Excretion of methadone in sweat of pregnant women throughout gestation after controlled methadone administration.
Sweat patches (n = 350) were collected throughout gestation from 29 opioid-dependent pregnant women participating in an outpatient methadone-assisted therapy program. Volunteers provided informed consent to participate in institutional review board-approved protocols. Methadone was eluted from sweat patches with sodium acetate buffer, followed by solid-phase extraction and quantification by gas chromatography mass spectrometry (limit of quantification > or = 10 ng/patch). Methadone was present in all weekly patches (n = 311) in concentrations ranging from 10.2 to 12,129.7 nanograms per patch and in 92.3% of short-term patches (n = 39, worn for 12 or 24 hours) in concentrations up to 3303.9 nanograms per patch. Correlation between patch concentrations and total amount of drug administered (r = 0.224), and concentrations and duration of patch wear (r = 0.129) were both weak. Although there were large intra- and intersubject variations in sweat drug concentrations, sweat testing was an effective alternative technique to qualitatively monitor illicit drug use and simultaneously document methadone medication-assisted treatment.


Ovulation induction disrupts luteal phase function.
Abnormalities in the luteal phase have been detected in virtually all the stimulation protocols used in in vitro fertilization, on both the hormonal and endometrial levels. Supraphysiological follicular or luteal sex steroid serum concentrations, altered estradiol: progesterone (E2/P) ratio, and disturbed luteinizing hormone pituitary secretion leading to corpus luteum insufficiency or a direct drug effect have been postulated as the main etiologic factors. Luteinizing hormone supports corpus luteum function, and low LH levels have been described after human menopausal gonadotropin treatment, after gonadotropin-releasing hormone (GnRH)-agonist treatment, or after GnRH-antagonist treatment. These low luteal LH levels may lead to an insufficient corpus luteum function and consequently to a shortened luteal phase or to the low luteal progesterone concentrations frequently described after ovulation induction. A direct effect of the GnRH agonist or GnRH antagonist on human corpus luteum or on human endometrium and thus on endometrial receptivity cannot be excluded, as GnRH receptors have been described in both compartments. Endometrial histology has revealed a wide range of abnormalities during the various stimulation protocols. In GnRH-agonist cycles, mid-luteal biopsies have revealed increased glandulo-stromal dyssynchrony and delay in endometrial development, strong positivity of endometrial glands for progesterone receptors, decreased alphavbeta3-integrin subunit expression, and earlier appearance of surface epithelium pinopodes. These factors suggest a shift forwards of the implantation window. Progesterone supplementation improves endometrial histology, and its necessity has been well established, at least in cycles using GnRH agonists.


Casuarina glauca prenodule cells display the same differentiation as the corresponding nodule cells.
Recent phylogenetic studies have implied that all plants able to enter root nodule symbioses with nitrogen-fixing bacteria go back to a common ancestor (D.E. Soltis, P.S. Soltis, D.R. Morgan, S.M. Swensen, B.C. Mullin, J.M. Dowd, and P.G. Martin, Proc. Natl. Acad. Sci. USA, 92:2647-2651, 1995). However, nodules formed by plants from different groups are distinct in nodule organogenesis and structure. In most groups, nodule organogenesis involves the induction of cortical cell divisions. In legumes these divisions lead to the formation of a nodule primordium, while in non-legumes they lead to the formation of a so-called prenodule consisting of infected and uninfected cells. Nodule primordium formation does not involve prenodule cells, and the function of prenodules is not known. Here, we examine the differentiation of actinorhizal prenodule cells in comparison to nodule cells with regard to both symbionts. Our findings indicate that prenodules represent primitive symbiotic organs whose cell types display the same characteristics as their nodule counterparts. The results are discussed in the context of the evolution of root nodule symbioses.


Aboriginal Gambling and Problem Gambling: A Review.
The prevention of gambling-related problems amongst Aboriginal communities has been neglected by most public health strategies which concentrate on mainstream populations. Research indicates that rates of problem gambling are higher for Aboriginal groups than the general population. Specific cultural, familial, and social patterns influence gambling by Aboriginal groups, which are individually different, making it difficult to implement a cohesive strategy to address gambling-related harms. Because of this complexity, a thorough literature review is necessary to identify gaps in policy and research. This paper uses a public health framework to consider multi-dimensional influences (personal, environmental, economic, cultural and social) that affect gambling uptake. Such analysis is also important for identifying risk factors which facilitate the development and maintenance of problem gambling and potentially for underpinning protection, prevention and treatment programs. It is advised that strategies be developed in consultation with Aboriginal peoples to guide public health policy and research to minimise any gambling-related harms.


pH-dependent secondary structure propensity of the influenza A virus M2 cytoplasmic tail.
The cytoplasmic C-terminal tail of the matrix protein 2 (M2) from influenza A virus has a well conserved sequence and is involved in interactions with several host proteins as well as the influenza matrix protein 1 (M1). Whereas the transmembrane domain of M2 has been well characterised structurally and functionally, high resolution information about the distal cytoplasmic tail is lacking. Here we report the chemical shifts of the cytoplasmic tail of M2 and the chemical shift perturbations at low pH and in the presence of membrane mimetics. The cytoplasmic tail residues are mostly disordered but an extended backbone conformation is adopted by the LC3 binding motif and the putative M1 interaction site has partial helical content with a small pH-dependence. The chemical shift assignments provide a basis for further investigations into interactions of the M2 cytoplasmic tail with viral and host cell factors.


Ovarian epithelial tumors of borderline malignancy. A clinical and pathologic study of 109 cases.
One hundred nine cases of ovarian tumors of low malignant potential (borderline tumors) diagnosed at Stanford University Medical Center from 1958 to 1982 were reviewed. The patients ranged in age from 10 to 79 years (mean, 40.5 years). The histologic types and corresponding stages of these neoplasms were 73 serous (Stage IA: 35 patients; Stage IB+C: 16 patients; stage II: 8 patients; Stage III: 14 patients), 30 mucinous (Stage IA: 27 patients; Stage IB+C: 3 patients), and 6 mixed seromucinous (all Stage IA). Borderline endometrioid, clear cell, and Brenner tumors were excluded. Follow-up information from 3 to 27 years from the time of initial diagnosis (mean, 7.6 years; median, 7.1 years) revealed that 89 patients are alive without further evidence of neoplasm, and three patients died of unrelated disease without recurrent tumor. Seventeen patients have developed persistent or recurrent neoplasms in the contralateral ovary (six patients) and/or elsewhere within the peritoneal cavity (15 patients) at 5 to 226 months (mean, 61 months) after the initial excision. All of the second neoplasms were borderline serous or seromucinous tumors histologically identical to the original tumor; none of the borderline mucinous tumors recurred. Patients who initially had Stage III borderline serous tumors developed persistent or recurrent neoplasms more commonly (64%) than did patients with lower stage tumors (12%). No correlation was found between the development of a subsequent serous neoplasm and patient age, the primary tumor size, or any single histologic feature. Following treatment of the subsequent neoplasms, 13 patients are free of neoplasm, one patient is alive with tumor, one patient has died of intercurrent disease with tumor, and two patients have died with widespread abdominal tumor 53 and 232 months after their initial diagnosis. These findings confirm the excellent prognosis for patients with borderline serous tumors, despite involvement of the peritoneal cavity and the development of recrudescent tumor, although long-term follow-up is indicated. Mucinous borderline tumors, as defined by published criteria, almost invariably present as localized (low-stage) tumors and, in our experience, do not recur when confined to the ovary.


Measurement of gastric meal and secretion volumes using magnetic resonance imaging.
MRI can assess multiple gastric functions without ionizing radiation. However, time consuming image acquisition and analysis of gastric volume data, plus confounding of gastric emptying measurements by gastric secretions mixed with the test meal have limited its use to research centres. This study presents an MRI acquisition protocol and analysis algorithm suitable for the clinical measurement of gastric volume and secretion volume. Reproducibility of gastric volume measurements was assessed using data from 10 healthy volunteers following a liquid test meal with rapid MRI acquisition within one breath-hold and semi-automated analysis. Dilution of the ingested meal with gastric secretion was estimated using a respiratory-triggered T1 mapping protocol. Accuracy of the secretion volume measurements was assessed using data from 24 healthy volunteers following a mixed (liquid/solid) test meal with MRI meal volumes compared to data acquired using gamma scintigraphy (GS) on the same subjects studied on a separate study day. The mean ± SD coefficient of variance between 3 observers for both total gastric contents (including meal, secretions and air) and just the gastric contents (meal and secretion only) was 3 ± 2% at large gastric volumes (>200 ml). Mean ± SD secretion volumes post meal ingestion were 64 ± 51 ml and 110 ± 40 ml at 15 and 75 min, respectively. Comparison with GS meal volumes, showed that MRI meal only volume (after correction for secretion volume) were similar to GS, with a linear regression gradient ± std err of 1.06 ± 0.10 and intercept -11 ± 24 ml. In conclusion, (i) rapid volume acquisition and respiratory triggered T₁ mapping removed the requirement to image during prolonged breath-holds (ii) semi-automatic analysis greatly reduced the time required to derive measurements and (iii) correction for secretion volumes provided accurate assessment of gastric meal volumes and emptying. Together these features provide the scientific basis of a protocol which would be suitable in clinical practice.


Development of a multilayered polymeric DNA biosensor using radio frequency technology with gold and magnetic nanoparticles.
This study utilized the radio frequency (RF) technology to develop a multilayered polymeric DNA sensor with the help of gold and magnetic nanoparticles. The flexible polymeric materials, poly (p-xylylene) (Parylene) and polyethylene naphtholate (PEN), were used as substrates to replace the conventional rigid substrates such as glass and silicon wafers. The multilayered polymeric RF biosensor, including the two polymer layers and two copper transmission structure layers, was developed to reduce the total sensor size and further enhance the sensitivity of the biochip in the RF DNA detection. Thioglycolic acid (TGA) was used on the surface of the proposed biochip to form a thiolate-modified sensing surface for DNA hybridization. Gold nanoparticles (AuNPs) and magnetic nanoparticles (MNPs) were used to immobilize on the surface of the biosensor to enhance overall detection sensitivity. In addition to gold nanoparticles, the magnetic nanoparticles has been demonstrated the applicability for RF DNA detection. The performance of the proposed biosensor was evaluated by the shift of the center frequency of the RF biosensor because the electromagnetic characteristic of the biosensors can be altered by the immobilized multilayer nanoparticles on the biosensor. The experimental results show that the detection limit of the DNA concentration can reach as low as 10 pM, and the largest shift of the center frequency with triple-layer AuNPs and MNPs can approach 0.9 and 0.7 GHz, respectively. Such the achievement implies that the developed biosensor can offer an alternative inexpensive, disposable, and highly sensitive option for application in biomedicine diagnostic systems because the price and size of each biochip can be effectively reduced by using fully polymeric materials and multilayer-detecting structures.


Thiosemicarbazone-based selective proliferation inactivators inhibit gastric cancer cell growth, invasion, and migration.
A series of novel thiosemicarbazone derivatives were synthesized and evaluated for their antiproliferative activity against several selected tumor cell lines of different origins using the MTT assay. The preliminary results indicated that the MGC-803 cell line was remarkably sensitive to all the synthesized compounds. Among this series, compound 5n showed the best inhibitory activity with an IC50 value of 0.93 μM (about 10-fold more potent than 3-AP) against MGC-803. Further mechanism studies revealed that compound 5n could obviously inhibit the proliferation of MGC-803 cells by inducing apoptosis and arresting the cell cycle at the S phase. Compound 5n also showed marked inhibition of cell migration and invasion, without significant cytotoxicity against gastric epithelial immortalized GES-1 cells.


Speech and language delay in children.
Speech and language delay in children is associated with increased difficulty with reading, writing, attention, and socialization. Although physicians should be alert to parental concerns and to whether children are meeting expected developmental milestones, there currently is insufficient evidence to recommend for or against routine use of formal screening instruments in primary care to detect speech and language delay. In children not meeting the expected milestones for speech and language, a comprehensive developmental evaluation is essential, because atypical language development can be a secondary characteristic of other physical and developmental problems that may first manifest as language problems. Types of primary speech and language delay include developmental speech and language delay, expressive language disorder, and receptive language disorder. Secondary speech and language delays are attributable to another condition such as hearing loss, intellectual disability, autism spectrum disorder, physical speech problems, or selective mutism. When speech and language delay is suspected, the primary care physician should discuss this concern with the parents and recommend referral to a speech-language pathologist and an audiologist. There is good evidence that speech-language therapy is helpful, particularly for children with expressive language disorder.


Documenting the experiences of health workers expected to implement guidelines during an intervention study in Kenyan hospitals.
Although considerable efforts are directed at developing international guidelines to improve clinical management in low-income settings they appear to influence practice rarely. This study aimed to explore barriers to guideline implementation in the early phase of an intervention study in four district hospitals in Kenya. We developed a simple interview guide based on a simple characterisation of the intervention informed by review of major theories on barriers to uptake of guidelines. In-depth interviews, non-participatory observation, and informal discussions were then used to explore perceived barriers to guideline introduction and general improvements in paediatric and newborn care. Data were collected four to five months after in-service training in the hospitals. Data were transcribed, themes explored, and revised in two rounds of coding and analysis using NVivo 7 software, subjected to a layered analysis, reviewed, and revised after discussion with four hospital staff who acted as within-hospital facilitators. A total of 29 health workers were interviewed. Ten major themes preventing guideline uptake were identified: incomplete training coverage; inadequacies in local standard setting and leadership; lack of recognition and appreciation of good work; poor communication and teamwork; organizational constraints and limited resources; counterproductive health worker norms; absence of perceived benefits linked to adoption of new practices; difficulties accepting change; lack of motivation; and conflicting attitudes and beliefs. While the barriers identified are broadly similar in theme to those reported from high-income settings, their specific nature often differs. For example, at an institutional level there is an almost complete lack of systems to introduce or reinforce guidelines, poor teamwork across different cadres of health worker, and failure to confront poor practice. At an individual level, lack of interest in the evidence supporting guidelines, feelings that they erode professionalism, and expectations that people should be paid to change practice threaten successful implementation.


Process standardization of Swarna Makshika Shodhana (purification) in Triphala Kwatha (decoction).
Swarna Makshika (SM) is a brassy golden yellowish mineral with chemical composition of CuFeS2 that is widely used in therapeutics to treat various disease conditions such as Prameha (diabetes), Panḍu (anemia), Kushtha (skin diseases) and Jwara (fever). This mineral needs to be processed by the following specified Ayurveda guidelines in order to make it therapeutically safe and more potent. These processes include Shodhana (preliminary process of eliminating unwanted substances), Marana (incineration) and Amritikarana (nectorization) that are mandatory and play a crucial role in therapeutics. However, till date, no published reports are available on standard manufacturing procedure of SM Shodhana. The objective of this study is to develop the standard manufacturing procedure of SM Shodhana. Methods described in Rasaratna Samuchhaya were followed to perform Shodhana process. Shodhana of SM was carried out in three batches (600 g in each batch) by seven quenching in Triphala Kwatha (TK, decoction of Terminalia chebula Retz., Terminalia bellirica Roxb. and Phyllanthus emblica Linn.) maintaining batch manufacturing records. Organoleptic and physicochemical analysis of media, i.e., TK and SM was carried out. After Shodhana, golden yellowish luster of SM was completely lost and it turned into dark black coarse powder. The hardness went on decreasing and brittleness went on increasing. Average 532 g of Shodhita SM (88.67%) from 600 g of SM was obtained. Average time required for achieving red hot stage was 24.81 min. Analysis of the media revealed an increase in pH, specific gravity, and total solid contents. The adopted method for Shodhana of 600 g of SM can be considered as easy, convenient and standard.


Does the Size of the Effect of Adverse Events at High Ages on Daily-Life Physical Functioning Depend on the Economic Conditions Around Birth?
This paper considers determinants of physical functional limitations in daily-life activities at high ages. Specifically, we quantify the extent to which the impact of adverse life events on this outcome is larger in case of exposure to adverse economic conditions early in life. Adverse life events include bereavement, severe illness in the family, and the onset of chronic diseases. We use a longitudinal data set of individuals born in the first decades of the 20th century. The business cycle around birth is used as an indicator of economic conditions early in life. We find that the extent to which functional limitations suffer from the onset of chronic diseases is larger if the individual was born in a recession. The long-run effect of economic conditions early in life on functional limitations at high ages runs primarily via this life event. Copyright © 2015 John Wiley & Sons, Ltd.


Utilization of genetic tests: analysis of gene-specific billing in Medicare claims data.
We examined the utilization of precision medicine tests among Medicare beneficiaries through analysis of gene-specific tier 1 and 2 billing codes developed by the American Medical Association in 2012. We conducted a retrospective cross-sectional study. The primary source of data was 2013 Medicare 100% fee-for-service claims. We identified claims billed for each laboratory test, the number of patients tested, expenditures, and the diagnostic codes indicated for testing. We analyzed variations in testing by patient demographics and region of the country. Pharmacogenetic tests were billed most frequently, accounting for 48% of the expenditures for new codes. The most common indications for testing were breast cancer, long-term use of medications, and disorders of lipid metabolism. There was underutilization of guideline-recommended tumor mutation tests (e.g., epidermal growth factor receptor) and substantial overutilization of a test discouraged by guidelines (methylenetetrahydrofolate reductase). Methodology-based tier 2 codes represented 15% of all claims billed with the new codes. The highest rate of testing per beneficiary was in Mississippi and the lowest rate was in Alaska. Gene-specific billing codes significantly improved our ability to conduct population-level research of precision medicine. Analysis of these data in conjunction with clinical records should be conducted to validate findings.Genet Med advance online publication 26 January 2017.


Fission yeast Cut8 is required for the repair of DNA double-strand breaks, ribosomal DNA maintenance, and cell survival in the absence of Rqh1 helicase.
Schizosaccharomyces pombe Rqh1 is a member of the RecQ DNA helicase family. Members of this protein family are mutated in cancer predisposition diseases, causing Bloom's, Werner, and Rothmund-Thomson syndromes. Rqh1 forms a complex with topoisomerase III and is proposed to process or disrupt aberrant recombination structures that arise during S phase to allow proper chromosome segregation during mitosis. Intriguingly, in the absence of Rqh1, processing of these structures appears to be dependent on Rad3 (human ATR) in a manner that is distinct from its role in checkpoint control. Here, we show that rad3 rqh1 mutants are normally committed to a lethal pathway of DNA repair requiring homologous recombination, but blocking this pathway by Rhp51 inactivation restores viability. Remarkably, viability is also restored by overexpression of Cut8, a nuclear envelope protein involved in tethering and proper function of the proteasome. In keeping with a recently described function of the proteasome in the repair of DNA double-strand breaks, we found that Cut8 is also required for DNA double-strand break repair and is essential for proper chromosome segregation in the absence of Rqh1, suggesting that these proteins might function in a common pathway in homologous recombination repair to ensure accurate nuclear division in S. pombe.


A Minimalistic Resource Allocation Model to Explain Ubiquitous Increase in Protein Expression with Growth Rate.
Most proteins show changes in level across growth conditions. Many of these changes seem to be coordinated with the specific growth rate rather than the growth environment or the protein function. Although cellular growth rates, gene expression levels and gene regulation have been at the center of biological research for decades, there are only a few models giving a base line prediction of the dependence of the proteome fraction occupied by a gene with the specific growth rate. We present a simple model that predicts a widely coordinated increase in the fraction of many proteins out of the proteome, proportionally with the growth rate. The model reveals how passive redistribution of resources, due to active regulation of only a few proteins, can have proteome wide effects that are quantitatively predictable. Our model provides a potential explanation for why and how such a coordinated response of a large fraction of the proteome to the specific growth rate arises under different environmental conditions. The simplicity of our model can also be useful by serving as a baseline null hypothesis in the search for active regulation. We exemplify the usage of the model by analyzing the relationship between growth rate and proteome composition for the model microorganism E.coli as reflected in recent proteomics data sets spanning various growth conditions. We find that the fraction out of the proteome of a large number of proteins, and from different cellular processes, increases proportionally with the growth rate. Notably, ribosomal proteins, which have been previously reported to increase in fraction with growth rate, are only a small part of this group of proteins. We suggest that, although the fractions of many proteins change with the growth rate, such changes may be partially driven by a global effect, not necessarily requiring specific cellular control mechanisms.


The International Observatory on End of Life Care: a new initiative to support palliative care development around the world.
The development of palliative care is proceeding rapidly in some areas of the world, but major problems continue to exist in several countries and regions. Comparative research evidence to inform palliative care development is limited and can be difficult to obtain, especially for resource poor settings. International collaboration is needed to promote and disseminate an evidence base to support the growth of palliative care. The aims and plans of the newly created International Observatory on End of Life Care are described, together with its orientation to global partnership and collaboration. The Observatory will build on public health models to provide research-based intelligence about palliative care around the world, drawing also on cultural, historical and ethical perspectives.


Building a bio-based industry in the Middle East through harnessing the potential of the Red Sea biodiversity.
The incentive for developing microbial cell factories for production of fuels and chemicals comes from the ability of microbes to deliver these valuable compounds at a reduced cost and with a smaller environmental impact compared to the analogous chemical synthesis. Another crucial advantage of microbes is their great biological diversity, which offers a much larger "catalog" of molecules than the one obtainable by chemical synthesis. Adaptation to different environments is one of the important drives behind microbial diversity. We argue that the Red Sea, which is a rather unique marine niche, represents a remarkable source of biodiversity that can be geared towards economical and sustainable bioproduction processes in the local area and can be competitive in the international bio-based economy. Recent bioprospecting studies, conducted by the King Abdullah University of Science and Technology, have established important leads on the Red Sea biological potential, with newly isolated strains of Bacilli and Cyanobacteria. We argue that these two groups of local organisms are currently most promising in terms of developing cell factories, due to their ability to operate in saline conditions, thus reducing the cost of desalination and sterilization. The ability of Cyanobacteria to perform photosynthesis can be fully exploited in this particular environment with one of the highest levels of irradiation on the planet. We highlight the importance of new experimental and in silico methodologies needed to overcome the hurdles of developing efficient cell factories from the Red Sea isolates.


This Is Africa.
Military deployments will always result in exposure to health hazards other than those from combat operations. The occupational and environmental health and endemic disease health risks are greater to the Special Operations Forces (SOF) deployed to the challenging conditions in Africa than elsewhere in the world. SOF are deployed to locations that lack life support infrastructures that have become standard for most military deployments; instead, they rely on local resources to sustain operations. Particularly, SOF in Africa do not generally have access to advanced diagnostic or monitoring capabilities or to medical treatment in austere locations that lack environmental or public health regulation. The keys to managing potential adverse health effects lie in identifying and documenting the health hazards and exposures, characterizing the associated risks, and communicating the risks to commanders, deployed personnel, and operational planners.


The renin-aldosterone system in exaggerated natriuresis of essential hypertension.
1. The effect of intravenous loading with 500 ml of sodium chloride solution (50 g/l) on plasma renin concentration, plasma aldosterone concentration, urinary sodium excretion and mean blood pressure was studied in 15 young patients with mild essential hypertension and 10 healthy normotensive control subjects. 2. Plasma renin concentration and plasma aldosterone concentration were suppressed to the same degree during loading in both the hypertensive and normotensive groups. Urinary sodium excretion was significantly higher in the hypertensive patients than in the normotensive subjects. Mean blood pressure increased slightly in both groups. 3. Plasma renin concentration and plasma aldosterone concentration were significantly correlated in both groups before sodium loading. The increase in urinary sodium excretion was significantly correlated to the suppression of plasma aldosterone concentration in the hypertensive, but not in the normotensive, group. No correlation was found between changes in urinary sodium excretion and changes in plasma renin concentration or mean blood pressure. 4. The results indicate that the suppressibility of the renin-aldosterone system by hyperosmotic sodium chloride solution is normal in young patients with mild essential hypertension. It is suggested that the changes in plasma aldosterone concentration induced by sodium loading might be involved in the regulation of exaggerated natriuresis in essential hypertension.


Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus.
The function of the subnuclear structure the promyelocytic leukaemia (PML) body is unclear largely because of the functional heterogeneity of its constituents. Here, we provide the evidence for a direct link between PML, higher-order chromatin organization and gene regulation. We show that PML physically and functionally interacts with the matrix attachment region (MAR)-binding protein, special AT-rich sequence binding protein 1 (SATB1) to organize the major histocompatibility complex (MHC) class I locus into distinct higher-order chromatin-loop structures. Interferon gamma (IFNgamma) treatment and silencing of either SATB1 or PML dynamically alter chromatin architecture, thus affecting the expression profile of a subset of MHC class I genes. Our studies identify PML and SATB1 as a regulatory complex that governs transcription by orchestrating dynamic chromatin-loop architecture.


Standardizing data reporting in the research community to enhance the utility of open data for SARS-CoV-2 wastewater surveillance.
SARS-CoV-2 RNA detection in wastewater is being rapidly developed and adopted as a public health monitoring tool worldwide. With wastewater surveillance programs being implemented across many different scales and by many different stakeholders, it is critical that data collected and shared are accompanied by an appropriate minimal amount of metainformation to enable meaningful interpretation and use of this new information source and intercomparison across datasets. While some databases are being developed for specific surveillance programs locally, regionally, nationally, and internationally, common globally-adopted data standards have not yet been established within the research community. Establishing such standards will require national and international consensus on what metainformation should accompany SARS-CoV-2 wastewater measurements. To establish a recommendation on minimum information to accompany reporting of SARS-CoV-2 occurrence in wastewater for the research community, the United States National Science Foundation (NSF) Research Coordination Network on Wastewater Surveillance for SARS-CoV-2 hosted a workshop in February 2021 with participants from academia, government agencies, private companies, wastewater utilities, public health laboratories, and research institutes. This report presents the primary two outcomes of the workshop: (i) a recommendation on the set of minimum meta-information that is needed to confidently interpret wastewater SARS-CoV-2 data, and (ii) insights from workshop discussions on how to improve standardization of data reporting.


Parental academic involvement in adolescence, academic achievement over the life course and allostatic load in middle age: a prospective population-based cohort study.
Parental involvement in their children's studies, particularly in terms of academic socialisation, has been shown to predict academic achievement, and is thus a candidate modifiable factor influencing life course socioeconomic circumstances. Socioeconomic disadvantage is thought to impact on health over the life course partly by allostatic load, that is, cumulative biological risk. We sought to elucidate the role of parental involvement at age 16 on the life course development of allostatic load. In a population-based cohort (365 women and 352 men, 67% of the eligible participants), we examined the association between parental involvement in their offspring's studies, measured by teacher and pupil ratings at age 16 and an allostatic load index summarising 12 physiological risk markers at age 43. Mediation through life course academic and occupational achievement was assessed by entering school grades, adult educational achievement and socioeconomic position at age 43 in a linear regression analysis in a stepwise manner and testing for mediation. Parental interest in their offspring's studies during the last year of compulsory school-rather than the parent's social class or availability of practical academic support-was found to predict adult allostatic load (β=-0.12, 95% CI -0.20 to -0.05). Further adjustments indicated that academic achievement over the life course mediated a large part of the effect of parental interest on allostatic load. Parental interest in their offspring's studies may have protective effects by decreasing the likelihood of a chain of risk involving low academic achievement, low socioeconomic position and high accumulated physiological stress.


Reconstructing protein complexes: from proteomics to systems biology.
Modern high throughput technologies in biological science often create lists of interesting molecules. The challenge is to reconstruct a descriptive model from these lists that reflects the underlying biological processes as accurately as possible. Once we have such a model or network, what can we learn from it? Specifically, given that we are interested in some biological process associated with the model, what new properties can we predict and subsequently test? Here, we describe, at an introductory level, a range of bioinformatics techniques that can be systematically applied to proteomic datasets. When combined, these methods give us a global overview of the network and the properties of the proteins and their interactions. These properties can then be used to predict functional pathways within the network and to examine substructure. To illustrate the application of these methods, we draw upon our own work concerning a complex of 186 proteins found in neuronal synapses in mammals. The techniques discussed are generally applicable and could be used to examine lists of proteins involved with the biological response to electric or magnetic fields.


Kernel based machine learning algorithm for the efficient prediction of type III polyketide synthase family of proteins.
Type III Polyketide synthases (PKS) are family of proteins considered to have significant roles in the biosynthesis of various polyketides in plants, fungi and bacteria. As these proteins shows positive effects to human health, more researches are going on regarding this particular protein. Developing a tool to identify the probability of sequence being a type III polyketide synthase will minimize the time consumption and manpower efforts. In this approach, we have designed and implemented PKSIIIpred, a high performance prediction server for type III PKS where the classifier is Support Vector Machines (SVMs). Based on the limited training dataset, the tool efficiently predicts the type III PKS superfamily of proteins with high sensitivity and specificity. The PKSIIIpred is available at http://type3pks.in/prediction/. We expect that this tool may serve as a useful resource for type III PKS researchers. Currently work is being progressed for further betterment of prediction accuracy by including more sequence features in the training dataset.


Vis4Heritage: visual analytics approach on Grotto wall painting degradations.
For preserving the Grotto wall paintings and protecting these historic cultural icons from the damage and deterioration in nature environment, a visual analytics framework and a set of tools are proposed for the discovery of degradation patterns. In comparison with the traditional analysis methods that used restricted scales, our method provides users with multi-scale analytic support to study the problems on site, cave, wall and particular degradation area scales, through the application of multidimensional visualization techniques. Several case studies have been carried out using real-world wall painting data collected from a renowned World Heritage site, to verify the usability and effectiveness of the proposed method. User studies and expert reviews were also conducted through by domain experts ranging from scientists such as microenvironment researchers, archivists, geologists, chemists, to practitioners such as conservators, restorers and curators.


Developing person-centred practice: nursing outcomes arising from changes to the care environment in residential settings for older people.
To present the nursing outcomes from the evaluation of developments in the care environment in residential settings for older people. The evaluation data reported here is derived from a larger national programme of work that focused on the development of person-centred practice in residential services for older people using an emancipatory practice development framework. A multi-method evaluation framework was utilised. Outcome data were collected at three time points between December 2007 and September 2009. The data reported here were collected using an instrument called the 'Person-Centred Nursing Index'. Heavy workload was the main cause of stress among nurses. Personal and professional satisfaction with the job was scored highest by the total sample of nurses. Nineteen factors were examined using the Person-Centred Nursing Index. Statistically significant changes were observed in 12 of these. In addition, there were statistically significant changes in nurses' perceptions of caring, indicating a shift from a dominant focus on 'technical' aspects of care, to one where 'intimate' aspects of care were more highly valued. The findings highlight the importance of the development of effective teamwork, workload management, time management and staff relationships in order to create a culture where there is a more democratic and inclusive approach to practice and space for the formation of person-centred relationships.


Dietary Pattern Associated with Frailty: Results from Nutrition and Health Survey in Taiwan.
To investigate whether dietary patterns are associated with frailty phenotypes in an elderly Taiwanese population. Cross-sectional. Nutrition and Health Survey in Taiwan (NAHSIT), 2014-2016. Noninstitutionalized Taiwanese nationals aged 65 years and older enrolled in the NAHSIT (N = 923). Dietary intake was assessed using a 79-item food-frequency questionnaire (FFQ). Presence of 5 frailty phenotypes was determined using modified Fried criteria and are summed into a frailty score. Using data from the NAHSIT (2014-15), reduced rank regression was used to find a dietary pattern that explained maximal degree of variation of the frailty scores. Logistic regression models were used to estimate the association between frailty and dietary pattern. The findings were validated with data from 2016. The derived dietary pattern was characterized with a high consumption of fruit, nuts and seeds, tea, vegetables, whole grains, shellfish, milk, and fish. The prevalence of frailty was 7.8% and of prefrailty was 50.8%, defined using the modified Fried criteria. Using data from the NAHSIT (2014-15), the dietary pattern score showed an inverse dose-response relationship with prevalence of frailty and pre-frailty. Individuals in the second dietary pattern tertile were one-third as likely to be frail as those in the first tertile (adjusted odds ratio (aOR) = 0.32, 95% confidence interval (CI) = 0.12-0.85), and those in the third tertile were 4% as likely to be frail as those in the first tertile (aOR = 0.04, 95% CI = 0.01-0.18). The dietary pattern score estimated using FFQ data from the NAHSIT 2016 was also significantly and inversely associated with frailty. Individuals with a dietary pattern with more phytonutrient-rich plant foods, tea, omega-3-rich deep-sea fish, and other protein-rich foods such as shellfish and milk had a reduced prevalence of frailty. Further research is necessary to confirm these findings and investigate whether related dietary interventions can reduce frailty in older adults.


Ligation of cell surface-associated glucose-regulated protein 78 by receptor-recognized forms of alpha 2-macroglobulin: activation of p21-activated protein kinase-2-dependent signaling in murine peritoneal macrophages.
Previous studies of the plasma proteinase inhibitor alpha2-macroglobulin (alpha2M) demonstrated that alpha2M-proteinase complexes (alpha2M*) modulate immune responses and promotes macrophage locomotion and chemotaxis. Alpha2M* binds to cell surface-associated glucose-regulated protein 78 (GRP78), which activates downstream signaling events. The role of p21-activated protein kinase-1 and -2 (PAK-1 and -2) in promoting cellular motility is well documented. In the current study, we examined the ability of alpha2M* to activate PAK-1 and PAK-2. Upon macrophage stimulation with alpha2M*, PAK-2 is autophosphorylated, resulting in increased kinase activity; however, PAK-1 is negligibly affected. Alpha2M*-stimulated macrophages showed a marked elevation in the levels of Rac x GTP. Receptor tyrosine phosphorylation upon binding of alpha2M* to GRP78, recruits PAK-2 to the plasma membrane via the adaptor protein NCK. Consistent with this hypothesis, silencing of GRP78 gene expression greatly attenuated the levels of membrane-associated PAK-2 and NCK. PAK-2 activity was markedly decreased by inhibition of tyrosine kinases and PI3K before alpha2M* stimulation. We further demonstrate that phosphorylation of Lin-11, Isl-1, Mec-3 (LIM) kinase and cofilin is promoted by treating macrophages with alpha2M*. Thus, alpha2M* regulates activation of the PAK-2-dependent motility mechanism in these cells.


Changes in diet, cardiovascular risk factors and modelled cardiovascular risk following diagnosis of diabetes: 1-year results from the ADDITION-Cambridge trial cohort.
To describe change in self-reported diet and plasma vitamin C, and to examine associations between change in diet and cardiovascular disease risk factors and modelled 10-year cardiovascular disease risk in the year following diagnosis of Type 2 diabetes. Eight hundred and sixty-seven individuals with screen-detected diabetes underwent assessment of self-reported diet, plasma vitamin C, cardiovascular disease risk factors and modelled cardiovascular disease risk at baseline and 1 year (n = 736) in the ADDITION-Cambridge trial. Multivariable linear regression was used to quantify the association between change in diet and cardiovascular disease risk at 1 year, adjusting for change in physical activity and cardio-protective medication. Participants reported significant reductions in energy, fat and sodium intake, and increases in fruit, vegetable and fibre intake over 1 year. The reduction in energy was equivalent to an average-sized chocolate bar; the increase in fruit was equal to one plum per day. There was a small increase in plasma vitamin C levels. Increases in fruit intake and plasma vitamin C were associated with small reductions in anthropometric and metabolic risk factors. Increased vegetable intake was associated with an increase in BMI and waist circumference. Reductions in fat, energy and sodium intake were associated with reduction in HbA1c , waist circumference and total cholesterol/modelled cardiovascular disease risk, respectively. Improvements in dietary behaviour in this screen-detected population were associated with small reductions in cardiovascular disease risk, independently of change in cardio-protective medication and physical activity. Dietary change may have a role to play in the reduction of cardiovascular disease risk following diagnosis of diabetes.


Aqueous humour dynamics and biometrics in the ageing Chinese eye.
This study evaluates ocular biometrics and aqueous humour dynamics (AHD) in healthy Chinese volunteers to determine how the various ocular parameters interact to maintain physiological intraocular pressure (IOP) at all ages. Sixty-nine volunteers enrolled in this cross-sectional study and were categorised into young (20-30 years) and old (≥50 years) groups. Measurements included IOP, ocular biometrics and AHD. Data were analysed using mixed model with random sampling to account for both eyes from the same individual. Spearman's rank correlation with bootstrap resampling was used to find associations between parameters. Compared with young subjects, old subjects had significantly (p<0.05) thinner corneas (CCT; 549.7±5.7 vs 530.6±5.3 µm; mean±SEM), shallower anterior chambers (3.14±0.05 vs 2.37±0.05 mm) and slower aqueous flow (Fa; 3.0±0.1 vs 2.7±0.1 µL/min). Uveoscleral outflow slowed (Fu; 1.0±0.2 vs 0.7±0.1) but not significantly. A positive linear association between IOP and episcleral venous pressure was found (young: R2=0.16; old: R2=0.08). Negative correlation between Fa and CCT (R2=0.06) and positive correlation between Fa and outflow facility (R2=0.08) was found in old participants. In the healthy ageing Chinese eye, IOP remains unchanged, while Fa slows, which is counterbalanced by slowing of Fu. Aqueous humour exits the eye preferentially through the trabecular route at all ages. Ageing is also associated with shallowing of the anterior chamber and thinning of the cornea. A slower Fa with lower outflow facility supports existence of autoregulatory mechanisms.


International Society of Sports Nutrition position stand: sodium bicarbonate and exercise performance.
Based on a comprehensive review and critical analysis of the literature regarding the effects of sodium bicarbonate supplementation on exercise performance, conducted by experts in the field and selected members of the International Society of Sports Nutrition (ISSN), the following conclusions represent the official Position of the Society: 1. Supplementation with sodium bicarbonate (doses from 0.2 to 0.5 g/kg) improves performance in muscular endurance activities, various combat sports, including boxing, judo, karate, taekwondo, and wrestling, and in high-intensity cycling, running, swimming, and rowing. The ergogenic effects of sodium bicarbonate are mostly established for exercise tasks of high-intensity that last between 30 s and 12 min. 2. Sodium bicarbonate improves performance in single- and multiple-bout exercise. 3. Sodium bicarbonate improves exercise performance in both men and women. 4. For single-dose supplementation protocols, 0.2 g/kg of sodium bicarbonate seems to be the minimum dose required to experience improvements in exercise performance. The optimal dose of sodium bicarbonate dose for ergogenic effects seems to be 0.3 g/kg. Higher doses (e.g., 0.4 or 0.5 g/kg) may not be required in single-dose supplementation protocols, because they do not provide additional benefits (compared with 0.3 g/kg) and are associated with a higher incidence and severity of adverse side-effects. 5. For single-dose supplementation protocols, the recommended timing of sodium bicarbonate ingestion is between 60 and 180 min before exercise or competition. 6. Multiple-day protocols of sodium bicarbonate supplementation can be effective in improving exercise performance. The duration of these protocols is generally between 3 and 7 days before the exercise test, and a total sodium bicarbonate dose of 0.4 or 0.5 g/kg per day produces ergogenic effects. The total daily dose is commonly divided into smaller doses, ingested at multiple points throughout the day (e.g., 0.1 to 0.2 g/kg of sodium bicarbonate consumed at breakfast, lunch, and dinner). The benefit of multiple-day protocols is that they could help reduce the risk of sodium bicarbonate-induced side-effects on the day of competition. 7. Long-term use of sodium bicarbonate (e.g., before every exercise training session) may enhance training adaptations, such as increased time to fatigue and power output. 8. The most common side-effects of sodium bicarbonate supplementation are bloating, nausea, vomiting, and abdominal pain. The incidence and severity of side-effects vary between and within individuals, but it is generally low. Nonetheless, these side-effects following sodium bicarbonate supplementation may negatively impact exercise performance. Ingesting sodium bicarbonate (i) in smaller doses (e.g., 0.2 g/kg or 0.3 g/kg), (ii) around 180 min before exercise or adjusting the timing according to individual responses to side-effects, (iii) alongside a high-carbohydrate meal, and (iv) in enteric-coated capsules are possible strategies to minimize the likelihood and severity of these side-effects. 9. Combining sodium bicarbonate with creatine or beta-alanine may produce additive effects on exercise performance. It is unclear whether combining sodium bicarbonate with caffeine or nitrates produces additive benefits. 10. Sodium bicarbonate improves exercise performance primarily due to a range of its physiological effects. Still, a portion of the ergogenic effect of sodium bicarbonate seems to be placebo-driven.


A Population-Based Study of Healthcare Resource Utilization in Patients with Mitral Valve Prolapse.
This study investigated differences in the utilization of healthcare services between subjects with mitral valve prolapse (MVP) and comparison subjects using data from Taiwan's National Health Insurance population-based database, 138,493 patients with MVP (study group) and 138,493 matched patients without MVP (comparison group). We calculated the utilization of healthcare services in the year 2016 for each study sample. Patients with MVP had more outpatient cardiological services during the year (5.3 vs. 0.7, p < 0.001) and higher outpatient cardiology costs (US$226.0 vs. US$30.8, p < 0.001) than patients without MVP. As expected, patients with MVP had a longer inpatient stay (0.5 vs. 0.1, p < 0.001) and higher inpatients costs (US$158.0 vs. US$22.9, p < 0.001) than patients without MVP for cardiology services. Furthermore, patients with MVP also had more outpatient non-cardiology services (20.8 vs. 16.5, p < 0.001) and associated costs (US$708.3 vs. US$518.7, p < 0.001) than patients without MVP in the year 2016. Multiple regression analysis indicated that patients with MVP had higher total costs for all healthcare services than patients without MVP after adjusting for the urbanization level, monthly income, and geographic region. This study demonstrated that healthcare utilization by patients with MVP is substantially higher than comparison patients. Future studies are encouraged to explore MVP treatment with less expensive modalities while maintaining care quality and without jeopardizing patient outcomes.


Comparing perspectives of family caregivers and healthcare professionals regarding caregiver burden in dementia care: results of a mixed methods study in a rural setting.
Persons with dementia (PwD) need support to remain in their own homes as long as possible. Family caregivers, homecare nurses and general practitioners (GPs) play an important role in providing this support, particularly in rural settings. Assessing caregiver burden is important to prevent adverse health effects among this population. This study analysed perceived burden and needs of family caregivers of PwD in rural areas from the perspectives of healthcare professionals and family caregivers. This was a sequential explanatory mixed methods study that used both questionnaires and semi-structured interviews. Questionnaires measuring caregiver burden, quality of life and nursing needs were distributed to the caregivers; health professionals received questionnaires with adjusted items for each group. Additionally, in-depth qualitative interviews were carried out with eight family caregivers. The cross-sectional survey population included GPs (n = 50), homecare nurses (n = 140) and family caregivers (n = 113). Healthcare professionals similarly assessed the psychosocial burden and stress caused by behavioural disturbances as most relevant. Psychological stress, social burden and disruptive behaviour (in that order) were regarded as the most important factors from the caregivers' perspective. It was found that 31% of caregivers reported permanent or frequent caregiver overload. Eight themes related to caregiver burden emerged from the subsequent interviews with caregivers. Professional support at home on an hourly basis was found to be highly relevant to prevent social isolation and compensate for lack of leisure among caregivers of PwD. Improvement of interprofessional dementia-related education is needed to ensure high-quality primary care.


High-resolution ZTE imaging of human teeth.
MRI with zero echo time (ZTE) is achieved by 3D radial centre-out encoding and hard-pulse RF excitation while the projection gradient is already on. Targeting short-T(2) samples, the efficient, robust and silent ZTE approach was implemented for high-bandwidth high-resolution imaging requiring particularly rapid transmit-receive switching and algebraic image reconstruction. The ZTE technique was applied to image extracted human teeth at 11.7T field strength, yielding detailed depictions with very good delineation of the mineralised dentine and enamel layers. ZTE results are compared with UTE (ultra-short echo time) MRI and micro-computed tomography (μCT), revealing significant differences in SNR and CNR yields. Compared to μCT, ZTE MRI appears to be less susceptible to artefacts caused by dental fillings and to offer superior sensitivity for the detection of early demineralisation and caries lesions.


Study of breast implants mammography examinations for identification of suitable image quality criteria.
To characterise the mammography technique used in breast cancer screening programmes for breast implants (BI) and to identify if the image quality (IQ) criteria available in literature are applicable to BI imaging. The study was conducted in two phases: literature review to find IQ criteria used in mammography combining keywords in several sources; and assessment of 1207 BI mammograms using the criteria that was identified previously to see if they were achieved or not. An observation grid was used to collect information about positioning, beam energy, compression force, and exposure mode. Descriptive statistics and Student's t test and χ2 test were performed according to the nature of the variables. Forty-seven out of 2188 documents were included in the analysis, with 13 items identified to assess the quality of positioning, 4 for sharpness, 3 for artefacts, and 2 for exposure parameters. After applying the criteria to BI mammograms, retroglandular fat was not included in 37.3% of the images. The "Pectoral-Nipple-Line" criterion was achieved in 35% of MLO/ML images. The placement of the implant (subpectoral/subglandular) or performing the Eklund had significant influence on the visible anatomy (p = < 0.005), alongside whether the breast was aligned to the detector's centre. Some of the criteria used to assess standard mammograms were not applicable to BI due to implant overlap. The alignment of the image with the detector's centre seems to have an impact on the amount of visible tissue. Further studies are necessary to define the appropriate protocol, technique, and suitable quality criteria to assess BI mammograms.


Odanacatib Restores Trabecular Bone of Skeletally Mature Female Rabbits With Osteopenia but Induces Brittleness of Cortical Bone: A Comparative Study of the Investigational Drug With PTH, Estrogen, and Alendronate.
Cathepsin K (CK), a lysosomal cysteine protease, is highly expressed in mature osteoclasts and degrades type 1 collagen. Odanacatib (ODN) is a selective and reversible CK inhibitor that inhibits bone loss in preclinical and clinical studies. Although an antiresorptive, ODN does not suppress bone formation, which led us to hypothesize that ODN may display restorative effect on the osteopenic bones. In a curative study, skeletally mature New Zealand rabbits were ovarectomized (OVX) and after induction of bone loss were given a steady-state exposure of ODN (9 mM/d) for 14 weeks. Sham-operated and OVX rabbits treated with alendronate (ALD), 17b-estradiol (E2), or parathyroid hormone (PTH) served as various controls. Efficacy was evaluated by assessing bone mineral density (BMD), bone microarchitecture (using micro-computed tomography), fluorescent labeling of bone, and biomechanical strength. Skeletal Ca/P ratio was measured by scanning electron microscopy (SEM) with X-ray microanalysis, crystallinity by X-ray diffraction, and bone mineral density distribution (tissue mineralization) by backscattered SEM. Between the sham and ODN-treated osteopenic groups, lumbar and femur metaphyseal BMD, Ca/P ratio, trabecular microstructure and geometric indices, vertebral compressive strength, trabecular lining cells, cortical parameters (femoral area and thickness and periosteal deposition), and serum P1NP were largely comparable. Skeletal improvements in ALD-treated or E2-treated groups fell significantly short of the sham/ODN/PTH group. However, the ODN group displayed reduced ductility and enhanced brittleness of central femur, which might have been contributed by higher crytallinity and tissue mineralization. Rabbit bone marrow stromal cells expressed CK and when treated with ODN displayed increased formation of mineralized nodules and decreased apoptosis in serum-deficient medium compared with control. In vivo, ODN did not suppress remodeling but inhibited osteoclast activity more than ALD. Taken together, we show that ODN reverses BMD, skeletal architecture, and compressive strength in osteopenic rabbits; however, it increases crystallinity and tissue mineralization, thus leading to increased cortical bone brittleness.


Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.
We have recently shown that insulin-resistant obese subjects exhibit impaired endothelial function. Here, we test the hypothesis that elevation of circulating FFA to levels seen in insulin-resistant subjects can impair endothelial function. We studied leg blood flow responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) or the endothelium-independent vasodilator sodium nitroprusside during the infusion of saline and after raising systemic circulating FFA levels exogenously via a low- or high-dose infusion of Intralipid plus heparin or endogenously by an infusion of somatostatin (SRIF) to produce insulinopenia in groups of lean healthy humans. After 2 h of infusion of Intralipid plus heparin, FFA levels increased from 562+/-95 to 1,303+/-188 micromol, and from 350+/-35 to 3,850+/-371 micromol (P < 0.001) vs. saline for both low- and high-dose groups, respectively. Mch-induced vasodilation relative to baseline was reduced by approximately 20% in response to the raised FFA levels in both groups (P < 0.05, saline vs. FFA, ANOVA). In contrast, similar FFA elevation did not change leg blood flow responses to sodium nitroprusside. During the 2-h SRIF infusion, insulin levels fell, and FFA levels rose from 474+/-22 to 1,042+/-116 micromol (P < 0.01); Mch-induced vasodilation was reduced by approximately 20% (P < 0.02, saline vs. SRIF, ANOVA). Replacement of basal insulin levels during SRIF resulted in a fall of FFA levels from 545+/-47 to 228+/-61 micromol, and prevented the impairment of Mch-induced vasodilation seen with SRIF alone. In conclusion, (a) elevated circulating FFA levels cause endothelial dysfunction, and (b) impaired endothelial function in insulin-resistant humans may be secondary to the elevated FFA concentrations observed in these patients.


Recognition and treatment of anaphylaxis.
The aim of this paper is to discuss the recognition, treatment and investigation of anaphylaxis. Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction. It is characterized by rapidly developing life-threatening airway and/or breathing and/or circulation problems usually associated with skin and/or mucosal changes. The incidence of anaphylaxis appears to be increasing. A wide range of triggers can cause anaphylaxis. Drugs are the commonest cause of anaphylaxis in hospital and foods in the out-of-hospital setting. Patients having anaphylaxis should be treated using the airway, breathing, circulation, disability, exposure (ABCDE) approach. Early treatment with intramuscular adrenaline is the treatment of choice for patients having anaphylaxis. Intravenous adrenaline must only be used when the patient is monitored and only by those skilled and experienced in its use. A raised serum mast cell tryptase suggests a diagnosis of anaphylaxis. All those who are suspected of having anaphylaxis should be referred to a specialist in allergy. Individuals at high risk of anaphylaxis where the trigger is difficult to avoid should carry an adrenaline auto-injector and receive training and support in its use.


Intrauterine cannabis exposure and fetal and maternal blood flow: a case-control study.
Cannabis consumption during pregnancy increases the risk of pregnancy and neonatal complications. Since the underlying mechanism is unknown, the purpose of this study is to evaluate the changes in maternal and fetal blood flow in pregnancies exposed to cannabis, Δ9-tetrahydrocannabinol (THC). A case-control study between 2013 and 2020, included women with continued cannabis exposure during the pregnancies, defined by qualitative detection of THC in urine (Cannabis Group), and low-risk pregnancy women divided into tobacco smokers (Tobacco Group), and non-tobacco smokers (Control Group). We evaluated the association between cannabis consumption and maternal and fetal blood flow parameters measured by Doppler ultrasound: uterine artery at 11-14, 20-22 and 33-35 weeks, umbilical artery and middle cerebral artery at 33-35 weeks. Cerebral-placental ratio was calculated. Overall, 275 participants were included, 60 in the Cannabis Group, 17 in the Tobacco Group and 198 in the Control Group. At 33-35 weeks, differences were found in the umbilical artery pulsatility index (PI) (1.05 ± 0.23, 1.06 ± 0.19, 0.93 ± 0.15, P < 0.01), middle cerebral artery PI (1.75 ± 0.35, 1.90 ± 0.45, 1.88 ± 0.34, P < 0.05), cerebral-placental ratio (1.69 ± 0.40, 1.85 ± 0.53, 2.07 ± 0.47, P < 0.05) and mean uterine artery PI (0.89 ± 0.26, 0.73 ± 0.19, 0.74 ± 0.20, P < 0.01), respectively. On logistic regression analysis, adjusted for maternal age, maternal body mass index, maternal weight and white ethnicity, both cannabis and tobacco were predictors for increased umbilical artery PI, but only cannabis was a predictor for a decreased cerebral-placental ratio and an increased uterine artery PI at 33-35 weeks. Data from a large cohort of continuous cannabis exposure pregnancies show that cannabis is associated with maternal and fetal blood flow changes. However, it is not possible to disentangle the association of the tobacco and cannabis.


The gaze stability of 4- to 10-week-old human infants.
The relationship between gaze stability, retinal image quality, and visual perception is complex. Gaze instability related to pathology in adults can cause a reduction in visual acuity (e.g., Chung, LaFrance, & Bedell, 2011). Conversely, poor retinal image quality and spatial vision may be a contributing factor to gaze instability (e.g., Ukwade & Bedell, 1993). Though much is known about the immaturities in spatial vision of human infants, little is currently understood about their gaze stability. To characterize the gaze stability of young infants, adult participants and 4- to 10-week-old infants were shown a dynamic random-noise stimulus for 30-s intervals while their eye positions were recorded binocularly. After removing adultlike saccades, we used 5-s epochs of stable intersaccade gaze to estimate bivariate contour ellipse area and standard deviations of vergence. The geometric means (with standard deviations) for infants' bivariate contour ellipse area were left eye = -0.697 ± 0.534 log(°2), right eye = -0.471 ± 0.367 log(°2). For binocular vergence stability, the infant geometric means (with standard deviations) were horizontal = -1.057 ± 0.743 log(°), vertical = -1.257 ± 0.573 log(°). These values were all not significantly different from those of the adult comparison sample, suggesting that gaze instability is not a significant limiting factor in retinal image quality and spatial vision during early postnatal development.


School alienation and academic achievement in Switzerland and Luxembourg: a longitudinal perspective.
Early adolescence represents a particularly sensitive period in the life of young learners, which is accompanied by an increase in school alienation. Due to its harmful nature (Hascher and Hadjar in Educ Res 60:171-188, 2018. 10.1080/00131881.2018.1443021), school alienation may lead to unfavorable consequences such as low academic achievement (Johnson in J Educ Technol Soc 8:179-189, 2005; Reinke and Herman in Psychol Schools 39:549-559, 2002). This study investigates the longitudinal relationship between school alienation domains, namely alienation from learning, from teachers, and from classmates, and academic achievement among secondary school students of grade 7 to grade 9 in Switzerland and Luxembourg. Data were collected from 403 students in the Swiss canton of Bern and 387 students in Luxembourg who participated in three waves of the "School Alienation in Switzerland and Luxembourg (SASAL)" research project. Cross-lagged modeling was applied to examine the correlations between school alienation domains and academic achievement at each of the three time points, the temporal stability of school alienation domains and academic achievement, and their cross-lagged effects across time, controlling for students' gender, school track, parental occupational status, and migration background. Results show that the pattern of relationships is defined by the school alienation domain and the cultural context, pointing to the complex interplay between the multidimensional construct of school alienation and academic outcomes of secondary school students.


Data management and design issues in an unmasked randomized trial of electroconvulsive therapy for relapse prevention of severe depression: the consortium for research in electroconvulsive therapy trial.
The use of double-blind designs, normally the criterion standard of clinical trials, is impossible when comparing medication therapy to procedural therapies for depression. In the Consortium for Research in Electroconvulsive Therapy (CORE) trial, depressed patients recently remitted with electroconvulsive therapy (ECT) were randomly assigned to receive continuation therapy with either ECT or medications. The purpose of this article is to describe the design characteristics and challenges of the trial and of our method of dealing with the lack of double-blind outcome assessment. The primary outcome measure was time to relapse of depression in the continuation phase. We developed a method to achieve partial blinding of depressive severity assessment. This consisted of videotaping the structured interviews, having the video tapes co-rated by personnel not involved in the patient's care, and a videotape-tracking maneuver so that the assessor of the videotapes could be blinded to phase and type of treatment. We enrolled 624 patients into the initial treatment phase of the trial. Of these, 201 met criteria for randomization into the second, continuation phase. Our videotape-tracking maneuver to reduce bias in outcome assessment worked well during the trial. The CORE study is the first multicenter, randomized controlled trial of continuation ECT in the relapse prevention of major depressive episodes. We successfully recruited a large number of severely depressed patients into a 6 month trial and used a method of reducing bias that might result from lack of blinding.


The current role for adjuvant and neoadjuvant therapy in renal cell cancer.
Here we explore the recent and relevant trials for treatment of renal cell cancer (RCC) in the adjuvant and neoadjuvant settings as well as recent updates to the guidelines for RCC management. Most phase III studies of tyrosine kinase inhibitors in the adjuvant setting have been negative. Notably, sunitinib received regulatory approval by the FDA after showing improved disease-free survival in high risk populations. Recent improvements in the genetic classification and understanding of RCC molecular and genetic disorder will hopefully improve patient selection. Meanwhile, recent advances in metastatic RCC treatment, particularly with the combination of tyrosine kinase inhibitors and immune checkpoint inhibitors, have given rise to hope that advances can be made by moving these treatment strategies forward to the adjuvant or neoadjuvant settings. In the absence of a clinical trial, observation remains the standard of care. Based on the S-TRAC data, sunitinib is approved for use in the adjuvant setting, and can be considered under select circumstances. Although there is optimism for checkpoint monotherapy and combination therapy in the adjuvant or neoadjuvant setting, ongoing studies will determine clinical benefit and tolerability in this setting. Therefore, for patients with high risk of recurrent disease clinical trials of checkpoint inhibitor therapy are viable options.


Patient and provider perspectives on eHealth interventions in Canada and Australia: a scoping review.
Despite the promises of universal health care in most developed countries, health inequities remain prevalent within and between rural and remote communities. Remote health technologies are often promoted as solutions to increase health system efficiency, to enhance quality of care, and to decrease gaps in access to care for rural and remote communities. However, there is mixed evidence for these interventions, particularly related to how they are received and perceived by health providers and by patients. Health technologies do not always adequately meet the needs of patients or providers. To examine this, a broad-based scoping review was conducted to provide an overview of patient and provider perspectives of eHealth initiatives in rural communities. The unique objective of this review was to prioritize the voices of patients and providers in discussing the disparities between health interventions and needs of people in rural communities. eHealth initiatives were reviewed for rural communities of Australia and Canada, two countries that have similar geographies and comparable health systems at the local level. Searches were performed in PubMed, Scopus, and Web of Science with results limited from 2000 to 2018. Keywords included combinations of 'eHealth', 'telehealth', 'telemedicine', 'electronic health', and 'rural/remote'. Individual patient and provider perspectives on health care were identified, followed by qualitative thematic coding based on the type of intervention, the feedback provided, the affected population, geographic location, and category of individual providing their perspective. Quotes from patients and providers are used to illustrate the identified benefits and disadvantages of eHealth technologies. Based on reviewed literature, 90.1% of articles reported that eHealth interventions were largely positive. Articles noted decreased travel time (18%), time/cost saving (15.1%), and increased access to services (13.9%) as primary benefits to eHealth. The most prevalent disadvantages of eHealth were technological issues (24.5%), lack of face-to-face contact (18.6%), limited training (10.8%), and resource disparities (10.8%). These results show where existing eHealth interventions could improve and can inform policymakers and providers in designing new interventions. Importantly, benefits to eHealth extend beyond geographic access. Patients reported ancillary benefits to eHealth that include reduced anxiety, disruption on family life, and improved recovery time. Providers reported closer connections to colleagues, improved support for complex care, and greater eLearning opportunity. Barriers to eHealth are recognized by patient and providers alike to be largely systemic, where lack of rural high-speed internet and unreliability of installed technologies were significant. Regional and national governments are seen as the key players in addressing these technical barriers. This scoping review diverges from many reviews of eHealth with the use of first-person perspectives. It is hoped that this focus will highlight the importance of patient voices in evaluating important healthcare interventions such as eHealth and associated technologies.


Effect of inhaled morphine on the development of breathlessness during exercise in patients with chronic lung disease.
Inhaled morphine has previously been shown to increase exercise endurance in patients with chronic lung disease. A similar study was performed to determine whether inhaled morphine reduces the sensation of breathlessness in this group of patients. A randomised double blind study on the effect of nebulised morphine on both exercise induced breathlessness and maximum achievable power output using isotonic saline as a control was performed in 10 patients with stable chronic lung disease. Each subject performed a progressive exercise test (Jones' stage I) on an electrically braked cycle ergometer. The work load was increased by 10 watts per minute and subjects exercised to exhaustion. At the end of each minute of exercise patients were asked to rate their degree of breathlessness according to a modified Borg scale. All subjects were randomised to receive either inhaled morphine sulphate 1 mg/ml (5 ml) or isotonic saline (5 ml) by wet nebulisation. The effect of morphine and saline on the achieved exercise capacity and the development of breathlessness during exercise was tested on separate days. The mean dose of morphine inhaled was 1.24 mg. There was no difference in maximum power output achieved, minute ventilation at maximum power output, nor the degree of breathlessness at maximum power output between the groups treated with morphine and placebo. The degree of breathlessness was related to the power output achieved during exercise by a power function relationship (mean r: morphine = 0.86, saline = 0.87). However, there was a wide variation in the sensation for any given power output in both groups. There was no difference in the group mean slopes (morphine = 1.15, saline = 1.00) or intercepts (morphine = 0.07, saline = 0.15) in this relationship between the morphine and saline treatment groups. In patients with severe chronic lung disease inhaled morphine in the doses used in this study does not relieve exercise induced breathlessness nor does it increase maximum power output achieved during progressive exercise.


Luminescent and transparent nanopaper based on rare-earth up-converting nanoparticle grafted nanofibrillated cellulose derived from garlic skin.
Highly flexible, transparent, and luminescent nanofibrillated cellulose (NFC) nanopaper with heterogeneous network, functionalized by rare-earth up-converting luminescent nanoparticles (UCNPs), was rapidly synthesized by using a moderate pressure extrusion paper-making process. NFC was successfully prepared from garlic skin using an efficient extraction approach combined with high frequency ultrasonication and high pressure homogenization after removing the noncellulosic components. An efficient epoxidation treatment was carried out to enhance the activity of the UCNPs (NaYF4:Yb,Er) with oleic acid ligand capped on the surface. The UCNPs after epoxidation then reacted with NFC in aqueous medium to form UCNP-grafted NFC nanocomposite (NFC-UCNP) suspensions at ambient temperature. Through the paper-making process, the assembled fluorescent NFC-UCNP hybrid nanopaper exhibits excellent properties, including high transparency, strong up-conversion luminescence, and good flexibility. The obtained hybrid nanopaper was characterized by transmission electron microscopy (TEM), atomic force microscope (AFM), Fourier transform infrared spectroscopy (FTIR), field emission-scanning electron microscope (FE-SEM), up-conversion luminescence (UCL) spectrum, and ultraviolet and visible (UV-vis) spectrophotometer. The experimental results demonstrate that the UCNPs have been successfully grafted to the NFC matrix with heterogeneous network. And the superiorly optical transparent and luminescent properties of the nanopaper mainly depend on the ratio of UCNPs to NFC. Of importance here is that, NFC and UCNPs afford the nanopaper a prospective candidate for multimodal anti-counterfeiting, sensors, and ion probes applications.


Inactivation of Cryptosporidium parvum oocysts in water using ultrasonic treatment.
Ultrasound in a liquid phase cause mass and heat transfer across the liquid through cavitational processes which act as nanoreactors to generate unstable mechanical equilibrium. The effect of 1 MHz ultrasound on the inactivation of Cryptosporidium parvum was investigated. Continuous irradiation of ultrasound (20 min) increased temperature due to cavitational phenomena. Ultrasound irradiation of liquid containing C. parvum showed significant quantitative changes in pH, temperature and inactivation of C. parvum (102.7 oocysts killed/s) with a minimum energy consumption (0.05 oocysts/s).


Quantifying Aptamer-Protein Binding via Thermofluorimetric Analysis.
Effective aptamer-based protein assays require coupling to a quantitative reporter of aptamer-protein binding. Typically, this involves a direct optical or electrochemical readout of DNA hybridization or an amplification step coupled to the readout. However, method development is often hampered by the multiplicity of aptamer-target binding mechanisms, which can interfere with the hybridization step. As a simpler and more generalizable readout of aptamer-protein binding, we report that thermofluorimetric analysis (TFA) can be used to quantitatively assay protein levels. Sub-nanomolar detection (0.74 nM) of platelet-derived growth factor (PDGF) with its corresponding aptamer is shown as a test case. In the presence of various DNA intercalating dyes, protein-bound aptamers exhibit a change in fluorescence intensity compared to the intercalated, unbound aptamer. This allows thermal resolution of bound and unbound aptamers using fluorescence melting analysis (-dF/dT curves). Remarkably, the homogeneous optical method allows subtraction of autofluorescence in human serum, giving PDGF detection limits of 1.8 and 10.7 nM in serum diluted 1:7 and 1:3, respectively. We have thus demonstrated that bound and unbound aptamers can be thermally resolved in a homogeneous format using a simple qPCR instrument-even in human serum. The simplicity of this approach provides an important step toward a robust, generalizable readout of aptamer-protein binding.


Physical growth and nutritional status assessment of school children in Enugu, Nigeria.
Physical growth of a child is a reflection of its state of nutrition. In some developing countries such as Nigeria with changing economy and rapidly growing population, the nutritional status of the children is a reflection of the general well-being of the society. This was a descriptive cross-sectional study in which participants were selected using a multistage sampling method. Heights and weights of randomly selected school children aged 6-12 years were measured using standard protocols. Weight-for-age, height-for-age, and body mass index (BMI)-for-age expressed as Z-scores were used to characterize the nutritional status. Descriptive statistics was used to determine the frequency and standard deviations (SDs) of the anthropometric measurements. Age and gender differences in the mean body weight, height, and BMI were evaluated using an independent samples t-test. Significant levels were set at P< 0.05. A total of 1305 males and 1311 females were enrolled in the study. The mean age was 8.9 ± 1.9 years. Their mean height, weight, and BMI were 136.6 ± 10.2 cm, 29.7 ± 7.7 kg, 15.7 ± 2.4 kg/m2, respectively. Their mean ± SD scores of the WAZ, HAZ, and BAZ were 0.33 ± 1.20, 0.78 ± 1.17, and - 0.51 ± 1.27, respectively. A majority (78.9%, 2090/2616) were in the normal growth category. Wasting, overweight, obesity, underweight, and stunting were noted in 9.3% (243/2616), 6.3% (166/2616), 4.4% (117/2616), 0.9% (26/2616), and 0.4% (13/2616) of the children, respectively. Wasting was more in males (P = 0.069), and overweight was more in females (P = 0.138). A majority of the children have normal growth with the remainder in both extremes of malnutrition. Institution of school-feeding programs in all Nigerian schools as well as nutrition education/campaign directed at parents and their children will help forestall the double burden of under- and over-nutrition among our children.


pi-Conjugation enlargement toward the creation of multi-porphyrinic systems with large two-photon absorption properties.
Recent progress in the synthesis of covalently linked porphyrin arrays with large two-Photon absorption (TPA) cross-section values has been reviewed with a particular focus on the relation of TPA properties with molecular structures. Covalently linked porphyrin arrays continue to be important and useful for the creation of functional materials owing to their chemical robustness, fine-tuning, and easy manipulation. More importantly, the porphyrin electronic systems are quite susceptible to periphery conjugative perturbations, hence allowing facile fabrications to extensively delocalized systems. This property has been used for exploration of porphyrin-based molecular systems with large TPA values, demonstrating a general trend that enhancement in electronic interactions leads to large TPA cross-section values. As a representative example, the porphyrin tapes exhibit larger TPA values owing to the fully delocalized nature of the pi-electrons. This Focus Review will help understand the structural requirements of porphyrin arrays with large TPA values, which will be useful for future applications in optical communication in the IR region.


Promoting thrombolysis in acute ischemic stroke.
Thrombolysis with intravenous recombinant tissue plasminogen activator is an effective treatment for acute ischemic stroke, but the number of treatable patients is limited. The PRomoting ACute Thrombolysis in Ischemic StrokE (PRACTISE) trial evaluated the effectiveness of a multidimensional implementation strategy for thrombolysis with intravenous recombinant tissue plasminogen activator in acute ischemic stroke. The PRACTISE trial was a national multicenter cluster-randomized controlled trial with randomization after pairwise matching. Twelve hospitals, both urban and community, academic and nonacademic, in the Netherlands participated. All patients admitted with stroke within 24 hours from onset of symptoms were registered. The intervention included 5 implementation meetings based on the Breakthrough Series model. The primary outcome was treatment with thrombolysis. Secondary outcomes were admission within 4 hours after onset of symptoms, death or disability at 3 months, and quality of life. Overall 5515 patients were included in the study' 308 patients (12.2%) in the control centers and 393 patients (13.1%) in the intervention centers were treated with thrombolysis (adjusted OR, 1.25; 95% CI, 0.93 to 1.68). Among the 1657 patients with ischemic stroke admitted within 4 hours from onset, 391 (44.5%) of 880 in the intervention centers were treated with thrombolysis and 305 (39.3%) of 777 in the control centers; the adjusted OR for treatment with thrombolysis was 1.58 (95% CI, 1.11 to 2.27). An intensive implementation strategy increases the proportion of patients with acute stroke treated with thrombolysis in real-life settings. An apparently pivotal factor in the improvement of the treatment rate is better application of contraindications for thrombolysis.


Differential apicobasal VEGF signaling at vascular blood-neural barriers.
The vascular endothelium operates in a highly polarized environment, but to date there has been little exploration of apicobasal polarization of its signaling. We show that VEGF-A, histamine, IGFBP3, and LPA trigger unequal endothelial responses when acting from the circulation or the parenchymal side at blood-neural barriers. For VEGF-A, highly polarized receptor distribution contributed to distinct signaling patterns: VEGFR2, which was found to be predominantly abluminal, mediated increased permeability via p38; in contrast, luminal VEGFR1 led to Akt activation and facilitated cytoprotection. Importantly, such differential apicobasal signaling and VEGFR distribution were found in the microvasculature of brain and retina but not lung, indicating that endothelial cells at blood-neural barriers possess specialized signaling compartments that assign different functions depending on whether an agonist is tissue or blood borne.


The brains of elite soccer players are subject to experience-dependent alterations in white matter connectivity.
Soccer is the only major sport with voluntary unprotected head-to-ball contact. It is crucial to determine if head impact through long-term soccer training is manifested in brain structure and connectivity, and whether such alterations are due to sustained training per se. Using diffusion tensor imaging, we documented a comprehensive view of soccer players' brains in a sample of twenty-five right-handed male elite soccer players aged from 18 to 22 years and twenty-five non-athletic controls aged 19-24 years. Importantly, none had recalled a history of concussion. We performed a whole-brain tract-based spatial statistical analysis, and a tract-specific probabilistic tractography method to measure the differences of white matter properties between groups. Whole-brain integrity analysis showed stronger microstructural integrity within the corpus callosum tract in soccer players compared to controls. Further, tract-specific probabilistic tractography revealed that the anterior part of corpus callosum may be the brain structure most relevant to training experience, which may put into perspective prior evidence showing corpus callosum alteration in retired or concussed athletes practicing contact sports. Intriguingly, experience-related alterations showed left hemispheric lateralization of potential early signs of concussion-like effects. In sum, we concluded that the observed gains and losses may be due to a consequence of engagement in protracted soccer training that incurs prognostic hallmarks associated with minor injury-induced neural inflammation.


Delayed sciatic nerve palsy following resurfacing hip arthroplasty caused by metal debris.
The rapid rise in the incidence of failed metal-on-metal hip articulations in recent years has led to many patients requiring complex revision surgery. These failed metal prostheses may produce local metallic debris, which promotes both local and systemic adverse effects. We report an unusual case of failed metal-on-metal resurfacing hip arthroplasty presenting with ipsilateral buttock pain and foot drop 6 months after surgery. After thorough investigations, the metal-on-metal bearing was revised to a metal-on-polyethylene total hip replacement. This resulted in marked improvement in the systemic symptoms, inflammatory marke and metal ion levels postoperatively. However, neither clinical nor neurophysiological sciatic nerve recovery followed. The patient eventually required tendon transfer surgery for her persistent foot drop.


Occludin OCEL-domain interactions are required for maintenance and regulation of the tight junction barrier to macromolecular flux.
In vitro and in vivo studies implicate occludin in the regulation of paracellular macromolecular flux at steady state and in response to tumor necrosis factor (TNF). To define the roles of occludin in these processes, we established intestinal epithelia with stable occludin knockdown. Knockdown monolayers had markedly enhanced tight junction permeability to large molecules that could be modeled by size-selective channels with radii of ~62.5 Å. TNF increased paracellular flux of large molecules in occludin-sufficient, but not occludin-deficient, monolayers. Complementation using full-length or C-terminal coiled-coil occludin/ELL domain (OCEL)-deficient enhanced green fluorescent protein (EGFP)-occludin showed that TNF-induced occludin endocytosis and barrier regulation both required the OCEL domain. Either TNF treatment or OCEL deletion accelerated EGFP-occludin fluorescence recovery after photobleaching, but TNF treatment did not affect behavior of EGFP-occludin(ΔOCEL). Further, the free OCEL domain prevented TNF-induced acceleration of occludin fluorescence recovery, occludin endocytosis, and barrier loss. OCEL mutated within a recently proposed ZO-1-binding domain (K433) could not inhibit TNF effects, but OCEL mutated within the ZO-1 SH3-GuK-binding region (K485/K488) remained functional. We conclude that OCEL-mediated occludin interactions are essential for limiting paracellular macromolecular flux. Moreover, our data implicate interactions mediated by the OCEL K433 region as an effector of TNF-induced barrier regulation.


Most primary care physicians are aware of prescription drug monitoring programs, but many find the data difficult to access.
State prescription drug monitoring programs are common tools intended to reduce prescription drug abuse and diversion, or the nonmedical use of a prescribed drug. The success of these programs depends largely upon physicians' awareness and use of them. We conducted a nationally representative mail survey of 1,000 practicing primary care physicians in 2014 to characterize their attitudes toward and awareness and use of prescription drug monitoring programs. A total of 420 eligible physicians (adjusted response rate: 58 percent) returned completed surveys. Among all physicians surveyed, 72 percent were aware of their state's prescription drug monitoring program, and 53 percent reported using one of the programs. We identified several barriers that may prevent greater use of the programs, including the time-consuming nature of information retrieval and the lack of an intuitive format for data provided by the programs. These results suggest that the majority of US primary care physicians are aware of and use prescription drug monitoring programs at least on occasion, although many did not access these programs routinely. To increase the use of the programs in clinical practice, states should consider implementing legal mandates, investing in prescriber education and outreach, and taking measures to enhance ease of access to and use of the programs.


TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.
Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .


An improved sequence based prediction protocol for DNA-binding proteins using SVM and comprehensive feature analysis.
DNA-binding proteins (DNA-BPs) play a pivotal role in both eukaryotic and prokaryotic proteomes. There have been several computational methods proposed in the literature to deal with the DNA-BPs, many informative features and properties were used and proved to have significant impact on this problem. However the ultimate goal of Bioinformatics is to be able to predict the DNA-BPs directly from primary sequence. In this work, the focus is how to transform these informative features into uniform numeric representation appropriately and improve the prediction accuracy of our SVM-based classifier for DNA-BPs. A systematic representation of some selected features known to perform well is investigated here. Firstly, four kinds of protein properties are obtained and used to describe the protein sequence. Secondly, three different feature transformation methods (OCTD, AC and SAA) are adopted to obtain numeric feature vectors from three main levels: Global, Nonlocal and Local of protein sequence and their performances are exhaustively investigated. At last, the mRMR-IFS feature selection method and ensemble learning approach are utilized to determine the best prediction model. Besides, the optimal features selected by mRMR-IFS are illustrated based on the observed results which may provide useful insights for revealing the mechanisms of protein-DNA interactions. For five-fold cross-validation over the DNAdset and DNAaset, we obtained an overall accuracy of 0.940 and 0.811, MCC of 0.881 and 0.614 respectively. The good results suggest that it can efficiently develop an entirely sequence-based protocol that transforms and integrates informative features from different scales used by SVM to predict DNA-BPs accurately. Moreover, a novel systematic framework for sequence descriptor-based protein function prediction is proposed here.


Is there an association between early weight status and utility-based health-related quality of life in young children?
Few studies focus on the health-related quality of life (HRQoL) of preschool children with overweight or obesity. This is relevant for evaluation of obesity prevention trials using a quality-adjusted life year (QALY) framework. This study examined the association between weight status in the preschool years and HRQoL at age 5 years, using a preference-based instrument. HRQoL [based on parent proxy version of the Health Utilities Index Mark 3 (HUI3)] and weight status were measured in children born in Australia between 2007 and 2009. Children's health status was scored across eight attributes of the HUI3-vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain, and these were used to calculate a multi-attribute utility score. Ordinary least squares (OLS), Tobit and two-part regressions were used to model the association between weight status and multi-attribute utility. Of the 368 children for whom weight status and HUI3 data were available, around 40% had overweight/obesity. After adjusting for child's sex, maternal education, marital status and household income, no significant association between weight status in the preschool years and multi-attribute utility scores at 5 years was found. Alternative approaches for capturing the effects of weight status in the preschool years on preference-based HRQoL outcomes should be tested. The application of the QALY framework to economic evaluations of obesity-related interventions in young children should also consider longitudinal effects over the life-course. Clinical Trial Registration The Healthy Beginnings Trial was registered with the Australian Clinical Trial Registry (ACTRNO12607000168459).