Multi-scale 2D tracking of articulated objects using hierarchical spring systems.
This paper presents a flexible framework to build a target-specific, part-based representation for arbitrary articulated or rigid objects. The aim is to successfully track the target object in 2D, through multiple scales and occlusions. This is realized by employing a hierarchical, iterative optimization process on the proposed representation of structure and appearance. Therefore, each rigid part of an object is described by a hierarchical spring system represented by an attributed graph pyramid. Hierarchical spring systems encode the spatial relationships of the features (attributes of the graph pyramid) describing the parts and enforce them by spring-like behavior during tracking. Articulation points connecting the parts of the object allow to transfer position information from reliable to ambiguous parts. Tracking is done in an iterative process by combining the hypotheses of simple trackers with the hypotheses extracted from the hierarchical spring systems.


Dombi power partitioned Heronian mean operators of q-rung orthopair fuzzy numbers for multiple attribute group decision making.
In this paper, a set of Dombi power partitioned Heronian mean operators of q-rung orthopair fuzzy numbers (qROFNs) are presented, and a multiple attribute group decision making (MAGDM) method based on these operators is proposed. First, the operational rules of qROFNs based on the Dombi t-conorm and t-norm are introduced. A q-rung orthopair fuzzy Dombi partitioned Heronian mean (qROFDPHM) operator and its weighted form are then established in accordance with these rules. To reduce the negative effect of unreasonable attribute values on the aggregation results of these operators, a q-rung orthopair fuzzy Dombi power partitioned Heronian mean operator and its weighted form are constructed by combining qROFDPHM operator with the power average operator. A method to solve MAGDM problems based on qROFNs and the constructed operators is designed. Finally, a practical example is described, and experiments and comparisons are performed to demonstrate the feasibility and effectiveness of the proposed method. The demonstration results show that the method is feasible, effective, and flexible; has satisfying expressiveness; and can consider all the interrelationships among different attributes and reduce the negative influence of biased attribute values.


Sex and relationships following childbirth: a first report from general practice of 131 couples.
Changes in a couple's sexual relationship following childbirth may be more significant than previous studies have suggested. Around 50% of first-time parents in this study described their sex life as 'poor' or 'not very good' eight months after the birth of their baby, and one in five said that they would like help for this. First-time parents rating their general relationship as 'poor' or 'not very good' rose from 1% before pregnancy to 20% eight months after childbirth. Changes in the general relationship and the quality of sex life were associated in these couples.


ADF proteins are involved in the control of flowering and regulate F-actin organization, cell expansion, and organ growth in Arabidopsis.
Based mostly on the results of in vitro experiments, ADF (actin-depolymerizing factor) proteins are thought to be key modulators of the dynamic organization of the actin cytoskeleton. The few studies concerned with the in vivo function of ADF proteins that have been reported to date were performed almost exclusively using single-cell systems and have failed to produce consistent results. To investigate ADF functions in vivo and during the development of multicellular organs, we generated transgenic Arabidopsis plants that express a cDNA encoding an ADF protein (AtADF1) in the sense or the antisense orientation under the control of a strong constitutively active promoter. Selected lines with significantly altered levels of AtADF protein expression were characterized phenotypically. Overexpression of AtADF1 resulted in the disappearance of thick actin cables in different cell types, caused irregular cellular and tissue morphogenesis, and reduced the growth of cells and organs. In contrast, reduced AtADF expression promoted the formation of actin cables, resulted in a delay in flowering, and stimulated cell expansion as well as organ growth. These results are consistent with the molecular functions of ADF as predicted by in vitro studies, support the global roles of ADF proteins during the development of a multicellular organism, and demonstrate that these proteins are key regulators of F-actin organization, flowering, and cell and organ expansion in Arabidopsis.


Purification and Characterization of Latent Polyphenol Oxidase from Apricot (Prunus armeniaca L.).
Polyphenol oxidase from apricot (Prunus armeniaca) (PaPPO) was purified in its latent form (L-PaPPO), and the molecular weight was determined to be 63 kDa by SDS-PAGE. L-PaPPO was activated in the presence of substrate at low pH. The activity was enhanced by CuSO4 and low concentrations (≤ 2 mM) of SDS. PaPPO has its pH and temperature optimum at pH 4.5 and 45 °C for catechol as substrate. It showed diphenolase activity and highest affinity toward 4-methylcatechol (KM = 2.0 mM) and chlorogenic acid (KM = 2.7 mM). L-PaPPO was found to be spontaneously activated during storage at 4 °C, creating a new band at 38 kDa representing the activated form (A-PaPPO). The mass of A-PaPPO was determined by mass spectrometry as 37 455.6 Da (Asp102 → Leu429). Both L-PaPPO and A-PaPPO were identified as polyphenol oxidase corresponding to the known PaPPO sequence (UniProt O81103 ) by means of peptide mass fingerprinting.


Mapping H5N1 highly pathogenic avian influenza risk in Southeast Asia.
The highly pathogenic avian influenza (HPAI) H5N1 virus that emerged in southern China in the mid-1990s has in recent years evolved into the first HPAI panzootic. In many countries where the virus was detected, the virus was successfully controlled, whereas other countries face periodic reoccurrence despite significant control efforts. A central question is to understand the factors favoring the continuing reoccurrence of the virus. The abundance of domestic ducks, in particular free-grazing ducks feeding in intensive rice cropping areas, has been identified as one such risk factor based on separate studies carried out in Thailand and Vietnam. In addition, recent extensive progress was made in the spatial prediction of rice cropping intensity obtained through satellite imagery processing. This article analyses the statistical association between the recorded HPAI H5N1 virus presence and a set of five key environmental variables comprising elevation, human population, chicken numbers, duck numbers, and rice cropping intensity for three synchronous epidemic waves in Thailand and Vietnam. A consistent pattern emerges suggesting risk to be associated with duck abundance, human population, and rice cropping intensity in contrast to a relatively low association with chicken numbers. A statistical risk model based on the second epidemic wave data in Thailand is found to maintain its predictive power when extrapolated to Vietnam, which supports its application to other countries with similar agro-ecological conditions such as Laos or Cambodia. The model's potential application to mapping HPAI H5N1 disease risk in Indonesia is discussed.


Prevalence of autism-spectrum conditions: UK school-based population study.
Recent reports estimate the prevalence of autism-spectrum conditions in the UK to be 1%. To use different methods to estimate the prevalence of autism-spectrum conditions, including previously undiagnosed cases, in Cambridgeshire. We carried out a survey of autism-spectrum conditions using the Special Educational Needs (SEN) register. A diagnosis survey was distributed to participating schools to be handed out to parents of all children aged 5-9 years. The mainstream primary school population was screened for unknown cases. The prevalence estimates generated from the SEN register and diagnosis survey were 94 per 10 000 and 99 per 10 000 respectively. A total of 11 children received a research diagnosis of an autism-spectrum condition following screening and assessment. The ratio of known:unknown cases is about 3:2 (following statistical weighting procedures). Taken together, we estimate the prevalence to be 157 per 10 000, including previously undiagnosed cases. This study has implications for planning diagnostic, social and health services.


[Topical photodynamic therapy in basal and squamous cell carcinoma and penile Bowen's disease with 20% aminolevulinic acid, and exposure to red light and infrared light].
Photodynamic therapy (PDT) is a noninvasive selective therapy for a specific group of skin tumors. 5-aminolevulinic acid 20% in a water-in-oil cream base was applied to the tumors as a photosensitizer and was followed after 12 hours by exposure to a high output light source emitting red (585-720 nm; 150 mW/cm2) and near infrared irradiation (1.25-1.6 mm; 50 mW/cm2) for 10-15 minutes (VersaLight, incoherent filtered light source). Complete responses were achieved after 1-3 treatments in 26/31 lesions of superficial or small nodular basal cell carcinoma (BCC) and 4/5 in superficial, squamous cell carcinoma (SCC) lesions. There was a patient with Bowen's disease of the penis. Follow-up was for 12-24 months. This noninvasive, nearly painless treatment gives excellent therapeutic and cosmetic results. Our data show its efficacy for certain subtypes of BCC, SCC and Bowen's disease. Further studies will determine the exact cure and recurrence rates with this modality and compare it to other modes of skin cancer therapy.


The role of climate change education on individual lifetime carbon emissions.
Strategies to mitigate climate change often center on clean technologies, such as electric vehicles and solar panels, while the mitigation potential of a quality educational experience is rarely discussed. In this paper, we investigate the long-term impact that an intensive one-year university course had on individual carbon emissions by surveying students at least five years after having taken the course. A majority of course graduates reported pro-environmental decisions (i.e., type of car to buy, food choices) that they attributed at least in part to experiences gained in the course. Furthermore, our carbon footprint analysis suggests that for the average course graduate, these decisions reduced their individual carbon emissions by 2.86 tons of CO2 per year. Surveys and focus group interviews identify that course graduates have developed a strong personal connection to climate change solutions, and this is realized in their daily behaviors and through their professional careers. The paper discusses in more detail the specific components of the course that are believed to be most impactful, and the uncertainties associated with this type of research design. Our analysis also demonstrates that if similar education programs were applied at scale, the potential reductions in carbon emissions would be of similar magnitude to other large-scale mitigation strategies, such as rooftop solar or electric vehicles.


Impact of Chronic Kidney Disease on Revascularization and Outcomes in Patients with ST-Elevation Myocardial Infarction.
Chronic kidney disease (CKD) in patients with ST-elevation myocardial infarction (STEMI) is associated with worse outcomes. We assessed the impact of CKD on guideline directed coronary revascularization and outcomes among STEMI patients. The Nationwide Inpatient Sample dataset from 2012-2014 was used to identify patients with STEMI using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patients were categorized as non-CKD, CKD without dialysis, and CKD with dialysis (CKD-HD). Outcomes were revascularization, death and acute renal failure requiring dialysis (ARFD). A total of 534,845 were included (88.9% non-CKD; 9.6% CKD without dialysis, and 1.5% CKD-HD). PCI was performed in 77.4% non-CKD, 56.2% CKD without dialysis, and 48% CKD-HD patients (p < 0.0001). In-hospital mortality and ARFD were significantly higher in CKD patients (16.5% and 40.6%) compared with non-CKD patients (7.12% and 7.17%) (p < 0.0001). In-hospital mortality was significantly lower in patients treated revascularization compared with patients treated medically (non-CKD: adjusted odds ratio (aOR) 0.280, p < 0.0001; CKD without dialysis: aOR 0.39, p < 0.0001; CKD-HD: aOR 0.48, p < 0.0001). CKD was associated with higher length of hospital stay and cost (5.86 ± 13.97, 7.57 ± 26.06 and 3.99 ± 11.09 days; p < 0.0001; $25,696 ± $63,024, $35,666 ± $104,940 and $23,264 ± $49,712; p < 0.0001 in non-CKD, CKD without dialysis and CKD-HD patients respectively). In conclusion, CKD patients with STEMI receive significantly less PCI compared with patients without CKD. Coronary revascularization for STEMI in CKD patients was associated with lower mortality compared to medical management. The presence of CKD in patients with STEMI is associated with higher mortality and ARFD, prolonged hospital stay and higher hospital cost.


Core of communities in bipartite networks.
We use the information present in a bipartite network to detect cores of communities of each set of the bipartite system. Cores of communities are found by investigating statistically validated projected networks obtained using information present in the bipartite network. Cores of communities are highly informative and robust with respect to the presence of errors or missing entries in the bipartite network. We assess the statistical robustness of cores by investigating an artificial benchmark network, the coauthorship network, and the actor-movie network. The accuracy and precision of the partition obtained with respect to the reference partition are measured in terms of the adjusted Rand index and the adjusted Wallace index, respectively. The detection of cores is highly precise, although the accuracy of the methodology can be limited in some cases.


Continent-scale global change attribution in European birds - combining annual and decadal time scales.
Species attributes are commonly used to infer impacts of environmental change on multiyear species trends, e.g. decadal changes in population size. However, by themselves attributes are of limited value in global change attribution since they do not measure the changing environment. A broader foundation for attributing species responses to global change may be achieved by complementing an attributes-based approach by one estimating the relationship between repeated measures of organismal and environmental changes over short time scales. To assess the benefit of this multiscale perspective, we investigate the recent impact of multiple environmental changes on European farmland birds, here focusing on climate change and land use change. We analyze more than 800 time series from 18 countries spanning the past two decades. Analysis of long-term population growth rates documents simultaneous responses that can be attributed to both climate change and land-use change, including long-term increases in populations of hot-dwelling species and declines in long-distance migrants and farmland specialists. In contrast, analysis of annual growth rates yield novel insights into the potential mechanisms driving long-term climate induced change. In particular, we find that birds are affected by winter, spring, and summer conditions depending on the distinct breeding phenology that corresponds to their migratory strategy. Birds in general benefit from higher temperatures or higher primary productivity early on or in the peak of the breeding season with the largest effect sizes observed in cooler parts of species' climatic ranges. Our results document the potential of combining time scales and integrating both species attributes and environmental variables for global change attribution. We suggest such an approach will be of general use when high-resolution time series are available in large-scale biodiversity surveys.


[Do behavioural problems existing at referral become worse in subsequent years? A study of young persons referred to the outpatient unit of the mental health service].
Although young persons with severe and complex emotional and behavioural problems are often referred to the outpatient unit of the mental health service, little information is available about whether these problems increase over the years. This information is urgently needed in order to ensure that the mental health service provides adequate care. To obtain more insight into any increase in young persons' emotional and behavioural problems that may occur over a period of six years following referral to an outpatient unit of the mental health service. The nature, severity and complexity of the emotional and behavioural problems of 123 young persons (1999) and of 149 young persons (2005) at the time of the referral - as rated by their parents on the basis of the Child Behavior Checklist (CBCL) - were assessed; the young persons' records were also checked for background characteristics. Compared to 1999, the year 2005 saw a slight decrease in the severity of the problems existing at referral; social problems also declined significantly compared to 1999. Problems identified in the 2005 group often seemed less complex than in 1999. The severity of delinquent behaviour as measured on the Delinquent Behaviour Scale seems to have risen in the 12 to 18 age group in 2005, whereas the severity declined in the 4 to 11-year olds. Emotional and behavioural problems as reported by the parents at the time their children were referred to the mental health service do not increase.


Colorectal cancer screening in asymptomatic populations.
Colorectal cancer is the second commonest cause of cancer death in the UK. An effective national screening programme is urgently required to reduce the substantial morbidity and mortality from the disease. The success of any screening programme will depend on the screening test detecting early Dukes's A carcinomas and adenomatous polyps. Prognosis is directly related to tumour staging and a proportion of carcinomas are thought to arise from polyps. Two screening methods exist--faecal occult blood testing and sigmoidoscopy. Large trials of faecal occult blood testing show that it detects more early lesions than in patients presenting with symptoms, but whether this reduces mortality is not yet confirmed and lack of sensitivity for cancers and polyps may ultimately limits its usefulness. The role of sigmoidoscopy in screening, particularly flexible sigmoidoscopy, has not been fully investigated. Flexible sigmoidoscopy has a greater sensitivity for distal lesions than stool testing and a randomised controlled trial of its efficacy is planned in Britain. Compliance with screening is essential to ensure its cost effectiveness in both health and economic terms. Large trials of faecal occult blood testing conducted over several years achieved compliance rates in excess of 60%, although in smaller studies these are often much less. Women frequently participate more than men. There are many reasons for non-compliance including lack of appreciation of the concept of asymptomatic illness and fear of the screening tests and cancer itself. Colorectal cancer screening is relatively cheap compared with breast and cervical cancer screening. Provisional cost estimates suggest that the amount spent to detect or prevent cancer by screening is similar to the amount required to treat a symptomatic patient.


Conformity cannot be identified based on population-level signatures.
Conformist transmission, defined as a disproportionate likelihood to copy the majority, is considered a potent mechanism underlying the emergence and stabilization of cultural diversity. However, ambiguity within and across disciplines remains as to how to identify conformist transmission empirically. In most studies, a population level outcome has been taken as the benchmark to evidence conformist transmission: a sigmoidal relation between individuals' probability to copy the majority and the proportional majority size. Using an individual-based model, we show that, under ecologically plausible conditions, this sigmoidal relation can also be detected without equipping individuals with a conformist bias. Situations in which individuals copy randomly from a fixed subset of demonstrators in the population, or in which they have a preference for one of the possible variants, yield similar sigmoidal patterns as a conformist bias would. Our findings warrant a revisiting of studies that base their conformist transmission conclusions solely on the sigmoidal curve. More generally, our results indicate that population level outcomes interpreted as conformist transmission could potentially be explained by other individual-level strategies, and that more empirical support is needed to prove the existence of an individual-level conformist bias in human and other animals.


Low score normal muscle weakness alters cardiac decorin expression: implication for cardiac collagen fibril organization.
Cardiac decorin and Type I collagen expression and collagen fibrosis were examined in a chicken line exhibiting the low score normal (LSN) genetic muscle weakness and compared to normal cardiac muscle at 14 and 20 d of embryonic development and at 1 and 6 wk posthatch. These extracellular matrix proteins were selected due to their role in regulating tissue elasticity, which is critical for normal cardiac function. Beginning at 1 wk posthatch, relative levels of decorin were higher in the LSN cardiac muscle than in the control, indicating a time-dependent increase in decorin expression. Type I collagen levels appeared to be unaffected by the LSN condition. Morphologically, myocardial and coronary artery fibrosis did not differ between the control and LSN at all stages examined. These results are suggestive of extracellular matrix remodeling in LSN cardiac muscle that is mediated through a decorin-dependent pathway.


Antibody-Mediated Phosphatidylserine Blockade Enhances the Antitumor Responses to CTLA-4 and PD-1 Antibodies in Melanoma.
In tumor-bearing animals, the membrane phospholipid phosphatidylserine (PS) suppresses immune responses, suggesting that PS signaling could counteract the antitumor effect of antibody-driven immune checkpoint blockade. Here, we show that treating melanoma-bearing mice with a PS-targeting antibody enhances the antitumor activity of downstream checkpoint inhibition. Combining PS-targeting antibodies with CTLA-4 or PD-1 blockade resulted in significantly greater inhibition of tumor growth than did single-agent therapy. Moreover, combination therapy enhanced CD4(+) and CD8(+) tumor-infiltrating lymphocyte numbers; elevated the fraction of cells expressing the proinflammatory cytokines IL2, IFNγ, and TNFα; and increased the ratio of CD8 T cells to myeloid-derived suppressor cells and regulatory T cells in tumors. Similar changes in immune cell profiles were observed in splenocytes. Taken together, these data show that antibody-mediated PS blockade enhances the antitumor efficacy of immune checkpoint inhibition. Cancer Immunol Res; 4(6); 531-40. ©2016 AACR.


Automatic bi-objective parameter tuning for inverse planning of high-dose-rate prostate brachytherapy.
We present an automatic bi-objective parameter-tuning approach for inverse planning methods for high-dose-rate prostate brachytherapy, which aims to overcome the difficult and time-consuming manual parameter tuning that is currently required to obtain patient-specific high-quality treatment plans. We modelled treatment planning as a bi-objective optimization problem, in which dose-volume-based planning criteria related to target coverage are explicitly separated from organ-sparing criteria. When this model is optimized, a large set of high-quality plans with different trade-offs can be obtained. This set can be visualized as an insightful patient-specific trade-off curve. In our parameter-tuning approach, the parameters of inverse planning methods are automatically tuned, aimed to maximize the two objectives of the bi-objective planning model. By generating trade-off curves for different inverse planning methods, their maximally achievable plan quality can be insightfully compared. Automatic parameter tuning furthermore allows to construct standard parameter sets (class solutions) representing different trade-offs in a principled way, which can be directly used in current clinical practice. In this work, we considered the inverse planning methods IPSA and HIPO. Thirty-nine previously treated prostate cancer patients were included. We compared automatic parameter tuning, random parameter sampling, and the maximally achievable plan quality obtained by directly optimizing the bi-objective planning model with the state-of-the-art optimization software GOMEA. We showed that for each patient, a set of plans with a wide range of trade-offs could be obtained using automatic parameter tuning for both IPSA and HIPO. By tuning HIPO, better trade-offs were obtained than by tuning IPSA. For most patients, automatic tuning of HIPO resulted in plans close to the maximally achievable plan quality obtained by optimizing the bi-objective planning model directly. Automatic parameter tuning was shown to improve plan quality significantly compared to random parameter sampling. Finally, from the automatically-tuned plans, three class solutions were successfully constructed representing different trade-offs.


Epigallocatechin-3-gallate attenuates cerebral cortex damage and promotes brain regeneration in acrylamide-treated rats.
Acrylamide (ACR) is a neurotoxic industrial chemical intermediate, which is also present in food and water. We investigated the neuroprotective effects of epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, on ACR-treated rat brain. Rats were pre-treated with EGCG for 4 d and then administered ACR and EGCG for 14 d. EGCG increased acetylcholinesterase (AChE) activity and the rate of Nissl-positive cells in ACR-treated rats. Senescence-associated β-galactosidase (SA-β-gal) staining indicated that EGCG attenuated ACR-induced senescence. Tumour necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) protein expression indicated that EGCG inhibited ACR-induced inflammation. In addition, immunohistochemical analysis of nestin and brain-derived neurotrophic factor (BDNF) revealed that EGCG promoted brain regeneration in ACR-treated rats. Altogether, our results suggest that EGCG can attenuate ACR-induced brain damage and promote regeneration in the cerebral cortex of rats. Therefore, we hypothesized that EGCG may alleviate ACR-related nerve injury.


Purification and characterization of infectious myonecrosis virus of penaeid shrimp.
The causative agent of myonecrosis affecting cultured Penaeus vannamei in Brazil was demonstrated to be a virus after purification of the agent from infected shrimp tissues. Purified viral particles were injected into specific pathogen-free P. vannamei, resulting in a disease that displayed the same characteristics as those found in the original shrimp used for purification. The virus was named infectious myonecrosis virus (IMNV). The viral particles were icosahedral in shape and 40 nm in diameter, with a buoyant density of 1.366 g ml(-1) in caesium chloride. The genome consisted of a single, double-stranded (dsRNA) molecule of 7560 bp. Sequencing of the viral genome revealed two non-overlapping open reading frames (ORFs). The 5' ORF (ORF 1, nt 136-4953) encoded a putative RNA-binding protein and a capsid protein. The coding region of the RNA-binding protein was located in the first half of ORF 1 and contained a dsRNA-binding motif in the first 60 aa. The second half of ORF 1 encoded a capsid protein, as determined by amino acid sequencing, with a molecular mass of 106 kDa. The 3' ORF (ORF 2, nt 5241-7451) encoded a putative RNA-dependent RNA polymerase (RdRp) with motifs characteristic of totiviruses. Phylogenetic analysis based on the RdRp clustered IMNV with Giardia lamblia virus, a member of the family Totiviridae. Based on these findings, IMNV may be a unique member of the Totiviridae or may represent a new dsRNA virus family that infects invertebrate hosts.


Cytotoxicity of bovine and porcine collagen membranes in mononuclear cells.
This study compared the cytotoxicity and the release of nitric oxide induced by collagen membranes in human mononuclear cells. Peripheral blood was collected from each patient and the separation of mononuclear cells was performed by Ficoll. Then, 2x10(5) cells were plated in 48-well culture plates under the membranes in triplicate. The polystyrene surface was used as negative control. Cell viability was assessed by measuring mitochondrial activity (MTT) at 4, 12 and 24 h, with dosage levels of nitrite by the Griess method for the same periods. Data had non-normal distribution and were analyzed by the Kruskal-Wallis test (p<0.05). Statistically significant differences (p<0.05) were observed between the membranes and the control in the experimental period, although there was a significant reduction in viability over time (p<0.01). At 4 and 12 h, the porcine membrane induced a higher release of nitrite compared with the control and bovine membrane, respectively (p<0.01), and this difference was maintained at 24 h (p<0.05). This in vitro study showed that the porcine collagen membrane induces an increased production of proinflammatory mediators by mononuclear cells in the first hours of contact, decreasing with time.


Comparison of 2 PCR assays on environmental samples cultured for Mycobacterium avium subsp. paratuberculosis.
Mycobacterium avium subsp. paratuberculosis (MAP) is the causal agent of paratuberculosis, a chronic, contagious, and incurable enteric disease of ruminants. An in-house IS900 PCR assay validated for MAP detection in sheep has been shown to have a higher sensitivity than a commercial PCR and fecal culture. We have now compared the performance of this in-house IS900 PCR assay with a commercial ISMap02 PCR assay for the detection of MAP DNA in bovine dairy farm environmental samples. We purposefully selected 30 culture-positive, 62 culture-negative, and 62 non-interpretable environmental samples. We applied the IS900 PCR assay directly to the frozen inoculum of these samples. Inocula were incubated in an automated system, and growth was confirmed by an acid-fast bacilli stain and the IS900 PCR assay. Among culture-positive samples before incubation, the IS900 PCR assay yielded significantly more positive results than the ISMap02 PCR assay; however, among culture-negative samples, the IS900 PCR assay yielded positive results both before and after incubation. The ISMap02 PCR assay did not flag positively among the culture-negative samples either before or after incubation. The IS900 PCR assay is a sensitive method that can be used to detect MAP DNA in environmental samples before incubation. The ISMap02 PCR assay is a specific method used to detect MAP DNA in environmental samples both before and after incubation.


The neural correlates of non-spatial working memory in velocardiofacial syndrome (22q11.2 deletion syndrome).
Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a neurogenetic disorder that is associated with both learning disabilities and a consistent neuropsychological phenotype, including deficits in executive function, visuospatial perception, and working memory. Anatomic imaging studies have identified significant volumetric reductions in the parietal lobe of individuals with VCFS, but several studies have reported that the frontal lobe is relatively preserved. We used functional magnetic resonance imaging to investigate the neural correlates of non-spatial working memory in 17 youths with VCFS, 10 of their unaffected siblings, and 10 community controls (with the same proportion of learning disabilities as the VCFS youths). Task performance of siblings tended to be more accurate than children with VCFS, who did not differ from community controls. All three-study groups recruited parietal regions that were equivalent in location and magnitude. Whereas the sibling group also recruited the dorsolateral prefrontal cortex (DLPFC), Broca's area, and anterior cingulate, DLPFC activation was absent in the whole brain analyses of children with VCFS and controls. Moreover, the magnitude of frontal activation in VCFS participants was restricted relative to both siblings and controls. These findings suggest that VCFS participants exhibit frontal hypoactivation that is not attributable to performance. In addition, VCFS children and controls (many with idiopathic learning disabilities) appear to rely on phonological rehearsal to hold information on line instead of the DLPFC. Despite previous anatomic MRI reports of preserved frontal lobe volumes in VCFS therefore, these fMRI findings suggest that the frontal component of the distributed network subserving executive function and working memory may be disrupted in youth with this disorder.


Papillary atrophy of the tongue and nutritional status of hospitalized alcoholics.
Atrophy of the papillae, mucosa, and dorsum of the tongue are considered classical signs of nutritional deficiencies. To assess the nutritional status of hospitalized alcoholics with or without papillary atrophy of the tongue. This study was performed with 21 hospitalized alcoholics divided into Atrophic Glossitis Group (n=13) and Normal Tongue Group (n=8). Healthy, non-alcoholic volunteers composed the Control Group (n=8). Anthropometry and bioelectric impedance were performed, and serum vitamins A, E, and B12 were determined. There were no statistical differences in relation to age (46.7 ± 8.7 vs. 46.8 ± 15.8 years) or gender (92.3% vs. 87.5% male), respectively. Control Group volunteers were also paired in relation to age (47.5 ± 3.1 years) and male predominance (62.5%). In relation to hospitalized alcoholics without atrophic lesions of the tongue and Control Group, patients with papillary atrophy showed lower BMI (18.6 ± 2,5 vs 23.8 ± 3.5 vs 26.7 ± 3,6 kg/m(2)) and body fat content 7.6 ± 3.5 vs 13.3 ± 6.5 vs 19.5 ± 4,9 kg). When compared with the Control Group, alcoholic patients with or without papillary atrophy of the tongue showed lower values of red blood cells (10.8 ± 2.2 vs 11.8 ± 2.2 vs 14.5 ± 1,6g/dL) and albumin (3.6 ± 0.9 vs 3.6 ± 0.8 vs 4.4 ± 0.2g/dL). The seric levels of vitamins A, E, and B12 were similar amongst the groups. Hospitalized alcoholics with papillary atrophy of the tongue had lower BMI and fat body stores than controls, without associated hypovitaminosis.


Mental Health Screening and Differences in Access to Care among Prisoners.
Disparities in mental health care exist between regional and demographic groups. While screening is recommended as part of a correctional mental health strategy, little work has been done to explore whether it can narrow regional and demographic disparities in access to care. We compared treatment access rates by sex, race, age, and region in relation to screening results. We conducted a retrospective cohort study using administrative data. All 7965 admissions to the prison system were followed for a median of 14 months. Males and non-Indigenous minority racial groups had lower rates of treatment regardless of screening results; they were less likely both to self-report needs and to receive treatment if these needs were reported. Regional differences revealed higher treatment rates in Atlantic Canada and Ontario, as well as higher rates of inmates self-reporting needs on screening who did not receive treatment in the Atlantic, Québec, and Pacific regions. There were minimal differences between inmates of different age groups. Findings suggest potential resource gaps and/or differences in the performance of screening to detect mental health needs across demographic and regional groups. Screening did not narrow, and may have widened, differences between groups.


Vibrating membrane devices deliver aerosols more efficient than standard devices: a study in a neonatal upper airway model.
Aerosol therapy in preterm infants is challenging, as a very small proportion of the drug deposits in the lungs. Our aim was to compare efficiency of standard devices with newer, more efficient aerosol delivery devices. Using salbutamol as a drug marker, we studied two prototypes of the investigational eFlow(®) nebulizer for babies (PARI Pharma GmbH), a jet nebulizer (Intersurgical(®) Cirrus(®)), and a pressurized metered dose inhaler (pMDI; GSK) with a detergent-coated holding chamber (AeroChamber(®) MV) in the premature infant nose throat-model (PrINT-model) of a 32-week preterm infant (1,750 g). A filter or an impactor was placed below the infant model's "trachea" to capture the drug dose or particle size, respectively, that would have been deposited in the lung. Lung dose (percentage of nominal dose) was 1.5%, 6.8%, and 18.0-20.6% for the jet nebulizer, pMDI-holding chamber, and investigational eFlow nebulizers, respectively (p<0.001). Jet nebulizer residue was 69.4% and 10.7-13.9% for the investigational eFlow nebulizers (p<0.001). Adding an elbow extension between the eFlow and the model significantly lowered lung dose (p<0.001). A breathing pattern with lower tidal volume decreased deposition in the PrINT-model and device residue (p<0.05), but did not decrease lung dose. In a model for infant aerosol inhalation, we confirmed low lung dose using jet nebulizers and pMDI-holding chambers, whereas newer, more specialized vibrating membrane devices, designed specifically for use in preterm infants, deliver up to 20 times more drug to the infant's lung.


Evaluating the Effects of a Novel Neuromuscular Neck Training Device on Multiplanar Static and Dynamic Neck Strength: A Pilot Study.
Versteegh, TH, Dickey, JP, Emery, CA, Fischer, LK, MacDermid, JC, and Walton, DM. Evaluating the effects of a novel neuromuscular neck training device on multiplanar static and dynamic neck strength: A pilot study. J Strength Cond Res 34(3): 708-716, 2020-The neck serves an important function in damping the transference of acceleration forces between the head and the trunk, such as that occurring during contact sports or motor vehicle collisions. An inability to adequately dissipate forces has been proposed as a potential mechanism for clinical conditions such as whiplash or concussion, but current approaches to neck training may not be targeting the correct mechanisms. The purpose of this study was to explore the training effect of a novel neuromuscular strengthening protocol on dynamic and static neck strength. This was a quasiexperimental pilot study design with intervention (n = 8) and control (n = 10) groups. The intervention group was trained (twice/week, ∼10 minutes, for 7 weeks) on a training device that uses self-generated centripetal force to create a dynamic rotational resistance. This protocol is intended to target the ability of the neck muscles to perform coordinated multiplanar plyometric contractions. Both groups also continued with traditional neck strengthening that included training on a straight-plane, isotonic, 4-way neck machine. Performance on the training device showed improvement after routine practice within 1 week, as evidenced by a trend toward increased peak speed in revolutions per minute (RPM). After 7 weeks, peak RPM increased from 122.8 (95% confidence interval [CI], 91.3-154.4) to 252.3 (95% CI, 241.5-263.1). There was also a large positive effect size (Hedge's d, 0.68) in isometric composite (multiplane) neck strength favoring the intervention group over the control group (difference, 20 N; 95% CI, -8 to 48). The largest magnitude strength improvement in a single plane was in axial rotation and also favored the intervention group over the control group (Hedge's d, 1.24; difference, 46 N; 95% CI, 9-83). Future studies should explore whether the dynamic training presented here could help reduce the risk of sports concussion, whiplash, or other head-neck trauma.


Effect of resistance training regimens on treadmill running and neuromuscular performance in recreational endurance runners.
The purpose of this study was to assess the effects of heavy resistance, explosive resistance, and muscle endurance training on neuromuscular, endurance, and high-intensity running performance in recreational endurance runners. Twenty-seven male runners were divided into one of three groups: heavy resistance, explosive resistance or muscle endurance training. After 6 weeks of preparatory training, the groups underwent an 8-week resistance training programme as a supplement to endurance training. Before and after the 8-week training period, maximal strength (one-repetition maximum), electromyographic activity of the leg extensors, countermovement jump height, maximal speed in the maximal anaerobic running test, maximal endurance performance, maximal oxygen uptake ([V·]O(₂max)), and running economy were assessed. Maximal strength improved in the heavy (P = 0.034, effect size ES = 0.38) and explosive resistance training groups (P = 0.003, ES = 0.67) with increases in leg muscle activation (heavy: P = 0.032, ES = 0.38; explosive: P = 0.002, ES = 0.77). Only the heavy resistance training group improved maximal running speed in the maximal anaerobic running test (P = 0.012, ES = 0.52) and jump height (P = 0.006, ES = 0.59). Maximal endurance running performance was improved in all groups (heavy: P = 0.005, ES = 0.56; explosive: P = 0.034, ES = 0.39; muscle endurance: P = 0.001, ES = 0.94), with small though not statistically significant improvements in [V·]O(₂max) (heavy: ES = 0.08; explosive: ES = 0.29; muscle endurance: ES = 0.65) and running economy (ES in all groups < 0.08). All three modes of strength training used concurrently with endurance training were effective in improving treadmill running endurance performance. However, both heavy and explosive strength training were beneficial in improving neuromuscular characteristics, and heavy resistance training in particular contributed to improvements in high-intensity running characteristics. Thus, endurance runners should include heavy resistance training in their training programmes to enhance endurance performance, such as improving sprinting ability at the end of a race.


Prevalence of asthma among adults in metropolitan versus nonmetropolitan areas in Montana, 2008.
Most US studies on asthma prevalence have been conducted in urban areas, and few have assessed the prevalence of asthma among residents of rural areas versus urban areas. The objective of this study was to compare the prevalence of asthma among adults living in metropolitan versus nonmetropolitan counties in Montana. We analyzed data from 6,846 adult Montanans who completed the Behavioral Risk Factor Surveillance System survey in 2008. We used Rural-Urban Continuum Codes to categorize respondents' county of residence as metropolitan (Metro), nonmetropolitan and adjacent to a metropolitan county (NMA), and nonmetropolitan and nonadjacent to a metropolitan county (NMNA). We compared the prevalence of current self-reported asthma among respondents in the 3 areas, overall and by selected characteristics, and conducted multivariable logistic regression analyses to identify factors independently associated with current self-reported asthma. No differences in the prevalence of self-reported asthma were found between residents of Metro and NMA or NMNA counties, overall or by age, sex, race, years of education, health insurance status, annual household income, or body mass index. Respondents aged 65 years or older (adjusted odds ratio [AOR], 0.7; 95% confidence interval [CI], 0.5-0.9) and men (AOR, 0.6; 95% CI, 0.5-0.8) were less likely to report current asthma than younger respondents and women, respectively. Obese respondents were more likely (AOR, 1.9; 95% CI, 1.4-2.7) to report asthma than were respondents who were not obese. Metropolitan county of residence was not independently associated with self-reported current asthma. The prevalence of self-reported current asthma is similar in metropolitan and nonmetropolitan counties in Montana, but other sociodemographic differences exist. Our findings highlight the need to conduct regional and state surveillance of asthma to understand the demographic risk factors associated with it and to determine the potential geographic variation of asthma prevalence in the United States.


Iron deficiency in athletes. Insights from high school swimmers.
Previous studies have indicated a high incidence of nonanemic iron deficiency in high school runners, but little is known regarding participants in other sports. The hematologic and iron status of 30 high school swimmers was assessed at the beginning and end of a competitive swim season. Iron depletion (serum ferritin level less than 12 micrograms/L) was initially present in 46.7% of the girls and none of the boys, yet among those subjects with hypoferritinemia there was no evidence of impaired red blood cell production. Serum haptoglobin levels were normal and did not correlate with serum ferritin levels. No significant change was observed in ferritin, hemoglobin, or haptoglobin concentrations during the course of the season. Dietary intake of iron was poor, particularly in the girls, in whom it averaged 43% of the recommended dietary allowance. Menstrual histories suggested an inverse relationship between the amount of menstrual flow and the serum ferritin level. These findings indicate a high prevalence of nonanemic iron deficiency in female high school swimmers that bears no relationship to swim training. Dietary inadequacies and menstrual blood flow appear to be important contributors to the hypoferritinemia observed in these athletes.


Association of Dual Eligibility for Medicare and Medicaid With Heart Failure Quality and Outcomes Among Get With The Guidelines-Heart Failure Hospitals.
The Centers for Medicare & Medicaid Services uses a new peer group-based payment system to compare hospital performance as part of its Hospital Readmissions Reduction Program, which classifies hospitals into quintiles based on their share of dual-eligible beneficiaries for Medicare and Medicaid. However, little is known about the association of a hospital's share of dual-eligible beneficiaries with the quality of care and outcomes for patients with heart failure (HF). To evaluate the association between a hospital's proportion of patients with dual eligibility for Medicare and Medicaid and HF quality of care and outcomes. This retrospective cohort study evaluated 436 196 patients hospitalized for HF using the Get With The Guidelines-Heart Failure registry from January 1, 2010, to December 31, 2017. The analysis included patients 65 years or older with available data on dual-eligibility status. Hospitals were divided into quintiles based on their share of dual-eligible patients. Quality and outcomes were analyzed using unadjusted and adjusted multivariable logistic regression models. Data analysis was performed from April 1, 2020, to January 1, 2021. The primary outcome was 30-day all-cause readmission. The secondary outcomes included in-hospital mortality, 30-day HF readmissions, 30-day all-cause mortality, and HF process of care measures. A total of 436 196 hospitalized HF patients 65 years or older from 535 hospital sites were identified, with 258 995 hospitalized patients (median age, 81 years; interquartile range, 74-87 years) at 455 sites meeting the study criteria and included in the primary analysis. A total of 258 995 HF hospitalizations from 455 sites were included in the primary analysis of the study. Hospitals in the highest dual-eligibility quintile (quintile 5) tended to care for patients who were younger, were more likely to be female, belonged to racial minority groups, or were located in rural areas compared with quintile 1 sites. After multivariable adjustment, hospitals with the highest quintile of dual eligibility were associated with lower rates of key process measures, including evidence-based β-blocker prescription, measure of left ventricular function, and anticoagulation for atrial fibrillation or atrial flutter. Differences in clinical outcomes were seen with higher 30-day all-cause (adjusted odds ratio, 1.24; 95% CI, 1.14-1.35) and HF (adjusted odds ratio, 1.14; 95% CI, 1.03-1.27) readmissions in higher dual-eligible quintile 5 sites compared with quintile 1 sites. Risk-adjusted in-hospital and 30-day mortality did not significantly differ in quintile 1 vs quintile 5 hospitals. In this cohort study, hospitals with a higher share of dual-eligible patients provided care with lower rates of some of the key HF quality of care process measures and with higher 30-day all-cause or HF readmissions compared with lower dual-eligibility quintile hospitals.


Wafer-scale monodomain films of spontaneously aligned single-walled carbon nanotubes.
The one-dimensional character of electrons, phonons and excitons in individual single-walled carbon nanotubes leads to extremely anisotropic electronic, thermal and optical properties. However, despite significant efforts to develop ways to produce large-scale architectures of aligned nanotubes, macroscopic manifestations of such properties remain limited. Here, we show that large (>cm(2)) monodomain films of aligned single-walled carbon nanotubes can be prepared using slow vacuum filtration. The produced films are globally aligned within ±1.5° (a nematic order parameter of ∼1) and are highly packed, containing 1 × 10(6) nanotubes in a cross-sectional area of 1 μm(2). The method works for nanotubes synthesized by various methods, and film thickness is controllable from a few nanometres to ∼100 nm. We use the approach to create ideal polarizers in the terahertz frequency range and, by combining the method with recently developed sorting techniques, highly aligned and chirality-enriched nanotube thin-film devices. Semiconductor-enriched devices exhibit polarized light emission and polarization-dependent photocurrent, as well as anisotropic conductivities and transistor action with high on/off ratios.


Imaging the mental components of a planning task.
The Tower of London task (TOL) has been widely used to assess the ability to plan. We used H(2)O(15)-positron emission tomography to isolate some of the cognitive components of the task. Ten male volunteers were scanned twice in each of six conditions. In two conditions (plan) the subjects had to plan the best solution to TOL problems. In two other conditions (plan-control) the subjects were required to generate four moves without being constrained by a goal. In plan and plan-control tasks the subjects either planned the moves and then executed them (MOVE conditions) or imagined the necessary moves (IMAGINE conditions). The plan and plan-control tasks were matched for the working memory load and "initial thinking time". A visuomotor control task and rest served as baseline conditions. Performance on the plan tasks, in contrast to the baseline conditions, was associated with activation in the dorsal prefrontal cortex, premotor and parietal cortex, and cerebellum. Performance of the plan-control tasks was associated with activation of the same areas. Contrasting the plan with the plan-control tasks revealed no residual activation in the prefrontal cortex. These data show that the activity of the dorsolateral prefrontal cortex on the TOL can be accounted for by the components of generating, selecting and/or remembering mental moves. The task of relating the moves to the goal involves a comparison with a representation of the goal in posterior association areas. We did not find evidence that activation of the dorsal prefrontal cortex is specifically related to the evaluation of a path towards a specified goal, a key component of planning.


Descriptive Analysis of Right and Left-sided Traumatic Diaphragmatic Injuries; Case Series from a Single Institution.
To investigate the presentation, management and outcomes of left and right-sided traumatic diaphragmatic injury (TDI) in a single level I trauma center. This cross-sectional study was conducted during a 7-year period from 2008 to 2015 in a level I trauma center in Qatar. We included all the patients who presented with TDIs during the study period. Data included demographics, mechanism of injury, associated injuries, initial vitals, emergency department disposition, length of ICU and hospital stay, ventilator days, management, and outcomes. The variables were analyzed and compared for patients with left (LTDI) and right (RTDI). A total of 52 TDI cases (79% LTDI and 21% RTDI) were identified with a mean age of 31±11. LTDI patients were more likely to have higher Injury severity scores (p=0.50) and greater AAST organ injury scoring (p=0.661 for all) than RTDI patients. Surgical repair was performed for 85% LTDI vs. 73% RTDI (p=0.342). Recurrent DIs was reported only in LTDI (5.1% vs. 0.0%; p=0.911). Twelve patients died (9 LTDI and 3 RTDI), of them 5 had associated head injury. This single-institution study confirms that LTDI are more commonly diagnosed than RTDI. Exploratory laparotomy is the most frequent procedure considered for the management of diaphragmatic injuries in the emergency settings. To improve outcomes in patients presenting with TDI, large prospective multicenter studies are needed to standardize the TDI management protocols including the diagnostic workup, timing of surgical intervention, and the most appropriate approach of treatment.


Cost impact of high staff turnover on primary care in remote Australia.
Objectives The aim of this study was to estimate the costs of providing primary care and quantify the cost impact of high staff turnover in Northern Territory (NT) remote communities. Methods This cost impact assessment used administrative data from NT Department of Health datasets, including the government accounting system and personnel information and payroll systems between 2004 and 2015, and the primary care information system from 2007 to 2015. Data related to 54 government-managed clinics providing primary care for approximately 27200 Aboriginal and non-Aboriginal people. Main outcome measures were average costs per consultation and per capita, cost differentials by clinic, year and levels of staff turnover. Linear regression and dominance analysis were used to assess the effect of staff turnover on primary care costs, after adjusting for remoteness and weighting analysis by service population. Both current and constant prices were used. Results On average, in constant prices, there was a nearly 10% annual increase in remote clinic expenditure between 2004 and 2015 and an almost 15% annual increase in consultation numbers since 2007. In real terms, the average costs per consultation decreased markedly from A$273 in 2007 to A$197 in 2015, a figure still well above the Medicare bulk-billing rate. The cost differentials between clinics were proportional to staff turnover and remoteness (both P<0.001). A 10% higher annual turnover rate pertains to an A$6.12 increase in costs per consultation. Conclusions High staff turnover exacerbates the already high costs of providing primary care in remote areas, costing approximately A$50 extra per consultation. This equates to an extra A$400000 per clinic per year on average, or A$21million annually for the NT government. Over time, sustained investments in developing a more stable primary care workforce should not only improve primary care in remote areas, but also reduce the costs of excessive turnover and overall service delivery costs. What is known about the topic? Population size and geographical remoteness are important cost drivers in remote clinics, whereas elsewhere in Australia the high use of short-term staff to fill positions has been identified as a major contributor to higher nurse turnover costs and to overall health service costs. Nursing staff expenditure accounts for a large proportion (46%) of total expenditure in NT remote health services, whereas expenditure on Aboriginal Health Practitioners (AHPs) comprises only 6%. Annual nurse turnover rates in remote NT clinics average approximately 150%, whereas levels of 40% in other contexts are considered high. What does this paper add? Annual expenditure for NT remote clinics has increased, on average, by 10% per annum between 2004 and 2015, but small declines in real expenditure have been observed from a maximum in 2012. Expenditure on nursing staff comprises 40% of overall expenditure in remote clinics, whereas expenditure on AHPs comprises less than 5%. The cost impact of every 10% increase in remote nurse and AHP annual turnover has been quantified as an extra A$6.12 per primary care consultation, which equates, on average, to an extra A$400000 per remote clinic, and an extra A$21million overall for the NT Department of Health each year. The average real expenditure per primary care consultation has decreased from A$273 in 2007 to A$197 in 2015, representing a statistically significant linear trend reduction of A$7.71 per consultation annually. What are the implications for practitioners (and other decision-makers)? Adjusting policy settings away from the high use of short-term staff to investment in appropriate training 'pipelines' for the remote primary care workforce may, in the medium and longer term, result in reduced turnover of resident staff and associated cost savings. Targeted recruitment and retention strategies that ensure individual primary care workers are an optimal fit with the remote communities in which they work, together with improved professional and personal support for staff residing in remote communities, may also help reduce turnover, improve workforce stability and lead to stronger therapeutic relationships and better health outcomes.


Changes in tropospheric composition and air quality due to stratospheric ozone depletion and climate change.
It is well-understood that reductions in air quality play a significant role in both environmental and human health. Interactions between ozone depletion and global climate change will significantly alter atmospheric chemistry which, in turn, will cause changes in concentrations of natural and human-made gases and aerosols. Models predict that tropospheric ozone near the surface will increase globally by up to 10 to 30 ppbv (33 to 100% increase) during the period 2000 to 2100. With the increase in the amount of the stratospheric ozone, increased transport from the stratosphere to the troposphere will result in different responses in polluted and unpolluted areas. In contrast, global changes in tropospheric hydroxyl radical (OH) are not predicted to be large, except where influenced by the presence of oxidizable organic matter, such as from large-scale forest fires. Recent measurements in a relatively clean location over 5 years showed that OH concentrations can be predicted by the intensity of solar ultraviolet radiation. If this relationship is confirmed by further observations, this approach could be used to simplify assessments of air quality. Analysis of surface-level ozone observations in Antarctica suggests that there has been a significant change in the chemistry of the boundary layer of the atmosphere in this region as a result of stratospheric ozone depletion. The oxidation potential of the Antarctic boundary layer is estimated to be greater now than before the development of the ozone hole. Recent modeling studies have suggested that iodine and iodine-containing substances from natural sources, such as the ocean, may increase stratospheric ozone depletion significantly in polar regions during spring. Given the uncertainty of the fate of iodine in the stratosphere, the results may also be relevant for stratospheric ozone depletion and measurements of the influence of these substances on ozone depletion should be considered in the future. In agreement with known usage and atmospheric loss processes, tropospheric concentrations of HFC-134a, the main human-made source of trifluoroacetic acid (TFA), is increasing rapidly. As HFC-134a is a potent greenhouse gas, this increasing concentration has implications for climate change. However, the risks to humans and the environment from substances, such as TFA, produced by atmospheric degradation of hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs) are considered minimal. Perfluoropolyethers, commonly used as industrial heat transfer fluids and proposed as chlorohydrofluorocarbon (CHFC) substitutes, show great stability to chemical degradation in the atmosphere. These substances have been suggested as substitutes for CHFCs but, as they are very persistent in the atmosphere, they may be important contributors to global warming. It is not known whether these substances will contribute significantly to global warming and its interaction with ozone depletion but they should be considered for further evaluation.


Coping skills among adolescent suicide attempters: results of a multisite study.
A multisite study was undertaken to advance our understanding of how coping skills, depression, and suicidal ideation are related among adolescents who attempt suicide. Two hypotheses were postulated: productive coping and nonproductive coping would be associated, respectively, with lower and higher depression scores when age, sex, and stressful life events (SLEs) were controlled; and productive coping and nonproductive coping would be associated, respectively, with the presence and absence of suicidal ideation when age, sex, and SLEs were controlled. Participants were 167 adolescents (13 to 17 years of age) hospitalized for attempting suicide in 5 pediatric departments across France. Four instruments were administered: the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version, the Adolescent Coping Scale, the Life Events Questionnaire, and the Columbia-Suicide Severity Rating Scale. Descriptive analyses and univariate and multiple regression models were completed. Both hypotheses were confirmed. Focus on the positive emerged as a significant variable in both models; depression emerged as a significant variable in the suicidal ideation model. The only sex difference observed was that girls made greater use of wishful thinking and seek social support. These findings suggest that coping skills are important mechanisms through which depression and suicidal ideation are maintained after attempting suicide. In intervening with adolescents who have attempted suicide, it may be useful to emphasize cognitive work geared to looking on the bright side, positive thinking, and fighting depression.


Synthesis and structure of trinuclear W3S4 clusters bearing aminophosphine ligands and their reactivity toward halides and pseudohalides.
The aminophosphine ligand (2-aminoethyl)diphenylphosphine (edpp) has been coordinated to the W3(μ-S)(μ-S)3 cluster unit to afford trimetallic complex [W3S4Br3(edpp)3](+) (1(+)) in a one-step synthesis process with high yields. Related [W3S4X3(edpp)3](+) clusters (X = F(-), Cl(-), NCS(-); 2(+)-4(+)) have been isolated by treating 1(+) with the corresponding halide or pseudohalide salt. The structure of complexes 1(+) to 4(+) contains an incomplete W3S4 cubane-type cluster unit, and only one of the possible isomers is formed: the one with the phosphorus atoms trans to the capping sulfur and the amino groups trans to the bridging sulphurs. The remaining coordination position on each metal is occupied by X. Detailed studies using stopped-flow, (31)P{(1)H} NMR, and ESI-MS have been carried out in order to understand the solution behavior and the kinetics of interconversion among species 1(+), 2(+), 3(+), and 4(+) in solution. Density functional theory (DFT) calculations have been also carried out on the reactions of cluster 1(+) with the different anions. The whole set of experimental and theoretical data indicate that the actual mechanism of substitutions in these clusters is strongly dependent on the nature of the leaving and entering anions. The interaction between an entering F(-) and the amino group coordinated to the adjacent metal have also been found to be especially relevant to the kinetics of these reactions.


Fibroblast growth factor 2 drives changes in gene expression following injury to murine cartilage in vitro and in vivo.
The articular cartilage is known to be highly mechanosensitive, and a number of mechanosensing mechanisms have been proposed as mediators of the cellular responses to altered mechanical load. These pathways are likely to be important in tissue homeostasis as well as in the pathogenesis of osteoarthritis. One important injury-activated pathway involves the release of pericellular fibroblast growth factor 2 (FGF-2) from the articular cartilage. Using a novel model of murine cartilage injury and surgically destabilized joints in mice, we examined the extent to which FGF-2 contributes to the cellular gene response to injury. Femoral epiphyses from 5-week-old wild-type mice were avulsed and cultured in serum-free medium. Explant lysates were Western blotted for phospho-JNK, phospho-p38, and phospho-ERK or were fixed for immunohistochemical analysis of the nuclear translocation of p65 (indicative of NF-κB activation). RNA was extracted from injured explants, rested explants that had been stimulated with recombinant FGF-2 or FGF-18, or whole joints from either wild-type mice or FGF-2(-/-) mice. Reverse transcription-polymerase chain reaction was performed to examine a number of inflammatory response genes that had previously been identified in a microarray analysis. Murine cartilage avulsion injury resulted in rapid activation of the 3 MAP kinase pathways as well as NF-κB. Almost all genes identified in murine joints following surgical destabilization were also regulated in cartilage explants upon injury. Many of these genes, including those for activin A (Inhba), tumor necrosis factor-stimulated gene 6 (Tnfaip6), matrix metalloproteinase 19 (Mmp19), tissue inhibitor of metalloproteinases 1 (Timp1), and podoplanin (Pdpn), were significantly FGF-2 dependent following injury to cartilage in vitro and to joint tissues in vivo. FGF-2-dependent gene expression occurs in vitro and in vivo in response to cartilage/joint injury in mice.


Haemophore-mediated signal transduction across the bacterial cell envelope in Serratia marcescens: the inducer and the transported substrate are different molecules.
Numerous bacteria are able to use free and haemoprotein-bound haem as iron sources because of the action of small secreted proteins called haemophores. Haemophores have very high affinity for haem, and can therefore extract haem from the haem-carrier proteins and deliver it to the cells by means of specific cell surface receptors. Haem is then taken up and the empty haemophores are recycled. Here, we report a study of the regulation of the Serratia marcescens has operon which is involved in haemophore-dependent haem acquisition. We characterized two genes encoding proteins homologous to specific ECF sigma and antisigma factors. We showed that they regulate the synthesis of the haemophore-specific outer membrane receptor, HasR, by a signal transduction mechanism similar to the siderophore surface-signalling systems. We also showed the essential role of HasR itself in this process. Using haem-loaded and haem-free haemophore, we identified the stimulus for the HasR-mediated signal transduction as being the binding of the haem-loaded haemophore to HasR. Thus, unlike siderophore-uptake systems, in which the signalling molecule is the transported substrate itself, in the haemophore-dependent haem uptake system the inducer and the transported substrate are different compounds.


Are postsynaptic 5-HT1A receptors involved in the anxiolytic effects of 5-HT1A receptor agonists and in their inhibitory effects on the firing of serotonergic neurons in the rat?
Previous studies have shown that injection of 5-hydroxytryptamine (serotonin) receptor agonists in the dorsal raphe nucleus (DRN) to stimulate somatodendritic 5-HT1A autoreceptors or in the hippocampus to stimulate postsynaptic 5-HT1A receptors, induces anxiolytic-like effects in the rat. The mechanisms triggered by the latter treatment were investigated by measuring both the electrical activity of serotonergic DRN neurons and the anxiolytic response in rats receiving injections with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) or ipsapirone into the dorsal hippocampus. Anxiety-related behavior was estimated by recording the time of ultrasonic vocalization (USV) due to electric foot shocks under standardized conditions. Intrahippocampal application of 8-OH-DPAT or ipsapirone produced a dose-dependent inhibition of the firing of serotonergic DRN neurons and of the shock-induced USV response. However, the range of efficient doses of 8-OH-DPAT via the intrahippocampal route (1-10 micrograms/rat) was larger than that using the i.v. route of injection (0.15-2.5 micrograms/rat). Furthermore, maximal inhibition of the firing of DRN serotonergic neurons occurred earlier when 8-OH-DPAT was injected i.v. (within 1-2 min) than when it was injected into the dorsal hippocampus (within 5 min). Interestingly, the injection of 8-OH-DPAT into the striatum, where 5-HT1A receptors are hardly detectable, or a lateral ventricle, also yielded dose-dependent reduction in both the firing rate of serotonergic DRN neurons and the USV response. Finally, local lesion with ibotenic acid to eliminate postsynaptic 5-HT1A receptors did not alter the inhibitory effects of intrahippocampal application of 8-OH-DPAT on the firing of serotonergic DRN neurons and the USV response. These data indicated that postsynaptic 5-HT1A receptors were not responsible for the inhibitory effects of 8-OH-DPAT and ipsapirone injected in forebrain areas on the electrical activity of serotonergic neurons and the USV response in rats. As shown by the autoradiographic labeling by [3H]8-OH-DPAT at distance from its injection site in the dorsal hippocampus, the diffusion of 5-HT1A receptor agonists (from injected areas in the forebrain to the DRN where they directly inhibit the electrical activity of serotonergic neurons) more likely accounted for their anxiolytic-like effects.


Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice.
Besides lowering cholesterol, statins exert multiple effects, such as anti-inflammatory activity and improvement of endothelial cell function. We examined whether simvastatin (SS) protects against the development of elastase-induced pulmonary emphysema in mice by using mean linear intercepts of alveoli (Lm) as a morphometric parameter of emphysema. After injection of intratracheal elastase on day 0, C57BL/6 mice were treated daily with SS (SS+ group) or PBS (SS- group) for 2 wk. A 21% decrease in Lm on day 7 was observed in the SS+ group vs. the SS- group. Anti-inflammatory effects of SS were observed as a decrease in percentage of neutrophils up to day 3, and in hydroxyproline concentration on day 3, in bronchoalveolar lavage fluid (BALF). SS also increased the number of proliferating cell nuclear antigen (PCNA)-positive alveolar epithelial cells between days 3 and 14. To confirm the role of statins in promoting proliferation of alveolar cells, mice were treated with SS (SS+) vs. PBS (SS-) for 12 days, starting 3 wk after elastase administration. After SS treatment, Lm decreased by 52% and PCNA-positive alveolar epithelial cells increased compared with the SS- group. Concentrations of vascular endothelial growth factor in BALF and endothelial nitric oxide synthase protein expression in pulmonary vessels tended to be higher in the SS+ group vs. the SS- group in this protocol. In conclusion, SS inhibited the development of elastase-induced pulmonary emphysema in mice. This therapeutic effect was due not only to anti-inflammation but also to the promotion of alveolar epithelial cell regeneration, partly mediated by restoring endothelial cell functions.


Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells.
Mesotheliomas are tumors arising from mesothelial cells and are associated with asbestos exposure and approximately 50% contain simian virus 40 (SV40) DNA sequences. SV40 infection of human mesothelial cells (HM) causes early cellular immortalization and late transformation. Aberrant methylation is a major mech-anism for loss of function of tumor suppressor genes (TSGs). We recently reported that of seven genes frequently methylated in epithelial tumors, only RASSF1A gene was frequently methylated in mesotheliomas, and its methylation was correlated with loss of RASSF1A expression and the presence of SV40. We studied whether SV40 infection of normal HM induces aberrant methylation of the genes previously studied in mesotheliomas. Of six infected foci examined at early passages (passages 8-30) there was no methylation of the seven genes examined. Of two foci examined at late passages (passages 51-86) after the appearance of morphological changes suggestive of transformation, methylation and loss of expression of RASSF1A was detected. Sequencing of the CpG dense region around the transcription start site and semi-quantitative real-time methylation specific PCR (MSP) assay for RASSF1A methylation demonstrated progressive methylation during late passages. Exposure to the demethylating agent 5-aza-2'-deoxycytidine restored RASSF1A expression, while exposure to the histone deacetylation inhibitor trichostatin A had no effect. These data, together with our previous findings, support a causal relationship between SV40 infection, progressive RASSF1A methylation and its silencing, and the pathogenesis of mesothelioma.


EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma.
To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4. EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4-expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective. Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti-PD-(L)1 treatment, liver metastases, or upper-tract disease. Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.


Effects of metsulfuron methyl and cypermethrin exposure on freshwater model ecosystems.
The aim of this study was to investigate the short-term (2 weeks) effects of the herbicide metsulfuron methyl alone and in combination with the insecticide cypermethrin in freshwater enclosures (80 l). We used a factorial design with four levels of herbicide (0, 1, 5, 20 microg/l) and two levels of insecticide (0 and 0.05 microg/l). The root growth of the macrophyte species Elodea canadensis and Myriophyllum spicatum decreased following exposure to the lowest concentration of metsulfuron methyl tested. Metsulfuron methyl exposure resulted in a decreased pH in the aquatic enclosure at the lowest concentration tested, which is most likely a further indication of decreased macrophyte primary production. The biomass of periphytic algae growing on the leaves of M. spicatum increased in the enclosures exposed to metsulfuron methyl. The species composition of the periphytic algae differed significantly from the controls in the enclosures exposed to 20 microg/l of the herbicide. The increased biomass of periphytic algae on the leaves of the macrophytes is probably an indirect effect of the herbicide exposure. The exposure to metsulfuron methyl possibly induced a leakage of nutrients from the macrophyte leaves, which promoted an increased algal growth. The exposure to metsulfuron methyl did not alter the biomass or the species composition of the phytoplankton community. The zooplankton communities in the enclosures were dominated by rotifers, which were not affected by the exposure to cypermethrin. However, a cypermethrin exposure of 0.05 microg/l initially decreased the abundance of copepod nauplii. Ten days after exposure, the abundance of nauplii was significantly higher in the insecticide-exposed enclosures compared with the non-exposed enclosures. This might be an indication of a sub-lethal stress response, which either increased the number of offspring produced or induced an increased hatching of copepod resting stages. No combined effects of the herbicide and insecticide exposure, either direct or indirect, were observed in the enclosure study. Significant effects on the macrophytes were observed following exposure to 1 microg metsulfuron methyl per litre in the enclosure study. Furthermore, a single species laboratory assay indicated that the shoot elongation of E. canadensis decreased following exposure to >or=0.1 microg metsulfuron methyl per litre. These concentrations are well within the range of expected environmental concentrations, thus this study shows that aquatic ecosystems, in particular those which are macrophyte-dominated, may be affected by metsulfuron methyl at concentrations that may well occur in water bodies adjacent to agricultural land.


Variations of bacterial populations in human feces measured by fluorescent in situ hybridization with group-specific 16S rRNA-targeted oligonucleotide probes.
Six 16S rRNA-targeted oligonucleotide probes were designed, validated, and used to quantify predominant groups of anaerobic bacteria in human fecal samples. A set of two probes was specific for species of the Bacteroides fragilis group and the species Bacteroides distasonis. Two others were designed to detect species of the Clostridium histolyticum and the Clostridium lituseburense groups. Another probe was designed for the genera Streptococcus and Lactococcus, and the final probe was designed for the species of the Clostridium coccoides-Eubacterium rectale group. The temperature of dissociation of each of the probes was determined. The specificities of the probes for a collection of target and reference organisms were tested by dot blot hybridization and fluorescent in situ hybridization (FISH). The new probes were used in initial FISH experiments to enumerate human fecal bacteria. The combination of the two Bacteroides-specific probes detected a mean of 5.4 x 10(10) cells per g (dry weight) of feces; the Clostridium coccoides-Eubacterium rectale group-specific probe detected a mean of 7.2 x 10(10) cells per g (dry weight) of feces. The Clostridium histolyticum, Clostridium lituseburense, and Streptococcus-Lactococcus group-specific probes detected only numbers of cells ranging from 1 x 10(7) to 7 x 10(8) per g (dry weight) of feces. Three of the newly designed probes and three additional probes were used in further FISH experiments to study the fecal flora composition of nine volunteers over a period of 8 months. The combination of probes was able to detect at least two-thirds of the fecal flora. The normal biological variations within the fecal populations of the volunteers were determined and indicated that these variations should be considered when evaluating the effects of agents modulating the flora.


Electrosprayed microparticles for intestinal delivery of prednisolone.
Single and coaxial electrospraying was used to prepare Eudragit L100-55 polymer microparticles containing prednisolone as the active pharmaceutical ingredient. Different compositions of prednisolone and Eudragit L100-55 were used to develop five different formulations with different polymer : drug ratios. The resultant microparticles had a toroidal shape with a narrow size distribution. Prednisolone was present in an amorphous physical state, as confirmed by X-ray diffraction analysis. Dissolution studies were carried out in order to investigate the feasibility of the proposed system for site-specific release of prednisolone. The release rates were interpreted in terms of diffusion-controlled release. It was shown that utilization of pH-responsive Eudragit L100-55 could minimize the release of prednisolone in the acidic conditions of the stomach, which was followed by rapid release as the pH of the release medium was adjusted to 6.8 after the first 2 h. This is especially desirable for the treatment of conditions including inflammatory bowel disease and colon cancer.


Phosphorylation of a major GPI-anchored surface protein of Trypanosoma brucei during transport to the plasma membrane.
The surface coat of procyclic forms of Trypanosoma brucei consists of related, internally repetitive glycoproteins known as EP and GPEET procyclins. Previously we showed that the extracellular domain of GPEET is phosphorylated. We now show that phosphorylation of this glycosylphosphatidylinositol-anchored surface protein can be induced in vitro using a procyclic membrane extract. Using antibodies that recognize either the phosphorylated or unphosphorylated form of GPEET, we analyzed their expression during differentiation of bloodstream forms to procyclic forms. Unphosphorylated GPEET, together with EP, was detected in cell lysates 2-4 hours after initiating differentiation whereas phosphorylated GPEET only appeared after 24 hours. Surface expression of EP and both forms of GPEET occurred after 24-48 hours and correlated with the detection of phosphorylated GPEET on immuno-blots. Electron micrographs showed that unphosphorylated GPEET was predominantly in the flagellar pocket whereas the phosphorylated form was distributed over the cell surface. In contrast, expression of a membrane-bound human placental alkaline phosphatase in procyclic forms caused the accumulation of dephosphorylated GPEET on the cell surface, while the phosphorylated form was restricted to the flagellar pocket. A GPEET-Fc fusion protein, which was retained intracellularly, was not phosphorylated. We propose that unphosphorylated GPEET procyclin is transported to a location close to or at the cell surface, most probably the flagellar pocket, where it becomes phosphorylated. To the best of our knowledge, this study represents the first localization of phosphorylated and unphosphorylated forms of a GPI-anchored protein within a cell.


Prevalence and correlates of cocaine physical dependence subtypes using the DSM-IV in outpatients receiving opioid agonist medication.
The present study used a cross-sectional design to examine the relationship between endorsement of physiological dependence to cocaine (i.e., tolerance and/or withdrawal) and lifetime, and current problem severity (i.e., psychiatric and substance use disorders, medical and psychosocial problems) for opioid and cocaine dependent individuals (n=719) newly admitted to a treatment program using opioid-agonist medication. All participants completed the structured clinical interview for the Diagnostic and Statistical Manual (DSM-IV) (SCID-IV) and the Addiction Severity Index (ASI). Participants were first classified into physiological (n=549) versus non-physiological (n=170) cocaine dependence groups for one set of analyses and then categorized into one of four groups for further analyses: (1) tolerance only (n=215), (2) tolerance plus withdrawal (n=279), (3) withdrawal only (n=55) or (4) no physiological dependence (n=170). Those participants who endorsed physiological dependence reported higher rates of lifetime psychiatric and substance use disorders, higher rates of current drug use and more current problems. The four-group analyses showed that endorsement of withdrawal, with or without tolerance, was associated with the most severe problems. These findings suggest that physiological dependence to cocaine (particularly the presence of withdrawal) is a marker for a more severe substance use disorder and higher rates of comorbid psychopathology and other problems.


Impact of preoperative immunosuppressive agents on postoperative outcomes in Crohn's disease.
Immunosuppressive agents are essential in the management of Crohn's disease. Their safety before surgery, however, is still controversial. The aim of this study is to evaluate whether the preoperative use of immunosuppressive agents is associated with increased postoperative complications in Crohn's disease. A literature search of PubMed, EMBASE, and The Cochrane Library was undertaken in February 2013. All studies describing postoperative outcomes of patients undergoing bowel resections for Crohn's disease were included if they reported data comparing patients on preoperative immunosuppressive agents with an appropriate control group. All immunosuppressive agents used to manage Crohn's disease were studied. The main outcomes measured were total overall complications and total infectious complications. Twenty-one eligible studies (20 retrospective and 1 prospective) with 6899 patients were included. When individual studies were examined, only 2/14 (14%), 4/13 (31%), and 1/8 (13%) studies found an association between postoperative complications and preoperative anti-tumor necrosis factor agents, corticosteroids, and thiopurines. In meta-analyses, patients on anti-tumor necrosis factor agents (risk ratio, 1.29; 95% CI, 1.07-1.55), and corticosteroids (risk ratio, 1.55; 95% CI, 1.23-1.95) were found to have a higher risk of postoperative infectious complications. The use of anti-tumor necrosis factor agents was also significantly associated with wound infection (risk ratio, 1.62; 95% CI, 1.12-2.34) and septic shock (risk ratio, 1.81; 95% CI, 1.03-3.17). There was no association between the use of thiopurines or combined immunomodulator drugs and postoperative complications. Most studies were retrospectively designed, and there were large variations in the patient populations and outcome definitions. Patients with Crohn's disease on preoperative immunosuppressive agents are at higher risk for complications. Both corticosteroids and anti-tumor necrosis factor agents may increase the risk of infections and septic shock. A preoperative drug-free interval, when feasible, might be considered to reduce the risk of infections. The adoption of any operative strategies that modify these outcomes may additionally counter these risks.


Challenges in accessing routinely collected data from multiple providers in the UK for primary studies: Managing the morass.
Researchers are increasingly using routinely collected data in addition to, or instead of, other data collection methods. The UK government continues to invest in research centres to encourage use of these data, and trials and cohort studies utilise data linkage methods in the follow-up of participants. This does not come without its limitations and challenges, such as data access delays. This paper outlines the challenges faced by three projects utilising individual-level routinely-collected linked data for the longer-term follow-up of participants. These studies are varied in design, study population and data providers. One researcher was common to the three studies and collated relevant study correspondence, formal documentary evidence such as data sharing agreements and, where relevant, meeting records to review. Key themes were identified and reviewed by other members of the research teams. Mitigating strategies were identified and discussed with a data provider representative and a broader group of researchers to finalise the recommendations presented. The challenges discussed are grouped into five themes: Data application process; Project timelines; Dependencies and considerations related to consent; Information Governance; Contractual. In presenting our results descriptively we summarise each case study, identify the main cross-cutting themes and consider the potential for mitigation of challenges. We make recommendations that identify responsibilities for both researchers and data providers for mitigating and managing data access challenges. A continued conversation within the research community and with data providers is needed to continue to enable researchers to access and utilise the wealth of routinely-collected data available. The suggestions made in this paper will help researchers be better prepared to deal with the challenges of applying for data from multiple data providers.


Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial.
Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years. BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported. Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up. Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.


Biotinylated Surfome Profiling Identifies Potential Biomarkers for Diagnosis and Therapy of Aspergillus fumigatus Infection.
Aspergillus fumigatus is one of the most common airborne molds capable of causing mycoses and allergies in humans. During infection, fungal surface proteins mediate the first contact with the human immune system to evade immune responses or to induce hypersensitivity. Several methods have been established for surface proteomics (surfomics). Biotinylation coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification of peptides is a particularly efficient method to identify the surface-exposed regions of proteins that potentially mediate interaction with the host. After biotinylation of surface proteins during spore germination, we detected 231 different biotinylated surface proteins (including several well-known proteins such as RodA, CcpA, and DppV; allergens; and heat shock proteins [HSPs]), as well as some previously undescribed surface proteins. The dynamic change of the surface proteome was illustrated by detection of a relatively high number of proteins exclusively at one developmental stage. Using immunofluorescence microscopy, we confirmed the surface localization of several HSPs of the HSP70 family, which may have moonlighting functions. Collectively, by comparing our data with data representative of previously published A. fumigatus surface proteomes, our study generated a comprehensive data set corresponding to the A. fumigatus surfome and uncovered the surface-exposed regions of many proteins on the surface of conidia or hyphae. These surface-exposed regions are candidates for direct interaction with host cells and may represent antigenic epitopes that either induce protective immune responses or mediate immune evasion. Thus, our data sets provided and compiled here represent reasonable immunotherapy and diagnostic targets for future investigations.IMPORTANCEAspergillus fumigatus is the most important airborne human-pathogenic mold, capable of causing both life-threatening invasive pulmonary aspergillosis in immunocompromised patients and allergy-inducing infections in individuals with atopic allergy. Despite its obvious medical relevance, timely diagnosis and efficient antifungal treatment of A. fumigatus infection remain major challenges. Proteins on the surface of conidia (asexually produced spores) and mycelium directly mediate host-pathogen interaction and also may serve as targets for diagnosis and immunotherapy. However, the similarity of protein sequences between A. fumigatus and other organisms, sometimes even including the human host, makes selection of targets for immunological-based studies difficult. Here, using surface protein biotinylation coupled with LC-MS/MS analysis, we identified hundreds of A. fumigatus surface proteins with exposed regions, further defining putative targets for possible diagnostic and immunotherapeutic design.


Discovery of hierarchical superstructures in block copolymers by integrating different liquid crystalline interactions.
Hierarchically assembled superstructures of block copolymers are discovered by introduction of the competition of anisotropy attributed from liquid crystalline ordering and nano-phase separation. When the two prototypical fields of liquid crystals (LCs), smectics (S) and nematics (N), are adjoined within the framework of diblock copolymers (S-N) in a variety of precisely tuned compositions, a novel class of superlattices with an interdigitated array of smectic layers between the nearest lamellae or cylinders are observed. This generates unconventional nano-phase separated orthorhombic (Lo) and pseudo-hexagonal (Ho) structures, where the stretched N tethers, projected regularly from the S layers, could transfer the local organization and guide the correlated assembly. This type of superstructure is highly frustrated in reversed cylindrical morphology and absent in S-coil diblock copolymers. The collective interplay of the S and N interactions with nano-phase separation induces the formation of the final complex yet equilibrium structures, providing unprecedented opportunities towards exquisite structural diversity.


An Examination of Metrics for a Simulated Ventriculostomy Part-Task.
As one of the most commonly performed neurosurgical procedures, ventriculostomy training simulators are becoming increasingly familiar features in research institutes and teaching facilities. Despite their widespread implementations and adoption, simulators to date have not fully explored the landscape of performance metrics that reflect surgical proficiency. They opt instead for measures that are qualitative or simple to compute and conceptualize. In this paper, we examine and compare the use of various metrics to characterize the performance of users on simulated part-task ventriculostomy scenarios derived from patient data. As an initial study, we examine how our metrics relate to expert classification of scenario difficulty as well as measures of anatomical variation.


Neural mechanisms of empathy in humans: a relay from neural systems for imitation to limbic areas.
How do we empathize with others? A mechanism according to which action representation modulates emotional activity may provide an essential functional architecture for empathy. The superior temporal and inferior frontal cortices are critical areas for action representation and are connected to the limbic system via the insula. Thus, the insula may be a critical relay from action representation to emotion. We used functional MRI while subjects were either imitating or simply observing emotional facial expressions. Imitation and observation of emotions activated a largely similar network of brain areas. Within this network, there was greater activity during imitation, compared with observation of emotions, in premotor areas including the inferior frontal cortex, as well as in the superior temporal cortex, insula, and amygdala. We understand what others feel by a mechanism of action representation that allows empathy and modulates our emotional content. The insula plays a fundamental role in this mechanism.