetic disease.


Fullerenes as Anti-Aging Antioxidants.
Here we review fullerenes biological effects focusing on their antioxidant and anti-ageing action. A scope of various poisonous and healing properties reported in literature for fullerene and its derivatives is analyzed. The review begins with the history of fullerenes discovery and their main properties. Then we focus on the longevity and antioxidant action, including the confrontation of available experimental data and theoretical modeling of buckminsterfullerene C60. Special attention is given to our hypothesis concerning the possibility of fullerenes to act as mitochondria protonophore and various simulations of the transport of C60 and its hydroxylated and other derivatives through lipid bilayer membranes, which can account for scavenging capacity of fullerenes for reactive oxygen species and their acting as mild mitochondrial respiration uncouplers. Extension of the theoretical modeling to the mitochondria membranes and implications on the real biological systems is analyzed. Finally, we focus on the toxicity evaluation and current therapeutic usage of fullerenes. The review contains a comprehensive discussion of both papers published by 2016 and our own research results.


A qualitative study of the transition to adulthood for youth with physical disabilities.
The purpose of this qualitative study was to explore the experiences, perceptions, and needs of youth with physical disabilities in transition from adolescence to adulthood. Purposeful sampling strategies were used to select 34 study participants who lived in three regions of south-central Ontario, Canada. Data collection methods were individual and focus group interviews, and were guided by a set of open-ended questions. An editing style of analysis sorted the text into codes for description and interpretation. Themes emerged about context, the transition process, needs, and services. Participants identified a poor fit between young persons with disabilities and the adult world they were entering. They recommended that services be focused on environmental supports to enable them to "build their own bridges" to the adult world. Community-based transition services need to be planned in collaboration with youth with disabilities and their parents. Concepts of person-environment fit and health promotion can be incorporated into services to enable young persons with disabilities to experience a smooth transition from adolescence to adulthood.