APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation.
Increasing evidence suggests that elevated Aβ42 fractions in the brain cause Alzheimer's disease (AD). Although γ-secretase modulators (GSMs), including a set of nonsteroidal anti-inflammatory drugs (NSAIDs), were found to lower Aβ42 in various model systems, NSAID-based GSMs proved to be surprisingly inefficient in human clinical trials. Reasoning that the nonhuman and nonneuronal cells typically used in pharmaceutical compound validation might not adequately reflect the drug responses of human neurons, we used human pluripotent stem cell-derived neurons from AD patients and unaffected donors to explore the efficacy of NSAID-based γ-secretase modulation. We found that pharmaceutically relevant concentrations of these GSMs that are clearly efficacious in conventional nonneuronal cell models fail to elicit any effect on Aβ42/Aß40 ratios in human neurons. Our work reveals resistance of human neurons to NSAID-based γ-secretase modulation, highlighting the need to validate compound efficacy directly in the human cell type affected by the respective disease.


Evaluation of e-prescribing in chain community pharmacy: best-practice recommendations.
To measure the attitudes and beliefs of community-based pharmacists and technicians toward electronic prescribing (e-prescribing) and the processing of e-prescriptions and to generate best-practice recommendations for changes to improve e-prescribing in the community setting. Descriptive, nonexperimental, cross-sectional study. 422 chain community pharmacies in six states that met a minimum dispensing volume of five e-prescriptions per day. Data were collected between April and July 2006. Pharmacists, technicians, and student interns. Receiving, processing, and dispensing of e-prescriptions assessed via self-administered survey and follow-up interviews of key pharmacy operations and information technology management in each participating chain pharmacy organization. Attitudes, beliefs, and satisfaction of pharmacy personnel regarding e-prescribing, compared with conventional prescribing, and recommendations for improving e-prescribing in the community practice setting. 1,094 surveys were returned from pharmacy personnel practicing in 276 chain community pharmacies. Pharmacy personnel preferred e-prescriptions over conventional prescriptions on each of seven desired outcomes of care. Pharmacists were found to view e-prescribing more positively than technicians (P < 0.05) for its net effect on three key outcomes: patient safety, effectiveness of care, and efficiency of care. A total of 2,235 written comments were received on the returned surveys. Of these, 57% (1,277) mentioned negative features of e-prescribing, while 43% (958) noted positive features. Improved clarity and/or legibility of prescriptions was the most frequently cited advantage of e-prescribing, followed closely by improved speed or efficiency of processing. Prescribing errors were the most commonly cited negative feature of e-prescribing, particularly those stating a wrong drug or wrong directions. Pharmacy personnel were generally satisfied with the current status of e-prescribing, but they also perceive key weaknesses in how it has been implemented in physicians' practices and their own organizations. A total of 11 best-practice recommendations are offered to improve e-prescribing in the chain community pharmacy setting.


Value of serum cartilage oligomeric matrix protein as a prognostic marker of large-joint damage in rheumatoid arthritis--data from the RAPIT study.
To investigate the utility of serum COMP level measurements as a predictor of future damage of the weight-bearing (large) joints in RA patients participating in intensive exercise. Data of the 281 completers of a 2-yr randomized controlled trial (Rheumatoid Arthritis Patients In Training; RAPIT) comparing the effects of usual care physical therapy with high-intensity weight-bearing exercises were analysed. The primary outcome variable was defined as the change in radiological joint damage (Larsen score) of the large joints. Potential predictors of outcome were defined: baseline and change in serum level of COMP after 3 months, baseline radiological damage of the large and small joints, number of months on glucocorticoids, change in disease activity and in physical capacity (aerobic fitness and muscle strength) after 2 yrs, and participation in the exercise group. In cross-sectional evaluation of baseline data, we found strong association between the high serum COMP level and current damage of the large joints. Serum COMP level at baseline, however, was not associated with an increased rate of radiological joint damage after 2 yrs of follow-up. Furthermore, neither interaction between baseline COMP level and participation in exercises, nor change in COMP level after 3 months of exercising were associated with future damage of the large joints. Neither baseline serum COMP level nor its individual change after 3 months from start of intensive exercise predict longitudinal progression of damage of the large joints in this population.


Estimation of allele frequency and association mapping using next-generation sequencing data.
Estimation of allele frequency is of fundamental importance in population genetic analyses and in association mapping. In most studies using next-generation sequencing, a cost effective approach is to use medium or low-coverage data (e.g., < 15X). However, SNP calling and allele frequency estimation in such studies is associated with substantial statistical uncertainty because of varying coverage and high error rates. We evaluate a new maximum likelihood method for estimating allele frequencies in low and medium coverage next-generation sequencing data. The method is based on integrating over uncertainty in the data for each individual rather than first calling genotypes. This method can be applied to directly test for associations in case/control studies. We use simulations to compare the likelihood method to methods based on genotype calling, and show that the likelihood method outperforms the genotype calling methods in terms of: (1) accuracy of allele frequency estimation, (2) accuracy of the estimation of the distribution of allele frequencies across neutrally evolving sites, and (3) statistical power in association mapping studies. Using real re-sequencing data from 200 individuals obtained from an exon-capture experiment, we show that the patterns observed in the simulations are also found in real data. Overall, our results suggest that association mapping and estimation of allele frequencies should not be based on genotype calling in low to medium coverage data. Furthermore, if genotype calling methods are used, it is usually better not to filter genotypes based on the call confidence score.


Signalling DNA damage by regulating p53 co-factor activity.
In response to DNA damage the related phosphatidylinositol-3-OH-kinase-like-kinases ATM and ATR phosphorylate downstream protein targets which facilitate the DNA damage response. A new pathway in which ATM phosphorylates the transcriptional co-factor Strap has been elucidated. Phosphorylation causes the stabilization of nuclear Strap and favours the formation of a stress-responsive co-activator complex. Strap activity enhances p53 acetylation, and augments the response to DNA damage. Most interestingly, in AT cells Strap remains cytoplasmic, and a mutant derivative that cannot be phosphorylated by ATM is similarly localised to the cytoplasm. These results argue that Strap is an important downstream effector in the DNA damage response.


An improved method for nematode infection assays in Drosophila larvae.
The infective juveniles (IJs) of entomopathogenic nematodes (EPNs) seek out host insects and release their symbiotic bacteria into their body cavity causing septicaemia, which eventually leads to host death. The interaction between EPNs and their hosts are only partially understood, in particular the host immune responses appears to involve pathways other than phagocytosis and the canonical transcriptional induction pathways. These pathways are genetically tractable and include for example clotting factors and lipid mediators. The aim of this study was to optimize the nematode infections in Drosophila melanogaster larvae, a well-studied and genetically tractable model organism. Here we show that two nematode species namely Steinernema feltiae and Heterorhabditis bacteriophora display different infectivity toward Drosophila larvae with the latter being less pathogenic. The effects of supporting media and IJ dosage on the mortality of the hosts were assessed and optimized. Using optimum conditions, a faster and efficient setup for nematode infections was developed. This newly established infection model in Drosophila larvae will be applicable in large scale screens aimed at identifying novel genes/pathways involved in innate immune responses.


Clinical recommendations regarding use of cone beam computed tomography in orthodontics. [corrected]. Position statement by the American Academy of Oral and Maxillofacial Radiology.
To summarize the potential benefits and risks of maxillofacial cone beam computed tomography (CBCT) use in orthodontic diagnosis, treatment and outcomes and to provide clinical guidance to dental practitioners. This statement was developed by consensus agreement of a panel convened by the American Academy of Oral and Maxillofacial Radiology (AAOMR). The literature on the clinical efficacy of and radiation dose concepts associated with CBCT in all aspects of orthodontic practice was reviewed. The panel concluded that the use of CBCT in orthodontic treatment should be justified on an individual basis, based on clinical presentation. This statement provides general recommendations, specific use selection recommendations, optimization protocols, and radiation-dose, risk-assessment strategies for CBCT imaging in orthodontic diagnosis, treatment and outcomes. The AAOMR supports the safe use of CBCT in dentistry. This position statement is periodically revised to reflect new evidence and, without reapproval, becomes invalid after 5 years.


Fiber Raman background study and its application in setting up optical fiber Raman probes.
Fiber Raman background spectra of different types of fused-silica fibers are studied and compared. The results show the following: (a) all the background spectra are very similar and comparable with Raman spectra of fused silica, regardless of the difference in the cladding and buffer materials; (b) the overall background intensity increases with the fiber numerical aperture but has no obvious relation with the core diameter. Both experimental evidence and theoretical explanation have been provided for these views. A simple and unfiltered fiber probe for surface-enhanced Raman scattering detection with low fiber Raman background interference is constructed, and the optimum configuration of the probe is suggested and discussed based on the results of the background study.


Dispersive solid-phase microextraction with graphene oxide based molecularly imprinted polymers for determining bis(2-ethylhexyl) phthalate in environmental water.
A novel graphene oxide-molecularly imprinted polymers (GO-MIPs) was prepared and applied for selective extraction and preconcentration of bis(2-ethylhexyl) phthalate (DEHP) in environmental water samples by using the dispersive solid-phase microextraction (DSPME) method. The GO-MIPs was synthesized via precipitation polymerization using GO, DEHP, methacrylic acid, and ethylene dimethacrylate as supporting materials, template molecules, functional monomer, and cross-linker, respectively. The prepared GO-MIPs were characterized by scanning electron microscope and Fourier transform infrared spectroscopy. The GO-MIPs-DSPME conditions including type and volume of elution solvents, adsorbents amount, initial concentration of DEHP, pH and ionic strength of water samples were investigated. Under optimized conditions, the DEHP was selectively and effectively extracted in real water samples and enrichment factors of over 100-fold were achieved. Good linearity was obtained with correlation coefficients (R2) over 0.999 and the detection limit (S/N=3) was 0.92ngmL-1. The average recoveries of the spiked samples at three concentration levels of DEHP ranged from 82% to 92% with the relative standard deviations less than 6.7%. The results indicated that the proposed GO-MIPs-DSPME extraction protocol combined with HPLC-UV determination could be applied for selective and sensitive analysis of trace DEHP phthalate in environmental water samples.


Clinical advantage of endoscopic submucosal dissection over endoscopic mucosal resection for early mesopharyngeal and hypopharyngeal cancers.
In previous series, endoscopic mucosal resection (EMR) has been used for the treatment of early-stage mesopharyngeal and hypopharyngeal cancers to preserve patients' quality of life. Endoscopic submucosal dissection (ESD) offers potential advantages in comparison to EMR. So the aim of this retrospective study was to assess the utility of ESD compared with EMR for early-stage cancers of the meso- and hypopharynx. We studied 56 patients with 69 lesions who underwent either EMR or ESD between April 2001 and December 2008. EMR was performed until January 2007, and ESD was performed from February 2007 onward. We evaluated the en bloc resection rate, R0 resection rate, and treatment-related complications as short-term outcomes. Local recurrence, lymph node metastasis, and disease-related deaths were compared to evaluate long-term outcomes. The en bloc and R0 resection rates were respectively 98 % and 79 % in the ESD group and 37 % and 26 % in the EMR group. There were no cases of treatment-related complications in the EMR group, but postoperative subcutaneous emphysema was observed in two patients in the ESD group. In the EMR group, one patient developed a local recurrence and one developed metastasis to the cervical lymph node and died of primary cancer. ESD is a useful method of treatment for early mesopharyngeal and hypopharyngeal cancers and may be superior to EMR.


Care seeking at time of childbirth, and maternal and perinatal mortality in Matlab, Bangladesh.
To examine the nature of the relationship between the use of skilled attendance around the time of delivery and maternal and perinatal mortality. We analysed health and demographic surveillance system data collected between 1987 and 2005 by the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) in Matlab, Bangladesh. The study recorded 59 165 pregnancies, 173 maternal deaths, 1661 stillbirths and 1418 early neonatal deaths in its service area over the study period. During that time, the use of skilled attendance during childbirth increased from 5.2% to 52.6%. More than half (57.8%) of the women who died and one-third (33.7%) of those who experienced a perinatal death (i.e. a stillbirth or early neonatal death) had sought skilled attendance. Maternal mortality was low among women who did not seek skilled care (160 per 100,000 pregnancies) and was nearly 32 times higher (adjusted odds ratio, OR: 31.66; 95% confidence interval, CI: 22.03-45.48) among women who came into contact with comprehensive emergency obstetric care. Over time, the strength of the association between skilled obstetric care and maternal mortality declined as more women sought such care. Perinatal death rates were also higher for those who sought skilled care than for those who did not, although the strength of association was much weaker. Given the high maternal mortality ratio and perinatal mortality rate among women who sought obstetric care, more work is needed to ensure that women and their neonates receive timely and effective obstetric care. Reductions in perinatal mortality will require strategies such as early detection and management of health problems during pregnancy.


Induction of specific immune unresponsiveness using purified mixed leukocyte culture-activated T lymphoblasts as autoimmunogen. I. Demonstration of general validity as to species and histocompatibility barriers.
Normal immunocompetent T lymphocytes can be induced into specific proliferation if confronted with the relevant alloantigen in vitro. Such mixed leuko-cyteculture-activated T lymphoblasts carring idiotypic receptors on their surface can be purified using velocity sedimentation and serve as immunogen if administered in adjuvant to the autologous host. Autoblast immunization can be shown to lead to specific, long-lasting unresponsiveness against the relevant alloantigens, while leaving reactivity against third-party antigens intact. When tested as to general validity, it could be shown to function in all species analyzed (mouse, rat, and guinea pig) as well as across both major and minor histocompatibility barriers. No negative side effects have been noted so far. It would thus seem clear that autoblast immunization using the above described scheme may serve as a general tool in inducing long-lasting, specific unresponsiveness in any species and across any histocompatibility barrier.


Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.
Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. Cancer Research UK and Roche.


Active blood parasite infection is not limited to the breeding season in a declining farmland bird.
Avian blood parasites can have significant impacts on adult breeding birds but studies of parasitism outside the breeding season are rare, despite their potentially important implications for host-parasite dynamics. Here we investigate temporal dynamics of blood parasite infection in adult yellowhammers Emberiza citrinella . We screened blood samples collected between December and April of 2 consecutive winters using PCR. We found a high prevalence of both Haemoproteus and Leucocytozoon parasites, with a mean prevalence of 50% across 2 winters. Prevalence of both parasites was higher during the second, colder winter of the study. Temporal trends differed between the 2 genera, suggesting that chronic Haemoproteus infections gradually disappear throughout the winter but that Leucocytozoon infections exhibit a relapse during late winter, possibly coincident with reduced food availability. Our results highlight the difference in temporal dynamics between 2 blood parasite genera infecting the same host population and emphasize the need for accurate assessment of infection status at appropriate time periods when examining impacts of, and associations with, blood parasite infection. We suggest that further research should investigate the implications of over-winter infection for birds' physiology, behavior, and survival.


Some mechanisms of the protective effect of ischemic preconditioning on rat liver ischemia-reperfusion injury.
Ischemia-reperfusion (I/R) injury is a multifactorial process that affects graft function after liver transplantation. An understanding of the mechanisms involved in I/R injury is essential for the design of therapeutic strategies to improve the outcome of liver transplantation. The generation of reactive oxygen species subsequent to reoxygenation inflicts tissue damage and initiates a cascade of deleterious cellular responses, leading to inflammation, cell death, and ultimate organ failure. Increasing experimental evidence has suggested that Kupffer cells and T-cells mediate activation of neutrophil inflammatory responses. Activated neutrophils infiltrate the injured liver in parallel with increased expression of adhesion molecules on endothelial cells. The heme oxygenase system is among the most critical of the cytoprotective mechanisms activated during cellular stress, exerting antioxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. Finally, the activation of toll-like receptors on Kupffer cells may play a fundamental role in exploring new therapeutic strategies based on the concept that hepatic I/R injury represents a case for host "innate" immunity. In the present study, there was a significant decrease in hepatic activity of glycogen in the I/R group as compared with corresponding values in the control group. On the other hand, there was a significant increase in the hepatic activity of glycogen in the I/R-IP (ischemic preconditioning) group as compared with corresponding values in the I/R group.


Switching from Negative-Cooperativity to No-Cooperativity in the Binding of Ion-Pair Dimers by a Bis(calix[4]pyrrole) Macrocycle.
We report the synthesis of a macrocyclic receptor containing two di- meso-phenylcalix[4]pyrrole units linked by two triazole spacers. The 1,4-substitution of the 1,2,3-triazole spacers conveys different binding affinities to the two heteroditopic binding sites. These features make the receptor an ideal candidate to investigate allosteric cooperativity in the binding of ion-pair dimers. We probed the interaction of tetraalkylammonium salts (TBA·Cl, TBA·OCN, and MTOA·Cl) with the tetra-heterotopic macrocyclic receptor in chloroform solution using 1H NMR spectroscopic titration experiments. The results obtained show that, at millimolar concentration, the addition of 2 equiv of the salt to the receptor's solution induced the quantitative pairwise binding of the ion-pairs. The 2:1 (ion-pair:receptor) complexes feature different binding geometries and binding cooperativities depending on the nature of the alkylammonium cation. The binding geometries assigned to the complexes of the ion-pair dimers in solution are fully supported by X-ray diffraction analyses of single crystals. The thermodynamic features of the binding processes (separate or concomitant formation of 1:1 and 2:1 complexes), derived from isothermal titration calorimetry (ITC) experiments, are rationalized by combining the different ion-pair binding modes of the salt dimers with the dissimilar electronic properties of the two nearby heteroditopic binding sites of the receptor.


Ethical dilemmas in palliative care in traditional developing societies, with special reference to the Indian setting.
There are intriguing and challenging ethical dilemmas in the practice of palliative care in a traditional developing society. To review the different ethical issues involved in cancer and palliative care in developing countries, with special reference to India. Published literature on pain relief and palliative care in the developing countries was reviewed to identify ethical issues and dilemmas related to these, and ways in which ethical principles could be observed in delivery of palliative care in such countries are discussed. The literature review revealed a number of ethical dilemmas and challenges that professionals, cancer patients and their families encountered during palliative care. It was noted that patients' preferences and decisions are influenced by family members. Dilemmas leave the professionals and families confused about how ethical their actions have been. Specific ethical issues were noted in relation to the availability and use of oral morphine for pain relief, spiritual care, lack of adequate palliative care services, and palliative care education. The four principles of ethics posed difficulties in understanding the complex ethical issues in a developing country with a traditional background. Ethical issues need to be handled delicately and sensitively in palliative care settings, within the framework of the traditions and culture of the society and financial constraints. The possible role of ethics committees in palliative care settings to help decision-making needs to be studied and discussed.


Event-based surveillance of food- and waterborne diseases in Europe: urgent inquiries (outbreak alerts) during 2008 to 2013.
During 2008 to 2013, 215 outbreak alerts, also known as 'urgent inquiries' (UI), for food- and waterborne diseases were launched in Europe, the majority of them (135; 63%) being related to salmonellosis. For 110 (51%) UI, a potential food vehicle of infection was identified, with vegetables being the most reported category (34;31%). A total of 28% (n = 60) of the outbreaks reported had an international dimension, involving at least two countries (mean: 4; standard deviation: 2; range:2–14). Participating countries posted 2,343 messages(initial posts and replies, excluding updates), with a median of 11 messages per urgent inquiry (range:1–28). Of 60 multicountry UI, 50 involved between two and four countries. The UI allowed early detection of multicountry outbreaks, facilitated the identification of the suspected vehicles and consequently contributed to the timely implementation of control measures. The introduction of an epidemic intelligence information system platform in 2010 has strengthened the role of the Food- and Waterborne Diseases and Zoonoses network in facilitating timely exchange of information between public health authorities of the participating countries.


A novel molecular therapy using bioengineered adenovirus for human gastrointestinal cancer.
Replication-selective tumor-specific viruses constitute a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85オ of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1 genes. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter would allow for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. We demonstrated that intratumoral injection of Telomelysin mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes. Moreover, using noninvasive whole-body imaging, we found that intratumoral injection of Telomelysin followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of oncolytic virotherapy as a promising strategy in the management of human gastrointestinal cancer.


Learning where to attend with deep architectures for image tracking.
We discuss an attentional model for simultaneous object tracking and recognition that is driven by gaze data. Motivated by theories of perception, the model consists of two interacting pathways, identity and control, intended to mirror the what and where pathways in neuroscience models. The identity pathway models object appearance and performs classification using deep (factored)-restricted Boltzmann machines. At each point in time, the observations consist of foveated images, with decaying resolution toward the periphery of the gaze. The control pathway models the location, orientation, scale, and speed of the attended object. The posterior distribution of these states is estimated with particle filtering. Deeper in the control pathway, we encounter an attentional mechanism that learns to select gazes so as to minimize tracking uncertainty. Unlike in our previous work, we introduce gaze selection strategies that operate in the presence of partial information and on a continuous action space. We show that a straightforward extension of the existing approach to the partial information setting results in poor performance, and we propose an alternative method based on modeling the reward surface as a gaussian process. This approach gives good performance in the presence of partial information and allows us to expand the action space from a small, discrete set of fixation points to a continuous domain.


Expression of a novel isoform of Na(+)/H(+) exchanger 3 in the kidney and intestine of banded houndshark, Triakis scyllium.
Na(+)/H(+) exchanger 3 (NHE3) provides one of the major Na(+) absorptive pathways of the intestine and kidney in mammals, and recent studies of aquatic vertebrates (teleosts and elasmobranchs) have demonstrated that NHE3 is expressed in the gill and plays important roles in ion and acid-base regulation. To understand the role of NHE3 in elasmobranch osmoregulatory organs, we analyzed renal and intestinal expressions and localizations of NHE3 in a marine elasmobranch, Japanese banded houndshark (Triakis scyllium). mRNA for Triakis NHE3 was most highly expressed in the gill, kidney, spiral intestine, and rectum. The kidney and intestine expressed a transcriptional isoform of NHE3 (NHE3k/i), which has a different amino terminus compared with that of NHE3 isolated from the gill (NHE3g), suggesting that NHE3k/i and NHE3g arise from a single gene by alternative promoter usage. Immunohistochemical analyses of the Triakis kidney demonstrated that NHE3k/i is expressed in the apical membrane of a part of the proximal and late distal tubules in the sinus zone. In the bundle zone of the kidney, NHE3k/i was expressed in the apical membrane of the early distal tubules known as the diluting segment. In the spiral intestine and rectum, NHE3k/i was localized toward the apical membrane of the epithelial cells. The transcriptional levels of NHE3k/i were increased in the kidney when Triakis was acclimated in 130% seawater, whereas those in the spiral intestine were increased in fish acclimated in diluted seawater. These results suggest that NHE3 is involved in renal Na(+) reabsorption, urine acidification, and intestinal Na(+) absorption in elasmobranchs.


When Does the Incremental Risk Format Aid Informed Medical Decisions? The Role of Learning, Feedback, and Number of Treatment Options.
Background. Informed medical decisions require understanding the benefits and risks of treatments. This entails comparing treatment outcomes to a control group. The incremental risk format has been recommended as it directly visualizes the differences between treatment and control group in 1 graph, whereas they have to be calculated from 2 separate graphs in the total risk format. We investigated when the incremental risk format aids understanding. Methods. In 2 experiments, participants received information about medical treatments, either as incremental or total risk format. We assessed verbatim knowledge (precise quantitative knowledge), gist knowledge (knowledge of essential meaning), and evaluations of the formats. Study 1 (N = 99) consisted of only 1 trial with medical information and also assessed recall. Study 2 (N = 222) assessed learning across multiple trials and also varied the presence of feedback and the number of treatment options. Results. In study 1, the incremental risk format (v. total risk format) led to worse knowledge, recall, and evaluations. In study 2, participants learned to understand the incremental risk format over time, resulting in comparable verbatim knowledge and evaluations as in the total risk format, as well as in even better gist knowledge. Feedback and number of treatment options did not moderate the effect of risk format. Limitations. The studies were conducted with nonpatient samples, and study 2 employed hypothetical treatments. Conclusions. The incremental risk format was initially less understandable than the total risk format. After a short learning period, however, the incremental risk format resulted in better gist knowledge and was comparable otherwise, which suggests that participants had to get used to that format. This has important implications for the study of new formats.


First contact pheromone identified for a longhorned beetle (Coleoptera: Cerambycidae) in the subfamily Prioninae.
Little is known of the reproductive behavior of longhorned beetles (Coleoptera: Cerambycidae) in the subfamily Prioninae. Mallodon dasystomus (Say), the hardwood stump borer, is a widely distributed prionine that is native to the southern U.S. Here, we explored the chemically-mediated mating behavior of M. dasystomus, and tested the hypothesis that males recognize females by a contact pheromone. In mating bioassays, all males tested attempted to mate with females only after contacting females with their antennae. Moreover, all males attempted to mate with solvent-washed dead females treated with as little as 0.15 ± 0.03 female equivalents of conspecific cuticular extracts, confirming that compounds on the cuticle of females are essential for mate recognition. Cuticular hydrocarbon profiles of females contained 13 compounds that were not present in profiles of males. Among the female-specific compounds, two co-dominant methyl-branched alkanes, 2-methylhexacosane (2Me-C(26)) and 2-methyloctacosane (2Me-C(28)), accounted for 17% of the total hydrocarbons. Our strategy for identifying the contact pheromone was to synthesize and test the bioactivity of female specific compounds, starting with the most abundant. In bioassays, males displayed mating behavior in response to synthetic 2Me-C(26) and 2Me-C(28) when tested individually. Furthermore, when these compounds were tested in combination, they elicited the full progression of mating behaviors, suggesting that 2Me-C(26) and 2Me-C(28) make up the contact pheromone. These findings are further evidence of the critical role of contact pheromones in mating systems of longhorned beetles.


G-quadruplex formation of FXYD1 pre-mRNA indicates the possibility of regulating expression of its protein product.
G-quadruplexes are higher-order nucleic acid structures formed of square-planar arrangements of four guanine bases held together by Hoogsteen-type hydrogen bonds. Stacks of guanine tetrads are stabilised by intercalating potassium ions. FXYD1 encodes for phospholemman, a regulatory subunit of the cardiac Na(+)/K(+)-ATPase. Computational sequence analysis of FXYD1 pre-mRNA predicted the formation of stable intramolecular G-quadruplexes in human and orthologue sequences. Multiple sequence alignment indicated that G-rich sequences are conserved in evolution suggesting a potential role of G-quadruplexes in FXYD1 gene expression. The existence of a non-functional alternative splicing product indicated that the G-quadruplex formation may control alternative splicing. Quadruplex formation of human and bovine oligonucleotides was confirmed in vitro by native polyacrylamide gel electrophoresis and intrinsic fluorescence emission spectroscopy. Taking together the evolutionary conservation of G-quadruplex forming sequences with the confirmation of G-quadruplex formation in vitro by two FXYD1 homologues the results point to a potential role of these structures in regulating the expression of FXYD1 and thus regulate indirectly the activity of the cardiac Na(+)/K(+)-ATPase.


Treatment interruptions and non-adherence with imatinib and associated healthcare costs: a retrospective analysis among managed care patients with chronic myelogenous leukaemia.
Identify treatment interruptions and non-adherence with imatinib; examine the clinical and patient characteristics related to treatment interruptions and non-adherence; and estimate the association between treatment interruptions and non-adherence with imatinib and healthcare costs for US managed care patients with chronic myeloid leukaemia (CML). This retrospective analysis utilised electronic healthcare claims data from a US managed care provider. Adult patients with CML (as determined by International Classification of Diseases, ninth revision, Clinical Modification [ICD-9-CM] diagnosis code) were identified who began treatment with imatinib from 1 June 2001 through 31 March 2004. Treatment interruptions (i.e. failure to refill imatinib within 30 days from the run-out date of the prior prescription) were identified during the 12-month follow-up period. Medication possession ratio (MPR), calculated as total days' supply of imatinib divided by 365, was also examined. Healthcare costs (i.e. paid amounts for all prescription medications and medical services received, including health plan and patient liability) were examined in three ways: (i) total healthcare costs; (ii) total healthcare costs exclusive of imatinib costs; and (iii) total medical costs. All costs were converted to US dollars (2004 values) using the medical component of the Consumer Price Index. MPR was modelled using ordinary least squares regression. Presence of treatment interruptions was modelled using logistic regression. The association between MPR and healthcare costs was estimated using a generalised linear model specified with a gamma error distribution and a log link. All models included adjustment for age, gender, number of concomitant medications, starting dose of imatinib and cancer complexity. A total of 267 patients were identified. Average age was approximately 50 years, and 43% were women. Mean MPR was 77.7%, with 31% of patients having a treatment interruption. However, all of these patients resumed imatinib within the study period. In this population, MPR decreased as the number of concomitant medications increased (p = 0.002), and was lower among women (p = 0.003), patients with high cancer complexity (p = 0.003) and patients with a higher starting dose of imatinib (p = 0.04). Women were approximately twice as likely as men to have a treatment interruption (p = 0.009), as were patients with a high cancer complexity (p = 0.03). After adjusting for the aforementioned covariates, MPR was found to be inversely associated with healthcare costs excluding imatinib (p < 0.001) and medical costs (p < 0.001). A 10% point difference in MPR was associated with a 14% difference in healthcare costs excluding imatinib and a 15% difference in medical costs. For example, patients with an MPR of 75% incur an additional 4072 US dollars in medical costs annually compared with patients with an MPR of 85%. Treatment interruptions and non-adherence with imatinib, both of which could lead to undesired clinical and economic outcomes, appear to be prevalent. Physicians and pharmacists should educate patients and closely monitor adherence to therapy, as improving adherence and limiting treatment interruptions may not only optimise clinical outcomes but also reduce the economic burden of CML.


Fish acute toxicity syndromes and their use in the QSAR approach to hazard assessment.
Implementation of the Toxic Substances Control Act of 1977 creates the need to reliably establish testing priorities because laboratory resources are limited and the number of industrial chemicals requiring evaluation is overwhelming. The use of quantitative structure activity relationship (QSAR) models as rapid and predictive screening tools to select more potentially hazardous chemicals for in-depth laboratory evaluation has been proposed. Further implementation and refinement of quantitative structure-toxicity relationships in aquatic toxicology and hazard assessment requires the development of a "mode-of-action" database. With such a database, a qualitative structure-activity relationship can be formulated to assign the proper mode of action, and respective QSAR, to a given chemical structure. In this review, the development of fish acute toxicity syndromes (FATS), which are toxic-response sets based on various behavioral and physiological-biochemical measurements, and their projected use in the mode-of-action database are outlined. Using behavioral parameters monitored in the fathead minnow during acute toxicity testing, FATS associated with acetylcholinesterase (AChE) inhibitors and narcotics could be reliably predicted. However, compounds classified as oxidative phosphorylation uncouplers or stimulants could not be resolved. Refinement of this approach by using respiratory-cardiovascular responses in the rainbow trout, enabled FATS associated with AChE inhibitors, convulsants, narcotics, respiratory blockers, respiratory membrane irritants, and uncouplers to be correctly predicted.


The regulatory content of intergenic DNA shapes genome architecture.
Factors affecting the organization and spacing of functionally unrelated genes in metazoan genomes are not well understood. Because of the vast size of a typical metazoan genome compared to known regulatory and protein-coding regions, functional DNA is generally considered to have a negligible impact on gene spacing and genome organization. In particular, it has been impossible to estimate the global impact, if any, of regulatory elements on genome architecture. To investigate this, we examined the relationship between regulatory complexity and gene spacing in Caenorhabditis elegans and Drosophila melanogaster. We found that gene density directly reflects local regulatory complexity, such that the amount of noncoding DNA between a gene and its nearest neighbors correlates positively with that gene's regulatory complexity. Genes with complex functions are flanked by significantly more noncoding DNA than genes with simple or housekeeping functions. Genes of low regulatory complexity are associated with approximately the same amount of noncoding DNA in D. melanogaster and C. elegans, while loci of high regulatory complexity are significantly larger in the more complex animal. Complex genes in C. elegans have larger 5' than 3' noncoding intervals, whereas those in D. melanogaster have roughly equivalent 5' and 3' noncoding intervals. Intergenic distance, and hence genome architecture, is highly nonrandom. Rather, it is shaped by regulatory information contained in noncoding DNA. Our findings suggest that in compact genomes, the species-specific loss of nonfunctional DNA reveals a landscape of regulatory information by leaving a profile of functional DNA in its wake.


Decisional balance and self-efficacy of physical activity among the elderly in Rasht in 2013 based on the transtheoretical model.
Regular physical activity has been considered as health promotion, and identifying different effective psycho-social variables on physical has proven to be essential. To identify the relationship between decisional balance and self-efficacy in physical activities using the transtheoretical model in the members of a retirement center in Rasht, Guillen. A descriptive cross-sectional study was conducted in 2013 by using convenient sampling on 262 elderly people who are the members of retirement centers in Rasht. Data were collected using Stages of change, Decisional balance, Self-efficacy and Physical Activity Scale for the Elderly (PASE). Data was analyzed using SPSS-16 software, descriptive and analytic statistic (Pearson correlation, Spearman, ANOVA, HSD Tukey, linear and ordinal regression). The majority of participants were in maintenance stage. Mean and standard deviation physical activity for the elderly was 119.35±51.50. Stages of change and physical activities were significantly associated with decisional balance and self-efficacy (p<0.0001); however, cons had a significant and reverse association. According to linear and ordinal regression the only predicator variable of physical activity behavior was self-efficacy. By increase in pros and self-efficacy on doing physical activity, it can be benefited in designing appropriate intervention programs.


Men's Knowledge of Obstetric Danger Signs, Birth Preparedness and Complication Readiness in Rural Tanzania.
Men's involvement in reproductive health is recommended. Their involvement in antenatal care service is identified as important in maternal health. Awareness of obstetric danger signs facilitates men in making a joint decision with their partners regarding accessing antenatal and delivery care. This study aims to assess the level of knowledge of obstetric complications among men in a rural community in Tanzania, and to determine their involvement in birth preparedness and complication readiness. A cross-sectional survey was conducted where 756 recent fathers were invited through a two-stage cluster sampling procedure. A structured questionnaire was used to collect socio-demographic characteristics, knowledge of danger signs and steps taken on birth preparedness and complication readiness. Data were analyzed using bivariate and multivariable logistic regression to determine factors associated with being prepared, with statistically significant level at p<0.05. Among the invited men, 95.9% agreed to participate in the community survey. Fifty-three percent could mention at least one danger sign during pregnancy, 43.9% during delivery and 34.6% during the postpartum period. Regarding birth preparedness and complication readiness, 54.3% had bought birth kit, 47.2% saved money, 10.2% identified transport, 0.8% identified skilled attendant. In general, only 12% of men were prepared. Birth preparedness was associated with knowledge of danger signs during pregnancy (AOR = 1.4, 95% CI: 1.8-2.6). It was less likely for men living in the rural area to be prepared (AOR=0.6, 95% CI; 0.5-0.8). There was a low level of knowledge of obstetric danger signs among men in a rural district in Tanzania. A very small proportion of men had prepared for childbirth and complication readiness. There was no effect of knowledge of danger signs during childbirth and postpartum period on being prepared. Innovative strategies that increase awareness of danger signs as well as birth preparedness and complication readiness among men are required. Strengthening counseling during antenatal care services that involve men together with partners is recommended.


A qualitative exploration of the use of calendar landmarking instruments in cancer symptom research.
Late diagnosis is considered to be a major factor contributing to poorer cancer survival rates in the UK. Interventions have focussed on the promotion of earlier diagnosis in patients with potential cancer symptoms. However, to assess the effectiveness of these interventions, the time from symptom onset to presentation needs to be reliably and accurately measured. This qualitative study explored the use of calendar landmarking instruments in cancer symptom research. We performed a secondary analysis of transcripts of interviews using the calendar landmarking instrument, undertaken with patients who had either been diagnosed with cancer (n = 40, IRCO study, Western Australia), or who had symptoms suggestive of cancer (n = 38, SYMPTOM study, North East and Eastern England). We used constant comparison methods to identify use of the calendar landmarking instruments and the impact of their application. The calendar landmarking instrument appeared to help many patients, either by acting as a prompt or helping to refine recall of events. A combination of personal (e.g. birthday) and national (e.g. Christmas) landmarks seemed to be the most effective. Calendar landmarking instruments appeared more useful where the time period between onset of symptoms and date of first consultation was less than three months. The interviewee's age, gender and cancer type did not appear to influence whether or not the instrument facilitated recall, and there were no instances where the use of the instrument resulted in the disclosure of a new first symptom. Symptoms of similar chronic conditions could create difficulties when applying the instrument; it was difficult for these participants to characterise and disentangle their symptoms which prompted their decisions to seek help. Some participants tended to prefer to use their own, already personalised, diaries to assist in their recall of events. This study is the first to describe the potential role of calendar landmarking instruments to support research interviews which explore symptoms and events along the cancer diagnostic pathway. The major challenge remains as to whether they actually improve accuracy of recall.


The Effect of Stress and Recovery on Field-test Performance in Floorball.
Physical and psychosocial stress and recovery are important performance determinants. A holistic approach that monitors these performance determinants over a longer period of time is lacking. Therefore this study aims to investigate the effect of a player's physical and psychosocial stress and recovery on field-test performance. In a prospective non-experimental cohort design 10 female Dutch floorball players were monitored over 6 months. To monitor physical and psychosocial stress and recovery, daily training-logs and 3-weekly the Recovery-Stress Questionnaire for Athletes (RESTQ-Sport) were filled out respectively. To determine field-test performance 6 Heart rate Interval Monitoring System (HIMS) and 4 Repeated Modified Agility T-test (RMAT) measurements were performed. Multilevel prediction models were applied to account for within-players and between-players field-test performance changes. The results show that more psychosocial stress and less psychosocial recovery over 3-6 weeks before testing decrease HIMS performance (p≤0.05). More physical stress over 6 weeks before testing improves RMAT performance (p≤0.05). In conclusion, physical and psychosocial stress and recovery affect submaximal interval-based running performance and agility up to 6 weeks before testing. Therefore both physical and psychosocial stress and recovery should be monitored in daily routines to optimize performance.


Emotion perception from dynamic and static body expressions in point-light and full-light displays.
Research on emotion recognition has been dominated by studies of photographs of facial expressions. A full understanding of emotion perception and its neural substrate will require investigations that employ dynamic displays and means of expression other than the face. Our aims were: (i) to develop a set of dynamic and static whole-body expressions of basic emotions for systematic investigations of clinical populations, and for use in functional-imaging studies; (ii) to assess forced-choice emotion-classification performance with these stimuli relative to the results of previous studies; and (iii) to test the hypotheses that more exaggerated whole-body movements would produce (a) more accurate emotion classification and (b) higher ratings of emotional intensity. Ten actors portrayed 5 emotions (anger, disgust, fear, happiness, and sadness) at 3 levels of exaggeration, with their faces covered. Two identical sets of 150 emotion portrayals (full-light and point-light) were created from the same digital footage, along with corresponding static images of the 'peak' of each emotion portrayal. Recognition tasks confirmed previous findings that basic emotions are readily identifiable from body movements, even when static form information is minimised by use of point-light displays, and that full-light and even point-light displays can convey identifiable emotions, though rather less efficiently than dynamic displays. Recognition success differed for individual emotions, corroborating earlier results about the importance of distinguishing differences in movement characteristics for different emotional expressions. The patterns of misclassifications were in keeping with earlier findings on emotional clustering. Exaggeration of body movement (a) enhanced recognition accuracy, especially for the dynamic point-light displays, but notably not for sadness, and (b) produced higher emotional-intensity ratings, regardless of lighting condition, for movies but to a lesser extent for stills, indicating that intensity judgments of body gestures rely more on movement (or form-from-movement) than static form information.


International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) - the propagation of knowledge in ultrasound for the improvement of OB/GYN care worldwide: experience of basic ultrasound training in Oman.
The aim of this study is to evaluate effectiveness of a new ISUOG (International Society of Ultrasound in Obstetrics and Gynecology) Outreach Teaching and Training Program delivered in Muscat, Oman. Quantitative assessments to evaluate knowledge and practical skills were administered before and after an ultrasound course for sonologists attending the ISUOG Outreach Course, which took place in November, 2017, in Oman. Trainees were selected from each region of the country following a national vetting process conducted by the Oman Ministry of Health. Twenty-eight of the participants were included in the analysis. Pre- and post-training practical and theoretical scores were evaluated and compared. Participants achieved statistically significant improvements, on average by 47% (p < 0.001), in both theoretical knowledge and practical skills. Specifically, the mean score in the theoretical knowledge test significantly increased from 55.6% (± 14.0%) to 81.6% (± 8.2%), while in the practical test, the mean score increased from 44.6% (± 19.5%) to 65.7% (± 23.0%) (p < 0.001). Performance was improved post-course among 27/28 participants (96.4%) in the theoretical test (range: 14 to 200%) and among 24/28 (85.7%) trainees in the practical skills test (range: 5 to 217%). Application of the ISUOG Basic Training Curriculum and Outreach Teaching and Training Course improved the theoretical knowledge and practical skills of local health personnel. Long-term re-evaluation is, however, considered imperative to ascertain and ensure knowledge retention.


PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator-activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-δ in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-δ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-δ using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-δ activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR-δ activation may be beneficial in HD and related disorders.


An optimized SYBR Green I/PI assay for rapid viability assessment and antibiotic susceptibility testing for Borrelia burgdorferi.
Lyme disease caused by Borrelia burgdorferi is the most common tick-borne disease in the US and Europe. Unlike most bacteria, measurements of growth and viability of B. burgdorferi are challenging. The current B. burgdorferi viability assays based on microscopic counting and PCR are cumbersome and tedious and cannot be used in a high throughput format. Here, we evaluated several commonly used viability assays including MTT and XTT assays, fluorescein diacetate assay, Sytox Green/Hoechst 33342 assay, the commercially available LIVE/DEAD BacLight assay, and SYBR Green I/PI assay by microscopic counting and by automated 96-well plate reader for rapid viability assessment of B. burgdorferi. We found that the optimized SYBR Green I/PI assay based on green to red fluorescence ratio is superior to all the other assays for measuring the viability of B. burgdorferi in terms of sensitivity, accuracy, reliability, and speed in automated 96-well plate format and in comparison with microscopic counting. The BSK-H medium which produced a high background for the LIVE/DEAD BacLight assay did not affect the SYBR Green I/PI assay, and the viability of B. burgdorferi culture could be directly measured using a microtiter plate reader. The SYBR Green I/PI assay was found to reliably assess the viability of planktonic as well as biofilm B. burgdorferi and could be used as a rapid antibiotic susceptibility test. Thus, the SYBR Green I/PI assay provides a more sensitive, rapid and convenient method for evaluating viability and antibiotic susceptibility of B. burgdorferi and can be used for high-throughput drug screens.


Distributed external cloak without embedded antiobjects.
We propose a distributed external cloak without embedded antiobjects, which contains tunable windows and a cloaking area. It consists of closed and standalone systems whose positions and parameters can be separately controlled by the design purpose and folded geometry. Such an external cloak does not rely on either cloaked material or the concept of the antiobject [Phys. Rev. Lett. 102, 093901 (2009)] in the complementary material, and can thus be kept unchanged when different objects are considered. The object lies outside the cloak and is not blinded in terms of multiple open windows desired by specific designs. Such a distributed cloak enables us to conceal arbitrary objects of varying shape in center areas, which may exceed the inner boundary of a perfect closed cloak.


Optimal probe length varies for targets with high sequence variation: implications for probe library design for resequencing highly variable genes.
Sequencing by hybridisation is an effective method for obtaining large amounts of DNA sequence information at low cost. The efficiency of SBH depends on the design of the probe library to provide the maximum information for minimum cost. Long probes provide a higher probability of non-repeated sequences but lead to an increase in the number of probes required whereas short probes may not provide unique sequence information due to repeated sequences. We have investigated the effect of probe length, use of reference sequences, and thermal filtering on the design of probe libraries for several highly variable target DNA sequences. We designed overlapping probe libraries for a range of highly variable drug target genes based on known sequence information and develop a formal terminology to describe probe library design. We find that for some targets these libraries can provide good coverage of a previously unseen target whereas for others the coverage is less than 30%. The optimal probe length varies from as short at 12 nt to as large as 19 nt and depends on the sequence, its variability, and the stringency of thermal filtering. It cannot be determined from inspection of an example gene sequence. Optimal probe length and the optimal number of reference sequences used to design a probe library are highly target specific for highly variable sequencing targets. The optimum design cannot be determined simply by inspection of input sequences or of alignments but only by detailed analysis of the each specific target. For highly variable sequences, shorter probes can in some cases provide better information than longer probes. Probe library design would benefit from a general purpose tool for analysing these issues. The formal terminology developed here and the analysis approaches it is used to describe will contribute to the development of such tools.


Federated Galaxy: Biomedical Computing at the Frontier.
Biomedical data exploration requires integrative analyses of large datasets using a diverse ecosystem of tools. For more than a decade, the Galaxy project (https://galaxyproject.org) has provided researchers with a web-based, user-friendly, scalable data analysis framework complemented by a rich ecosystem of tools (https://usegalaxy.org/toolshed) used to perform genomic, proteomic, metabolomic, and imaging experiments. Galaxy can be deployed on the cloud (https://launch.usegalaxy.org), institutional computing clusters, and personal computers, or readily used on a number of public servers (e.g., https://usegalaxy.org). In this paper, we present our plan and progress towards creating Galaxy-as-a-Service-a federation of distributed data and computing resources into a panoptic analysis platform. Users can leverage a pool of public and institutional resources, in addition to plugging-in their private resources, helping answer the challenge of resource divergence across various Galaxy instances and enabling seamless analysis of biomedical data.


Tuning the cavity of cyclodextrins: altered sugar adaptors in protein pores.
Cyclodextrins (CDs) have been widely used in host-guest molecular recognition because of their chiral and hydrophobic cavities. For example, β-cyclodextrin (βCD) lodged as a molecular adaptor in protein pores such as α-hemolysin (αHL) is used for stochastic sensing. Here, we have tuned the cavity and overall size of βCD by replacing a single oxygen atom in its ring skeleton by a disulfide unit in two different configurations to both expand our ability to detect analytes and understand the interactions of βCD with protein pores. The three-dimensional structures of the two stereoisomeric CDs have been determined by the combined application of NMR spectroscopy and molecular simulation and show distorted conformations as compared to natural βCD. The interactions of these synthetic βCD analogues with mutant αHL protein pores and guest molecules were studied by single-channel electrical recording. The dissociation rate constants for both disulfide CDs from the mutant pores show ∼1000-fold increase as compared to those of unaltered βCD, but are ∼10-fold lower than the dissociation rate constants for βCD from wild-type αHL. Both of the skeleton-modified CDs show altered selectivity toward guest molecules. Our approach expands the breadth in sensitivity and diversity of sensing with protein pores and suggests structural parameters useful for CD design, particularly in the creation of asymmetric cavities.


The effect of perforator location on epigastric perforator flap survival: an experimental and stereological study in guinea pigs.
One challenge most often seen in perforator-based flaps is the topographic relationship between the flap and its perforator, which determines flap design and pedicle length. Thirty female guinea pigs were used in this study. They were divided into four different groups including three experimental groups (n = 8), which were designed as central, lateral, and distal groups according to the perforator location, and one control group (n = 6). Flap survival and vessel density rates were assessed. There was no statistically significant difference ( P > 0.05) among either the surviving skin areas or the vascular density rates of the experimental groups, although all flaps were necrosed in the control group. We concluded that perforator flaps can safely be raised on the perforators located very distal or lateral to the flaps, as well as central classical location. Moreover, perforator flaps larger than suggested can safely be harvested in the same donor sites.


Node-Structured Integrative Gaussian Graphical Model Guided by Pathway Information.
Up to date, many biological pathways related to cancer have been extensively applied thanks to outputs of burgeoning biomedical research. This leads to a new technical challenge of exploring and validating biological pathways that can characterize transcriptomic mechanisms across different disease subtypes. In pursuit of accommodating multiple studies, the joint Gaussian graphical model was previously proposed to incorporate nonzero edge effects. However, this model is inevitably dependent on post hoc analysis in order to confirm biological significance. To circumvent this drawback, we attempt not only to combine transcriptomic data but also to embed pathway information, well-ascertained biological evidence as such, into the model. To this end, we propose a novel statistical framework for fitting joint Gaussian graphical model simultaneously with informative pathways consistently expressed across multiple studies. In theory, structured nodes can be prespecified with multiple genes. The optimization rule employs the structured input-output lasso model, in order to estimate a sparse precision matrix constructed by simultaneous effects of multiple studies and structured nodes. With an application to breast cancer data sets, we found that the proposed model is superior in efficiently capturing structures of biological evidence (e.g., pathways). An R software package nsiGGM is publicly available at author's webpage.


Why are photosynthetic reaction centres dimeric?
All photosynthetic organisms convert solar energy into chemical energy through charge separation in dimeric reaction centres. It is unknown why early reaction centres dimerised and completely displaced their monomeric ancestors. Here, we discuss several proposed explanations for reaction-centre dimerism and conclude-with only weak assumptions about the primordial dimerisation event-that the most probable explanation for the dimerism is that it arose because it enhanced light-harvesting efficiency by deepening the excitonic trap, i.e., by enhancing the rate of exciton transfer from an antenna complex and decreasing the rate of back transfer. This effect would have outweighed the negative effect dimerisation would have had on charge transfer within the reaction centre. Our argument implies that dimerisation likely occurred after the evolution of the first antennas, and it explains why the lower-energy state of the special pair is bright.


Gene expression profiling and clinical outcome in breast cancer.
Pathologic and clinical heterogeneity of breast cancer reflects the poorly documented, complex, and combinatory molecular basis of the disease and is in part responsible for therapeutic failures. The DNA microarray technique allows the analysis of RNA expression of several thousands of genes simultaneously in a sample. There are multiple potential applications of the technique in cancer research. A number of recent studies have shown the promising role of gene expression profiling in breast cancer by identifying new prognostic subclasses unidentifiable by conventional parameters and new prognostic and/or predictive gene signatures, whose predictive impact is superior to conventional histoclinical prognostic factors. In this review we describe current use of DNA microarrays in the prognosis of breast cancer. We also discuss issues that need to be addressed in the near future to allow the method to reach its full potential.


Investigating potential associations between chronic exposure to polychlorinated biphenyls and infectious disease mortality in harbour porpoises from England and Wales.
Bioaccumulation of immunosuppressive organochlorines like polychlorinated biphenyls (PCBs) may pose a threat to the health and viability of cetacean populations. To investigate possible associations between chronic exposure to PCBs and infectious disease mortality in harbour porpoises Phocoena phocoena in UK waters, blubber concentrations of 25 individual chlorobiphenyl (CB) congeners in 34 healthy harbour porpoises that died due to physical trauma (mainly by-catch) were compared with CB concentrations in 33 animals that died due to infectious disease. The infectious disease group had significantly greater total 25 CBs (sigma 25CBs) concentrations than the physical trauma group (P < 0.001). The mean sigma 25CBs concentration in animals that died due to physical trauma was 13.6 mg kg-1 extractable lipid whereas the mean concentration in the infectious disease group was 31.1 mg kg-1 extractable lipid. The relationship between higher sigma 25CBs and the infectious disease group was not confounded by age, sex, nutritional status, season, location or year of stranding. In addition, adult females had significantly lower sigma 25CBs levels than adult males (P < 0.05) due to maternal transfer of CBs to offspring. These findings are consistent with the hypothesis that chronic PCB exposure predisposes harbour porpoises in UK waters to infectious disease mortality, although further research is required to test these associations more robustly.


Pain response in depersonalization: a functional imaging study using hypnosis in healthy subjects.
Depersonalization (DP) is characterized by persistent or recurrent episodes of detachment from one's self with reduced pain perception being a common feature. Alterations in the body schema similar to the cortico-limbic disconnection syndrome of pain asymbolia are suggested to be responsible for DP. In this study we used hypnosis to induce DP in healthy subjects and to examine neural patterns of pain perception in the state of DP by means of functional magnetic resonance imaging (fMRI). Pain perception was investigated in 7 healthy subjects with high susceptibility to hypnosis in three different mental states: waking state (N-W), hypnotic relaxation (H-R) and hypnotic DP (H-DP). Pain was induced with electrical stimulation to the median nerve at the right wrist. fMRI measurements were performed during all states. Nociceptive stimuli led to an activation of the well described pain network including somatosensory and insular regions and the cerebellum. Activation was markedly reduced in the contralateral somatosensory cortex, parietal cortex (Brodmann area 40, BA40), prefrontal cortex (BA9), putamen and the ipsilateral amygdala during H-DP. Subjects also reported a significant decrease in pain intensity from N-W to H-DP. Pain response during H-DP was reduced in sensory and affective pain-related areas, reflecting the diminished intensity of the perceived pain. Moreover, a network of cortical and subcortical areas that have been implicated in the perception of the own body was less responsive during DP, which might point to a specific neural mechanism underlying the 'out-of-body' experience. Although the small number of subjects does not allow a generalization of our findings, H-DP seems to be a promising tool for the investigation of psychological and biological mechanisms of self-inflicted injuries as well as the mind-body interplay within the realm of psychosomatic disorders.


Storage, Degradation, and New Connectivity of Face-Related Semantic Memory in Alzheimer's Disease.
Excepting amnesia, impairment of other domains also hampers the activity of daily living in Alzheimer's disease (AD). Although prosopagnosia poses problem in interacting with other persons, it rarely causes problem during interaction with close relatives as known voice acts as cue for recognition. In a cohort of AD, we planned to study errors in recognition, naming, and assigning relationship of close relatives, to assess the type and frequency of errors and to explain with current knowledge and hypothesis. This cross-sectional study was conducted in Memory Clinic of Medical College Hospital, Kolkata, India, between July 2013 and June 2015. Patients were evaluated by history, general neurological examination, and neuropsychological tests. A structured questionnaire was used to assess recognition (use of honorifics) and naming defect of close relatives. AD was diagnosed in 42 patients. Prosopagnosia was found in 14 and anomia in 6 patients. Four patients exhibited problem during conversation with close relatives. They assigned name and relation of one generation earlier to close relatives with proper recognitions. We got predictive error of name and relation assignment of close relatives by one generation back with normal recognition. It can be explained by two memory traces in connection of face-visual and name (with/without relation) representation, earlier being hierarchically older and more resistant to wearing. We hypothesize that the name/relation store is orderly conserved. In AD, after degradation of part of name/relation store, a new wiring might be built up between these two traces.


The generation and properties of human macrophage populations from hemopoietic stem cells.
Information about the development and function of human macrophage lineage populations, such as osteoclasts, is limited because of the lack of defined in vitro systems for their large-scale generation. Two M-CSF-containing cytokine cocktails were found under serum-free conditions to expand dramatically and to differentiate over time human CD34(+) hemopoietic stem cells into nonadherent and adherent macrophage populations. These populations exhibited increasing degrees of maturity over a 3-week period characterized by morphology, surface marker expression (CD11b, CD86, CD64, CD14, and c-Fms), phagocytic function, and gene-expression profiling using quantitative PCR and microarray analysis (principal component analysis, k-means clustering, and gene ontology classification). As assessed by the last criterion, the adherent population obtained at 3 weeks from the one protocol tested had high similarity to the well-studied peripheral blood monocyte-derived macrophages. The one population tested could be induced to differentiate into osteoclasts in the presence of M-CSF and receptor activator of NF-kappaB ligand, as judged by morphology, gene expression, and bone-resorbing ability. In addition to the large numbers of macrophage lineage cells able to be produced, this replicating system may be suitable for the molecular analysis of macrophage lineage commitment and progression and for gene targeting and delivery.


Antitumor effects and drug interactions of the proteasome inhibitor bortezomib (PS341) in gastric cancer cells.
The proteasome inhibitor bortezomib (PS341) inhibits the function of the 26S proteasome and has been extensively investigated in the clinical setting of hematologic malignancies. Remarkable efficacy has been reported in the treatment of multiple myeloma, but there have been few studies of its use in the treatment of gastrointestinal malignancy, especially gastric cancer. Here, we demonstrate its efficacy, both alone and in combination with other cytotoxic agents, in gastric cancer cell lines. The human gastric cancer cell lines AZ521, MKN45 and NUGC3 were used as experimental models. Bortezomib produced significant growth inhibition in these cells (mean IC50 values: 1.26, 9.44 and 8.63 micromol/l, respectively) and was also observed to decrease the activity of the extracellular signal-regulated kinase 1/2 and Akt signal pathways, increasing the accumulation of p21. Cell-cycle analysis revealed that a low concentration of bortezomib (10-100 nmol/l) increased accumulation in the G1 phase. Moreover, bortezomib showed synergistic growth inhibition in combination with the conventional cytotoxic agents 5-fluorouracil, paclitaxel, doxorubicin and SN-38, and also downregulates the activity of nuclear factor -kappaB, which is induced by these agents. Our results demonstrate that bortezomib could be an effective antitumor agent in the treatment of gastric cancer, both as single-agent therapy and in combination with conventional chemotherapeutic agents.


Extent of lymph node dissection for adenocarcinoma of the stomach.
The impact of lymphadenectomy extent on the survival of patients with primary resectable gastric carcinoma is debated. We aimed to systematically review and meta-analyze the evidence on the impact of the three main types of progressively more extended lymph node dissection (that is, D1, D2 and D3 lymphadenectomy) on the clinical outcome of patients with primary resectable carcinoma of the stomach. The primary objective was to assess the impact of lymphadenectomy extent on survival (overall survival [OS], disease specific survival [DSS] and disease free survival [DFS]). The secondary aim was to assess the impact of lymphadenectomy on post-operative mortality. We searched CENTRAL, MEDLINE and EMBASE until 2001, including references from relevant articles and conference proceedings. We also contacted known researchers in the field. For the updated review, CENTRAL, MEDLINE and EMBASE were searched from 2001 to February 2015. We considered randomized controlled trials (RCTs) comparing the three main types of lymph node dissection (i.e., D1, D2 and D3 lymphadenectomy) in patients with primary non-metastatic resectable carcinoma of the stomach. Two authors independently extracted data from the included studies. Hazard ratios (HR) and relative risks (RR) along with their 95% confidence intervals (CI) were used to measure differences in survival and mortality rates between trial arms, respectively. Potential sources of between-study heterogeneity were investigated by means of subgroup and sensitivity analyses. The same two authors independently assessed the risk of bias of eligible studies according to the standards of the Cochrane Collaboration and the quality of the overall evidence based on the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria. Eight RCTs (enrolling 2515 patients) met the inclusion criteria. Three RCTs (all performed in Asian countries) compared D3 with D2 lymphadenectomy: data suggested no significant difference in OS between these two types of lymph node dissection (HR 0.99, 95% CI 0.81 to 1.21), with no significant difference in postoperative mortality (RR 1.67, 95% CI 0.41 to 6.73). Data for DFS were available only from one trial and for no trial were DSS data available. Five RCTs (n = 3 European; n = 2 Asian) compared D2 to D1 lymphadenectomy: OS (n = 5; HR 0.91, 95% CI 0.71 to 1.17) and DFS (n=3; HR 0.95, 95% CI 0.84 to 1.07) findings suggested no significant difference between these two types of lymph node dissection. In contrast, D2 lymphadenectomy was associated with a significantly better DSS compared to D1 lymphadenectomy (HR 0.81, 95% CI 0.71 to 0.92), the quality of the body of evidence being moderate; however, D2 lymphadenectomy was also associated with a higher postoperative mortality rate (RR 2.02, 95% CI 1.34 to 3.04). D2 lymphadenectomy can improve DSS in patients with resectable carcinoma of the stomach, although the increased incidence of postoperative mortality reduces its therapeutic benefit.


Atypical neural self-representation in autism.
The 'self' is a complex multidimensional construct deeply embedded and in many ways defined by our relations with the social world. Individuals with autism are impaired in both self-referential and other-referential social cognitive processing. Atypical neural representation of the self may be a key to understanding the nature of such impairments. Using functional magnetic resonance imaging we scanned adult males with an autism spectrum condition and age and IQ-matched neurotypical males while they made reflective mentalizing or physical judgements about themselves or the British Queen. Neurotypical individuals preferentially recruit the middle cingulate cortex and ventromedial prefrontal cortex in response to self compared with other-referential processing. In autism, ventromedial prefrontal cortex responded equally to self and other, while middle cingulate cortex responded more to other-mentalizing than self-mentalizing. These atypical responses occur only in areas where self-information is preferentially processed and does not affect areas that preferentially respond to other-referential information. In autism, atypical neural self-representation was also apparent via reduced functional connectivity between ventromedial prefrontal cortex and areas associated with lower level embodied representations, such as ventral premotor and somatosensory cortex. Furthermore, the magnitude of neural self-other distinction in ventromedial prefrontal cortex was strongly related to the magnitude of early childhood social impairments in autism. Individuals whose ventromedial prefrontal cortex made the largest distinction between mentalizing about self and other were least socially impaired in early childhood, while those whose ventromedial prefrontal cortex made little to no distinction between mentalizing about self and other were the most socially impaired in early childhood. These observations reveal that the atypical organization of neural circuitry preferentially coding for self-information is a key mechanism at the heart of both self-referential and social impairments in autism.


Spontaneous oscillations of elastic contractile materials with turnover.
Single and collective cellular oscillations driven by the actomyosin cytoskeleton have been observed in numerous biological systems. Here, we propose that these oscillations can be accounted for by a generic oscillator model of a material turning over and contracting against an elastic element. As an example, we show that during dorsal closure of the Drosophila embryo, experimentally observed changes in actomyosin concentration and oscillatory cell shape changes can, indeed, be captured by the dynamic equations studied here. We also investigate the collective dynamics of an ensemble of such contractile elements and show that the relative contribution of viscous and friction losses yields different regimes of collective oscillations. Taking into account the diffusion of force-producing molecules between contractile elements, our theoretical framework predicts the appearance of traveling waves, resembling the propagation of actomyosin waves observed during morphogenesis.


Evaluation of ki-67 staining levels as an independent biomarker of biochemical recurrence after salvage radiation therapy for prostate cancer.
We recently published a scoring algorithm to predict biochemical recurrence (BCR) after salvage radiation therapy (SRT) for prostate cancer. Currently, this algorithm is based on clinicopathologic features and does not incorporate information from tumor-based biomarkers. Herein, we evaluate the ability of Ki-67 staining in primary prostate cancer to independently aid in the prediction of BCR among men undergoing SRT. We identified 147 patients who were treated with SRT between July 1987 and July 2003 at Mayo Clinic (Rochester, MN; Jacksonville, FL; Scottsdale, AZ). Staining levels of Ki-67 in primary tumor samples were detected by use of a monoclonal antibody and quantified by use of a computer-assisted method. We used Cox proportional hazards models to examine the association of Ki-67 staining and BCR in single-variable models and after multivariable adjustment. The risk of BCR for men with tumors in the highest tertile of Ki-67 staining is approximately two times that for men with tumors in the lower two tertiles (relative risk, 2.02; 95% confidence interval, 1.23-3.32; p = 0.005) after adjustment for the features in our original scoring algorithm. Further adjustment for additional covariates did not attenuate this association. Evidence from concordance index values supports that Ki-67 staining adds to the predictive ability of our existing scoring algorithm. Our data suggest that higher levels of Ki-67 staining are associated with increased risk of BCR after SRT, independent of existing clinicopathologic covariates. Future studies involving larger numbers of patients are required to validate these results and also explore possible means of combining this biomarker with existing prognostic tools.


Effect of Age on Working Memory Performance and Cerebral Activation after Mild Traumatic Brain Injury: A Functional MR Imaging Study.
To evaluate the age effect on working memory (WM) performance and functional activation after mild traumatic brain injury (MTBI). This study was approved by the local research ethics committee. All participants provided written informed consent. N-back WM cerebral activation was assessed with functional magnetic resonance (MR) imaging in 13 younger (mean age, 26.2 years ± 2.9; range, 21-30 years) and 13 older (mean age, 57.8 years ± 6.6; range, 51-68 years) patients with MTBI and 26 age- and sex-matched control subjects. Two functional MR images were obtained within 1 month after injury and 6 weeks after the initial study. Group comparison and regression analysis were performed among postconcussion symptoms, neuropsychologic tests, and WM activity in both groups. In younger patients, initial hyperactivation was seen in the right precuneus and right inferior parietal gyrus (P = .047 and P = .025, respectively) in two-back greater than one-back conditions compared with younger control subjects, whereas in older patients, hypoactivation was seen in the right precuneus and right inferior frontal gyrus (P = .013 and P =.019, respectively) compared with older control subjects. Increased WM activity was associated with increased postconcussion symptoms in the right precuneus (r = 0.57; P = .026) and right inferior frontal gyrus (r = 0.60; P = .019) and poor WM performance in the right precuneus (r = -0.55; P = .027) in younger patients at initial studies but not in older patients. At follow-up examinations, partial recovery of activation pattern and decreased postconcussion symptoms (P = .04) were observed in younger patients but not in older patients. The different manifestations of postconcussion symptoms at functional MR imaging between younger and older patients confirmed the important role of age in the activation, modulation, and allocation of WM processing resources after MTBI. These findings also supported that younger patients have better neural plasticity and clinical recovery than do older patients.


Early Description of Coronavirus 2019 Disease in Kidney Transplant Recipients in New York.
The novel SARS-CoV-2 virus has caused a global pandemic of coronavirus disease 2019 (COVID-19). Although immunosuppressed individuals are thought to be at an increased risk of severe disease, little is known about their clinical presentation, disease course, or outcomes. We report 15 kidney transplant recipients from the Columbia University kidney transplant program who required hospitalization for confirmed COVID-19, and describe their management, clinical course, and outcomes. Patients presented most often with a fever (87%) and/or cough (67%). Initial chest x-ray most commonly showed bilateral infiltrates, but 33% had no acute radiographic findings. Patients were managed with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin. Although 27% of our patients needed mechanical ventilation, over half were discharged home by the end of follow-up. Kidney transplant recipients with COVID-19 have presentations that are similar to that of the general population. Our current treatment protocol appears to be associated with favorable outcomes, but longer follow-up of a larger cohort of patients is needed.


Cohesin Is limiting for the suppression of DNA damage-induced recombination between homologous chromosomes.
Double-strand break (DSB) repair through homologous recombination (HR) is an evolutionarily conserved process that is generally error-free. The risk to genome stability posed by nonallelic recombination or loss-of-heterozygosity could be reduced by confining HR to sister chromatids, thereby preventing recombination between homologous chromosomes. Here we show that the sister chromatid cohesion complex (cohesin) is a limiting factor in the control of DSB repair and genome stability and that it suppresses DNA damage-induced interactions between homologues. We developed a gene dosage system in tetraploid yeast to address limitations on various essential components in DSB repair and HR. Unlike RAD50 and RAD51, which play a direct role in HR, a 4-fold reduction in the number of essential MCD1 sister chromatid cohesion subunit genes affected survival of gamma-irradiated G(2)/M cells. The decreased survival reflected a reduction in DSB repair. Importantly, HR between homologous chromosomes was strongly increased by ionizing radiation in G(2)/M cells with a single copy of MCD1 or SMC3 even at radiation doses where survival was high and DSB repair was efficient. The increased recombination also extended to nonlethal doses of UV, which did not induce DSBs. The DNA damage-induced recombinants in G(2)/M cells included crossovers. Thus, the cohesin complex has a dual role in protecting chromosome integrity: it promotes DSB repair and recombination between sister chromatids, and it suppresses damage-induced recombination between homologues. The effects of limited amounts of Mcd1and Smc3 indicate that small changes in cohesin levels may increase the risk of genome instability, which may lead to genetic diseases and cancer.


Fast numerical generation and encryption of computer-generated Fresnel holograms.
In the past two decades, generation and encryption of holographic images have been identified as two important areas of investigation in digital holography. The integration of these two technologies has enabled images to be encrypted with more dimensions of freedom on top of simply employing the encryption keys. Despite the moderate success attained to date, and the rapid advancement of computing technology in recent years, the heavy computation load involved in these two processes remains a major bottleneck in the evolution of the digital holography technology. To alleviate this problem, we have proposed a fast and economical solution which is capable of generating, and at the same time encrypting, holograms with numerical means. In our method, the hologram formation mechanism is decomposed into a pair of one-dimensional (1D) processes. In the first stage, a given three-dimensional (3D) scene is partitioned into a stack of uniformed spaced horizontal planes and converted into a set of hologram sublines. Next, the sublines are expanded to a hologram by convolving it with a 1D reference signal. To encrypt the hologram, the reference signal is first convolved with a key function in the form of a maximum length sequence (also known as MLS, or M-sequence). The use of a MLS has two advantages. First, an MLS is spectrally flat so that it will not jeopardize the frequency spectrum of the hologram. Second, the autocorrelation function of an MLS is close to a train of Kronecker delta function. As a result, the encrypted hologram can be decoded by correlating it with the same key that is adopted in the encoding process. Experimental results reveal that the proposed method can be applied to generate and encrypt holograms with a small number of computations. In addition, the encrypted hologram can be decoded and reconstructed to the original 3D scene with good fidelity.


High prevalence of physical inactivity among patients from the Swiss HIV Cohort Study.
Physical activity (PA) can improve cardiorespiratory status, strength, body composition and quality of life for patients infected with HIV. Evidence from HIV-uninfected populations also shows that PA is associated with a lower risk of mortality, primarily death due to cardiovascular causes. There is, however, a lack of data on how physically active HIV-infected patients are. In this study, we assessed levels of self-reported PA over time in patients enrolled in the Swiss HIV Cohort Study, a large multicentre prospective observational cohort study. We included a total of 10,540 patients who completed at least one report of PA between December 2009 and November 2014 during routine clinical follow-up (scheduled every 6 months). In the first year after December 2009 there was a higher rate of non-response so these data are of a lesser reliability. Over the next four years, the percentage of patients reporting no free-time PA at all declined from 49% to 44%. In contrast, in two "Sport Switzerland" surveys of the general population in 2008 and 2014, the percentage of individuals reporting no sports activities at all was considerably lower and relatively stable over time (27% in 2008; 26% in 2014). In our analysis, the percentage of patients reporting sedentary activity at work increased from 23% to 26% over the four years. Subgroup findings suggest differences between women and men and between patients classified by their age, stage of infection and CD4 cell count. Integrating PA counselling into the routine care of HIV-infected patients and promoting PA among this population has the potential to improve the general state of health and quality of life for HIV-infected patients and reduce their risk of cardiovascular disease.


Comparison of Dentinal Wall Thickness in the Furcation Area (Danger Zone) in the First and Second Mesiobuccal Canals in the Maxillary First and Second Molars Using Cone-Beam Computed Tomography.
Differences in the morphology of the root canal system might result in favorable or adverse treatment outcomes. The present study compared the thickness of the dentinal wall in the danger zone (furcation area) of the first and second mesiobuccal canals in the maxillary first and second molars using cone beam computed tomography. In this cross-sectional study, 50 CBCT images of maxillary first and second molars were evaluated from one of the specialized radiology centers in Kerman, Iran. The images were prepared by a Planmeca Promax 3D Max machine (Planmeca, Helsinki, Finland), with a field of view (FOV) of 8×8 cm and a resolution of 0.1 mm and analyzed with Romexis Viewer software version 3.1.1 (Planmeca, Helsinki, Finland). In the 0.1-mm-thick axial cross-sections with a distance of 1 mm, the distances from the center of the MB1 and MB2 root canals to the furcation area were measured in three areas: A) furcation area, B) 2 mm below the furcation area, and C) 4 mm below the furcation area (at a magnification of ×10). The data were then analyzed with paired t-test. The thickness of the dentinal wall in the MB2 root canal was significantly less than that in the MB1 root canal in all the specimens (P<0.05). In both maxillary first and second molars, the thicknesses of the MB1 and MB2 root canals were significantly different in the furcation area and 4 mm below the furcation area (P=0.001). There was no significant difference between the maxillary first and second molars 2 mm below the furcation area; however, the difference was marginal (P=0.07). Considering the low thickness of the dentinal wall in the MB2 root canal compared with the MB1 root canal in the maxillary first and second molars, the anti-curvature techniques away from the furcation should be used to prepare this root canal to reduce the risk of strip perforation. On the other hand, it might indicate that highly tapered instruments and other aggressive instruments, such as Gates-Glidden drills, should be used with caution in these root canals.