Determinants of knowledge-sharing networks in primary care.
Around the world, health reforms are increasingly fostering collaboration and integration among primary care physicians with the aim of facilitating knowledge sharing and evidence-informed decision-making. Although extant research on this topic is abundant, the evidence and results regarding social and organizational factors affecting the formation of knowledge-sharing networks in this setting are inconclusive. The aim of this article is to explore multiple theoretical mechanisms explaining the formation of knowledge-sharing networks among primary care physicians across relevant clinical areas. The data are collected from two local health authorities in the Italian National Health Service that are responsible for delivering primary care in two Italian regions. Exponential random graph models are used to test the hypotheses. Our findings indicate that knowledge-sharing networks are highly correlated across clinical areas. In addition, knowledge-sharing networks are highly reciprocal and clustered. We also observe that formal models adopted to foster collaboration have remarkably different effects on the formation of knowledge networks, depending upon the diverse knowledge management approaches adopted in the surveyed local health authorities. Primary care organizations need to develop and implement knowledge management practices in order to help physicians in identifying knowledge domain experts as well as to support connections through formal groupings and incentives.


Identification of depression in women during pregnancy and the early postnatal period using the Whooley questions and the Edinburgh Postnatal Depression Scale: protocol for the Born and Bred in Yorkshire: PeriNatal Depression Diagnostic Accuracy (BaBY PaNDA) study.
Perinatal depression is well recognised as a mental health condition but <50% of cases are identified by healthcare professionals in routine clinical practice. The Edinburgh Postnatal Depression Scale (EPDS) is often used to detect symptoms of postnatal depression in maternity and child services. The National Institute for Health and Care Excellence (NICE) recommends 2 'ultra-brief' case-finding questions (the Whooley questions) to aid identification of depression during the perinatal period, but this recommendation was made in the absence of any validation studies in a perinatal population. Limited research exists on the acceptability of these depression case-finding instruments and the cost-effectiveness of routine screening for perinatal depression. The diagnostic accuracy of the Whooley questions and the EPDS will be determined against a reference standard (the Client Interview Schedule-Revised) during pregnancy (around 20 weeks) and the early postnatal period (around 3-4 months post partum) in a sample of 379 women. Further outcome measures will assess a range of psychological comorbidities, health-related quality of life and resource utilisation. Women will be followed up 12 months postnatally. The sensitivity, specificity and predictive values of the Whooley questions and the EPDS will be calculated against the reference standard at 20 weeks pregnancy and 3-4 months post partum. Acceptability of the depression case-finding instruments to women and healthcare professionals will involve in-depth qualitative interviews. An existing decision analytic model will be adapted to determine the cost-effectiveness of routine screening for perinatal depression. This study is considered low risk for participants. Robust protocols will deal with cases where risk of depression, self-harm or suicide is identified. The protocol received favourable ethical opinion from the North East-York Research Ethics Committee (reference: 11/NE/0022). The study findings will be published in peer-reviewed journals and presented at relevant conferences.


Characterization of a chemically reactive propranolol metabolite that binds to microsomal proteins of rat liver.
We have characterized a chemically reactive propranolol (PL) metabolite which binds to proteins in rat liver microsomes. During incubation with rat liver microsomes (1 mg of protein) fortified with an NADPH-generating system, 4-hydroxypropranolol (4-OH-PL) quickly disappeared from the reaction medium, but none of the possible metabolite peaks was detected under the high-performance liquid chromatographic conditions used. The consumption of 4-OH-PL depended on microsomes and NADPH. The reaction was not affected by inhibitors of cytochrome P450 or FAD monooxygenase, but was markedly diminished in the presence of cytosol and ascorbic acid. The effect of cytosol was inhibited by potassium cyanide but not by sodium benzoate or dimethyl sulfoxide, and was also not affected by heating at 60 degrees C for 30 min, suggesting that superoxide (SO) ion was involved in the reaction and that it was blocked by superoxide dismutase (SOD) present in the cytosol. Cu,Zn-SOD, purified from cytosol, effectively mimicked the suppressive effect of cytosol. Incubation of 4-OH-PL in an SO-generating system of xanthine and xanthine oxidase generated 1,4-naphthoquinone (1,4-NQ), which was identified by TLC, HPLC, and GC/MS. 1,4-NQ was also formed in microsomal incubates containing NADPH and small amounts of microsomes (below 0.1 mg of protein). These results indicate that 4-OH-PL is converted by SO, or some reactive oxygen species derived from it, to 1,4-NQ which binds to proteins and is one of the reactive metabolites of PL.


Attending an STI Foundation course increases chlamydia testing in primary care, but not HIV testing.
The Sexually Transmitted Infection Foundation course (STIF) is a recommended training course for UK general practitioners (GPs) and others delivering sexual health services in the community. We assessed the impact of attending the course on testing for HIV and chlamydia. Thirty-one GPs attending Brighton STIF courses were identified and the laboratory database was searched to identify all chlamydia and HIV tests they requested in the three months prior to attending, the first three months after attending and the subsequent three months. Three hundred and eight chlamydia tests were performed precourse, 390 postcourse and 342 in the following three months. This represented a significant increase from baseline to postcourse (P = 0.007), which was lost by three to six months (P = 0.25). The proportion of positives did not change. A total of 98, 111 and 131 HIV tests were performed in the three time periods of which; none were positive. Barriers other than training may need to be overcome to increase HIV testing in primary care.


A study of ECG pattern, cardiac structural abnormalities and familial tendency in patients with early repolarisation syndrome in South India.
Early repolarisation (ER) on ECG, which was initially believed to be benign, has of late been considered otherwise. Brugada syndrome has recently been thought to be an extension of the ER spectrum, and the familial tendency of the ER pattern is being highlighted. With attention being drawn to ER's association with idiopathic ventricular fibrillation (VF), the prognosis and lineage of patients with an ER pattern are under scrutiny. To analyse ER patterns on ECG, their presence in first-degree relatives and their association with structural heart disease. To classify different types of ER and estimate the prevalence of the high-risk notch/slur pattern in the population studied. We screened all patients presenting to our department from December 2011 to July 2014 for ER patterns. We excluded patients with other causes of ST elevation that mimicked the ER pattern, those aged <18 years, and those not willing to participate in the study. A complete physical examination, 12-lead ECG and echocardiography were performed on all study patients. Willing first-degree relatives were screened with a 12-lead ECG. Of the 963 patients with ER that we initially screened, 843 completed the study. A total of 4116 relatives were screened. Of the 843 patients who completed the study, 687 (81.5%) were male and 156 (18.5%) were female. The majority were asymptomatic (70.11%), but had been referred for ECG abnormalities. Fifteen patients with chest pain were inadvertently thrombolysed and were later diagnosed to have ER. Their ER pattern was exaggerated during chest pain, which made this error highly likely. Among the 48 patients who had acute coronary syndrome (ACS), ER pattern was noticed in a different lead than those affected by ACS. Of these, 27 (56.25%) had ventricular tachycardia/VF during the acute phase. Six patients had electrical storm without evidence of ACS, and all had a global ER pattern with prominent notching/slurring on baseline ECG. The most common type of ER pattern was type I (lateral leads; 55.87%). Twenty-one patients had a Brugada pattern. Of all the patients with ER, only a third (34.16%) had the possibly high-risk notched/slurred ECG pattern. The majority (82.92%) had a structurally normal heart. We found that mitral valve prolapse (MVP), as assessed by >2 mm leaflet prolapse from the annulus, was more common in patients with ER (11.39%). Of the 4116 relatives screened, 2625 (63.78%) had an ER pattern; a quarter of family members had the inferolateral variety and over 60% of relatives had the lateral variety. We also noticed different ER patterns in the same family. We found that exaggeration of the ER pattern during chest pain may lead to inadvertent thrombolysis. A notched/slurred ER pattern is found in only a third of patients, who need to be grouped separately, as they may constitute a high-risk category. Patients with ER had MVP at a higher prevalence (almost double) than the general population, probably explaining the high incidence of sudden cardiac death associated with MVP. A familial tendency to an ER pattern was found in more than half of first-degree relatives, with different ER patterns, even the Brugada pattern, found in the same family. This may be because Brugada and other ER patterns belong to the same spectrum and may share the same prognosis. Thus we conclude that further studies regarding ER, its association with MVP, risk stratification by notched ECG pattern, and familial distribution along with gene analysis are warranted.


Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab.
Clostridium difficile infection (CDI) represents the most prevalent cause of antibiotic-associated gastrointestinal infections in health care facilities in the developed world. Disease symptoms are caused by the two homologous exotoxins, TcdA and TcdB. Standard therapy for CDI involves administration of antibiotics that are associated with a high rate of disease recurrence, highlighting the need for novel treatment paradigms that target the toxins rather than the organism itself. A combination of human monoclonal antibodies, actoxumab and bezlotoxumab, directed against TcdA and TcdB, respectively, has been shown to decrease the rate of recurrence in patients treated with standard-of-care antibiotics. However, the exact mechanism of antibody-mediated protection is poorly understood. In this study, we show that the antitoxin antibodies are protective in multiple murine models of CDI, including systemic and local (gut) toxin challenge models, as well as primary and recurrent models of infection in mice. Systemically administered actoxumab-bezlotoxumab prevents both the damage to the gut wall and the inflammatory response, which are associated with C. difficile in these models, including in mice challenged with a strain of the hypervirulent ribotype 027. Furthermore, mutant antibodies (N297Q) that do not bind to Fcγ receptors provide a level of protection similar to that of wild-type antibodies, demonstrating that the mechanism of protection is through direct neutralization of the toxins and does not involve host effector functions. These data provide a mechanistic basis for the prevention of recurrent disease observed in CDI patients in clinical trials.


Physicochemical control of bacterial and protist community composition and diversity in Antarctic sea ice.
Due to climate change, sea ice experiences changes in terms of extent and physical properties. In order to understand how sea ice microbial communities are affected by changes in physicochemical properties of the ice, we used 454-sequencing of 16S and 18S rRNA genes to examine environmental control of microbial diversity and composition in Antarctic sea ice. We observed a high diversity and richness of bacteria, which were strongly negatively correlated with temperature and positively with brine salinity. We suggest that bacterial diversity in sea ice is mainly controlled by physicochemical properties of the ice, such as temperature and salinity, and that sea ice bacterial communities are sensitive to seasonal and environmental changes. For the first time in Antarctic interior sea ice, we observed a strong eukaryotic dominance of the dinoflagellate phylotype SL163A10, comprising 63% of the total sequences. This phylotype is known to be kleptoplastic and could be a significant primary producer in sea ice. We conclude that mixotrophic flagellates may play a greater role in the sea ice microbial ecosystem than previously believed, and not only during the polar night but also during summer when potential food sources are abundant.


Aldehyde dehydrogenase 2 protects against acute kidney injury by regulating autophagy via the Beclin-1 pathway.
The mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of acetaldehyde and endogenous lipid aldehydes. Approximately 40% of East Asians, accounting for 8% of the human population, carry the E504K mutation in ALDH2 that leads to accumulation of toxic reactive aldehydes and increases the risk for cardiovascular disease, cancer, and Alzheimer disease, among others. However, the role of ALDH2 in acute kidney injury (AKI) remains poorly defined and is therefore the subject of the present study using various cellular and organismal sources. In murine models, in which AKI was induced by either the contrast agent iohexol or renal ischemia/reperfusion, KO, activation/overexpression of ALDH2 were associated with increased and decreased renal injury, respectively. In murine renal tubular epithelial cells (RTECs), ALDH2 upregulated Beclin-1 expression, promoted autophagy activation, and eliminated ROS. In vivo and in vitro, both 3-MA and Beclin-1 siRNAs inhibited autophagy and abolished ALDH2-mediated renoprotection. In mice with iohexol-induced AKI, ALDH2 knockdown in RTECs using AAV-shRNA impaired autophagy activation and aggravated renal injury. In human renal proximal tubular epithelial HK-2 cells exposed to iohexol, ALDH2 activation potentiated autophagy and attenuated apoptosis. In mice with AKI induced by renal ischemia/reperfusion, ALDH2 overexpression or pretreatment regulated autophagy mitigating apoptosis of RTECs and renal injury. In summary, our data collectively substantiate a critical role of ALDH2 in AKI via autophagy activation involving the Beclin-1 pathway.


A regenerative microchannel device for recording multiple single-unit action potentials in awake, ambulatory animals.
Despite significant advances in robotics, commercially advanced prosthetics provide only a small fraction of the functionality of the amputated limb that they are meant to replace. Peripheral nerve interfacing could provide a rich controlling link between the body and these advanced prosthetics in order to increase their overall utility. Here, we report on the development of a fully integrated regenerative microchannel interface with 30 microelectrodes and signal extraction capabilities enabling evaluation in an awake and ambulatory rat animal model. In vitro functional testing validated the capability of the microelectrodes to record neural signals similar in size and nature to those that occur in vivo. In vitro dorsal root ganglia cultures revealed striking cytocompatibility of the microchannel interface. Finally, in vivo, the microchannel interface was successfully used to record a multitude of single-unit action potentials through 63% of the integrated microelectrodes at the early time point of 3 weeks. This marks a significant advance in microchannel interfacing, demonstrating the capability of microchannels to be used for peripheral nerve interfacing.


Self-assembled monolayers containing terminal mono-, bis-, and tris-nitrilotriacetic acid groups: characterization and application.
We have undertaken a structural and functional study of self-assembled monolayers (SAMs) formed on gold from a series of alkylthiol compounds containing terminal multivalent chelators (MCHs) composed of mono-, bis-, and tris-nitrilotriacetic acid (NTA) moieties. SAMs were formed from single-component solutions of the mono-, bis-, and tris-NTA compounds, as well as from mixtures with a tri(ethylene glycol)-terminated alkylthiol (EG(3)). Contact angle goniometry, null ellipsometry, and infrared spectroscopy were used to explore the structural characteristics of the MCH SAMs. Ellipsometric measurements show that the amount of the MCH groups on surfaces increases with increasing mol % of the MCH thiols in the loading solution up to about 80 mol %. We also conclude that mixed SAMs, prepared in the solution composition regime 0-30 mol % of the MCH thiols, consist of a densely packed alkyl layer, an amorphous ethylene glycol layer, and an outermost layer of MCH groups exposed toward the ambient. Above 30 mol %, a significant degree of disorder is observed in the SAMs. Finally, functional evaluation of the three MCH SAMs prepared at 0-30 mol% reveals a consistent increase in binding strength with increasing multivalency. The tris-NTA SAM, in particular, is enabled for stable and functional immobilization of a His6-tagged extracellular receptor subunit, even at low chelator surface concentrations, which makes it suitable for applications when a low surface density of capturing sites is desirable, e.g., in kinetic analyses.


Neural response suppression predicts repetition priming of spoken words and pseudowords.
An important method for studying how the brain processes familiar stimuli is to present the same item on more than one occasion and measure how responses change with repetition. Here we use repetition priming in a sparse functional magnetic resonance imaging (fMRI) study to probe the neuroanatomical basis of spoken word recognition and the representations of spoken words that mediate repetition priming effects. Participants made lexical decisions to words and pseudowords spoken by a male or female voice that were presented twice, with half of the repetitions in a different voice. Behavioral and neural priming was observed for both words and pseudowords and was not affected by voice changes. The fMRI data revealed an elevated response to words compared to pseudowords in both posterior and anterior temporal regions, suggesting that both contribute to word recognition. Both reduced and elevated activation for second presentations (repetition suppression and enhancement) were observed in frontal and posterior regions. Correlations between behavioral priming and neural repetition suppression were observed in frontal regions, suggesting that repetition priming effects for spoken words reflect changes within systems involved in generating behavioral responses. Based on the current results, these processes are sufficiently abstract to display priming despite changes in the physical form of the stimulus and operate equivalently for words and pseudowords.


Time-Frequency Analysis of Peptide Microarray Data: Application to Brain Cancer Immunosignatures.
One of the gravest dangers facing cancer patients is an extended symptom-free lull between tumor initiation and the first diagnosis. Detection of tumors is critical for effective intervention. Using the body's immune system to detect and amplify tumor-specific signals may enable detection of cancer using an inexpensive immunoassay. Immunosignatures are one such assay: they provide a map of antibody interactions with random-sequence peptides. They enable detection of disease-specific patterns using classic train/test methods. However, to date, very little effort has gone into extracting information from the sequence of peptides that interact with disease-specific antibodies. Because it is difficult to represent all possible antigen peptides in a microarray format, we chose to synthesize only 330,000 peptides on a single immunosignature microarray. The 330,000 random-sequence peptides on the microarray represent 83% of all tetramers and 27% of all pentamers, creating an unbiased but substantial gap in the coverage of total sequence space. We therefore chose to examine many relatively short motifs from these random-sequence peptides. Time-variant analysis of recurrent subsequences provided a means to dissect amino acid sequences from the peptides while simultaneously retaining the antibody-peptide binding intensities. We first used a simple experiment in which monoclonal antibodies with known linear epitopes were exposed to these random-sequence peptides, and their binding intensities were used to create our algorithm. We then demonstrated the performance of the proposed algorithm by examining immunosignatures from patients with Glioblastoma multiformae (GBM), an aggressive form of brain cancer. Eight different frameshift targets were identified from the random-sequence peptides using this technique. If immune-reactive antigens can be identified using a relatively simple immune assay, it might enable a diagnostic test with sufficient sensitivity to detect tumors in a clinically useful way.


Development and Optimization by Quality by Design Strategies of Frovatriptan Orally Disintegrating Tablets for Migraine Management.
Frovatriptan is a potent anti-migraine agent with unfavourable slow onset of action, available on the market as film-coated tablets. Optimization, by Quality by Designs strategies, of an orally disintegrating tablet (ODT) formulation of frovatriptan aimed to make its oral administration easier and its dissolution faster than the commercial tablets, thus improving its effectiveness in migraine management. A screening D-optimal design was applied to investigate the effects of different levels of kind and amount of ODT special excipient and disintegrant agents (identified as the critical variables) on disintegration time (DT) and % drug dissolved at 30 s (%Diss), selected as the responses to optimize. The best excipients combination, emerged by the screening step, was in-depth investigated by a Response Surface Methodology. A design space was defined where every combination of the selected variables fulfilled the required values for the responses with P ≥ 95%. In particular, the optimized formulation (Pharmaburst® 60% and Na alginate 15%), showed DT = 1.62±0.08 s and %Diss= 9.02±0.47%, with good agreement between measured and calculated values. Moreover, the developed ODT complied with the USP uniformity weight and drug content requirements, exhibited proper hardness and low friability, and provided 100 % dissolved drug within 5 min. A frovatriptan ODT formulation was successfully developed by Quality by Design. It represents an effective alternative to conventional tablets, allowing easier oral administration (also to paediatric and geriatric people) and very faster drug dissolution, enhancing patient compliance and facilitating an earlier treatment of migraine attacks.


Denigrins A-C: new antitubercular 3,4-diarylpyrrole alkaloids from Dendrilla nigra.
Chemical diversity is vital to antitubercular drug discovery as it ensures a novel bioactivity profile. Marine sponges have so far provided more than 1000 new bioactive molecules. Ethyl acetate extract of the marine sponge Dendrilla nigra on bioactivity-guided screening yielded three new compounds denigrins A-C, with potent antitubercular activity. Spectral and chemical analyses confirmed that these three compounds belong to the 3,4-diaryl pyrrole alkaloid category. The presence of monohydroxy substitution on benzene rings is not very common in lamellarin and related 3,4-diaryl pyrrole alkaloids isolated from marine invertebrates. Among these, denigrin C showed highest potency (minimum inhibitory concentration 4 μg/mL) against Mycobacterium tuberculosis H37Rv.


In vivo measurements of precision of fit involving implant-supported prostheses in the edentulous jaw.
The objective of this study was to measure and compare the precision of fit of implant-supported prostheses in the edentulous jaw by using both the master cast replicas and the intraoral implants as references. Seven maxillary and 10 mandibular prostheses were randomly selected and measured by means of a three-dimensional (3-D) photogrammetric technique. The results indicated that prostheses routinely connected to osseointegrated implants could demonstrate distortion between the framework and individual implants of up to several hundred microns. When master casts were used as a reference, the mean 3-D distortion of the center point of gold cylinders was 37 microns (SD 18) and 75 microns (SD 40) for mandibular and maxillary prostheses, respectively. The corresponding mean displacement was 90 microns (SD 51) and 111 microns (SD 59), respectively, when the intraoral implants were used as references. The mean 3-D distortion was significantly higher for the intraoral measurements in both arches (P < .001 and P < .05). Furthermore, the overall distortion was significantly higher for the maxillary prostheses when the master casts were used as the reference (P < .05). However, for the intraoral measurements, no statistically significant difference of fit between the arches was possible to observe (P < .05). This could possibly be explained by the finding that intraoral measurements of the mandibular prostheses indicated a deformation and rotation of the mandible that was not observed in the maxillary prostheses. A further factor in the lack of statistical significance could be the relatively small sample size.


Olive leaf extract facilitates healing of experimental cartilaginous injuries in rabbits.
We investigated the restorative effect of orally administered olive leaf extract (OLE) on experimentally produced cartilaginous injuries in rabbits. In total, three holes in the left stifle joint, including one in the medial trochlear ridge and two in the trochlear sulcus (proximal and distal) of articular cartilage, were prepared surgically using a drill. For the control group only tap water alone was administered daily, and for the OLE group a water-based solution of OLE (500 mg/kg/day) was administered daily. The injured areas were observed macroscopically and histologically at 3 weeks after the operation. The results indicate that OLE facilitated healing of the three holes and increased the weight of the biceps femoris muscle. Histological examination revealed that in the OLE group, matured cartilage tissues and connective tissues were mixed with regenerated or maturing cartilage tissues with massive proliferation in the injured parts, around which the proliferation of undifferentiated blast cells and the tissue with cartilage substrates were observed. The histological score of the OLE group was significantly lower than that of the control group. The percentage of proliferating cell nuclear antigen-positive cartilage cells in the OLE group was higher than in the control group. Mean density of the restored area observed with Safranin O staining was higher in the OLE group than in the control group. Therefore, OLE is effective for enhancing the healing of cartilaginous injuries. OLE may also have a beneficial effect of slowing and reducing the pathogenesis of degenerative joint diseases in humans.


Mapping Chromatin Occupancy of Ppp1r1b-lncRNA Genome-Wide Using Chromatin Isolation by RNA Purification (ChIRP)-seq.
Long non-coding RNA (lncRNA) mediated transcriptional regulation is increasingly recognized as an important gene regulatory mechanism during development and disease. LncRNAs are emerging as critical regulators of chromatin state; yet the nature and the extent of their interactions with chromatin remain to be fully revealed. We have previously identified Ppp1r1b-lncRNA as an essential epigenetic regulator of myogenic differentiation in cardiac and skeletal myocytes in mice and humans. We further demonstrated that Ppp1r1b-lncRNA function is mediated by the interaction with the chromatin-modifying complex polycomb repressive complex 2 (PRC2) at the promoter of myogenic differentiation transcription factors, TBX5 and MyoD1. Herein, we employed an unbiased chromatin isolation by RNA purification (ChIRP) and high throughput sequencing to map the repertoire of Ppp1r1b-lncRNA chromatin occupancy genome-wide in the mouse muscle myoblast cell line. We uncovered a total of 99732 true peaks corresponding to Ppp1r1b-lncRNA binding sites at high confidence (P-value < 1e-5 and enrichment score ≥ 10). The Ppp1r1b-lncRNA-binding sites averaged 558 bp in length and were distributed widely within the coding and non-coding regions of the genome. Approximately 46% of these true peaks were mapped to gene elements, of which 1180 were mapped to experimentally validated promoter sequences. Importantly, the promoter-mapped binding sites were enriched in myogenic transcription factors and heart development while exhibiting focal interactions with known motifs of proximal promoters and transcription initiation by RNA polII, including TATA, transcription initiator, CCAAT-box, and GC-box, supporting Ppp1r1b-lncRNA role in transcription initiation of myogenic regulators. Remarkably, nearly 40% of Ppp1r1b-lncRNA-binding sites mapped to gene introns, were enriched with the Homeobox family of transcription factors, and exhibited TA-rich motif sequences, suggesting potential motif specific Ppp1r1b-lncRNA-bound introns. Lastly, more than 136521enhancer sequences were detected in Ppp1r1b-lncRNA-occupancy sites at high confidence. Among these enhancers,12% exhibited cell type/tissue-specific enrichment in fetal heart and muscles. Together, our findings provide further insights into the genome-wide Ppp1r1b-lncRNA: Chromatin interactome that may potentially dictate its function in myogenic differentiation and potentially other cellular and biological processes.


A primary care evaluation of three near patient coagulometers.
To compare the reliability and relative costs of three international normalised ratio (INR) near patient tests. Protime (ITC Technidyne), Coaguchek (Boehringer Mannheim), and TAS (Diagnostic Testing). All patients attending one inner city general practice anticoagulation clinic were asked to participate, with two samples provided by patients not taking warfarin. A 5 ml sample of venous whole blood was taken from each patient and a drop immediately added to the prepared Coaguchek test strip followed by the Protime cuvette. The remainder was added to a citrated bottle. A drop of citrated blood was then placed on the TAS test card and the remainder sent to the reference laboratory for analysis. Parallel INR estimation was performed on the different near patient tests at each weekly anticoagulation clinic from July to December 1997. 19 patients receiving long term warfarin treatment provided 62 INR results. INR results ranged from 0.8-8.2 overall and 1.0-5.7 based on the laboratory method. Taking the laboratory method as the gold standard, 12/62 results were < 2.0 and 2/62 were > 4.5. There were no statistical or clinically significant differences between results from the three systems, although all near patient tests showed slightly higher mean readings than the laboratory, and 19-24% of tests would have resulted in different management decisions based on the machine used in comparison with the laboratory INR value. The cost of the near patient test systems varied substantially. All three near patient test systems are safe and efficient for producing acceptable and reproducible INR results within the therapeutic range in a primary care setting. All the systems were, however, subject to operator dependent variables at the time of blood letting. Adequate training in capillary blood sampling, specific use of the machines, and quality assurance procedures is therefore essential.


Induction of rat hepatic mixed-function oxidases by acetone and other physiological ketones: their role in diabetes-induced changes in cytochrome P450 proteins.
1. To evaluate the role of ketone bodies in diabetes-induced changes in hepatic cytochrome P450 composition, rats were treated with acetone, 3-hydroxybutyrate or 1,3-butanediol. 2. Treatment with acetone enhanced the rat hepatic O-dealkylations of ethoxyresorufin and methoxyresorufin, and the hydroxylation of p-nitrophenol, but had no effect on lauric acid hydroxylation and ethylmorphine N-demethylation. Neither 3-hydroxybutyrate nor 1,3-butanediol modulated the metabolism of the above substrates. 3. Immunoblot analysis of hepatic microsomal proteins revealed that treatment with acetone increased the apoprotein levels of P4501A2, P4502B1/2 and P4502E1. 4. It is concluded that acetone is responsible, at least partly, for the diabetes-induced increase in hepatic microsomal P4501A2, P4502B1/2 and P4502E1 proteins but does not mediate the increases in the P4503A1 and P4504A1 proteins. On the basis of work from our own and other laboratories a mechanism for the diabetes-induced changes in hepatic cytochrome P450 proteins is proposed.


Patient and physician views of shared decision making in cancer.
Engaging patients in shared decision making involves patient knowledge of treatment options and physician elicitation of patient preferences. Our aim was to explore patient and physician perceptions of shared decision making in clinical encounters for cancer care. Patients and physicians were asked open-ended questions regarding their perceptions of shared decision making throughout their cancer care. Transcripts of interviews were coded and analysed for shared decision-making themes. At an academic medical centre, 20 cancer patients with a range of cancer diagnoses, stages of cancer and time from diagnosis, and eight physicians involved in cancer care were individually interviewed. Most physicians reported providing patients with written information. However, most patients reported that written information was too detailed and felt that the physicians did not assess the level of information they wished to receive. Most patients wanted to play an active role in the treatment decision, but also wanted the physician's recommendation, such as what their physician would choose for him/herself or a family member in a similar situation. While physicians stated that they incorporated patient autonomy in decision making, most provided data without making treatment recommendations in the format preferred by most patients. We identified several communication gaps in cancer care. While patients want to be involved in the decision-making process, they also want physicians to provide evidence-based recommendations in the context of their individual preferences. However, physicians often are reluctant to provide a recommendation that will bias the patient.


The Effect of Pedaling Cadence on Skeletal Muscle Oxygenation During Cycling at Moderate Exercise Intensity.
The aim of this study was to assess the changes determined by increased cadence on skeletal muscle oxygenation during cycling at an exercise intensity equal to the ventilatory threshold (Tvent).Nine healthy, active individuals with different levels of cycling experience exercised at a power output equal to Tvent, pedaling at cadences of 40, 50, 60, 70, 80 and 90 rpm, each for 4 min. Cadences were tested in a randomized counterbalanced sequence. Cardiopulmonary and metabolic responses were studied using an ECG for heart rate, and gas calorimetry for pulmonary oxygen uptake and carbon dioxide production. NIRS was used to determine the tissue saturation index (TSI), a measure of vastus lateralis oxygenation.TSI decreased from rest to exercise; the magnitude of this TSI reduction was significantly greater when pedaling at 90 rpm (-14±4%), compared to pedaling at 40 (-12±3%) and 50 (-12±3%) rpm (P=0.027 and 0.017, respectively). Albeit small, the significant decrease in ΔTSI at increased cadence recorded in this study suggests that skeletal muscle oxygenation is relatively more affected by high cadence when exercise intensity is close to Tvent.


The relationship among oceanography, prey fields, and beaked whale foraging habitat in the Tongue of the Ocean.
Beaked whales, specifically Blainville's (Mesoplodon densirostris) and Cuvier's (Ziphius cavirostris), are known to feed in the Tongue of the Ocean, Bahamas. These whales can be reliably detected and often localized within the Atlantic Undersea Test and Evaluation Center (AUTEC) acoustic sensor system. The AUTEC range is a regularly spaced bottom mounted hydrophone array covering >350 nm(2) providing a valuable network to record anthropogenic noise and marine mammal vocalizations. Assessments of the potential risks of noise exposure to beaked whales have historically occurred in the absence of information about the physical and biological environments in which these animals are distributed. In the fall of 2008, we used a downward looking 38 kHz SIMRAD EK60 echosounder to measure prey scattering layers concurrent with fine scale turbulence measurements from an autonomous turbulence profiler. Using an 8 km, 4-leaf clover sampling pattern, we completed a total of 7.5 repeat surveys with concurrently measured physical and biological oceanographic parameters, so as to examine the spatiotemporal scales and relationships among turbulence levels, biological scattering layers, and beaked whale foraging activity. We found a strong correlation among increased prey density and ocean vertical structure relative to increased click densities. Understanding the habitats of these whales and their utilization patterns will improve future models of beaked whale habitat as well as allowing more comprehensive assessments of exposure risk to anthropogenic sound.


Effect of gabapentin on postoperative pain and operation complications: a randomized placebo controlled trial.
Prevention and treatment of postoperative pain and operation complications such as nausea and vomiting are most important concerns in postoperative care. There are several mechanisms involved in postoperative pain. Gabapentin is a gamma aminobutyric acid analogue that is known as an anticonvulsant drug. This drug is tolerated well and has known effects on pain and anxiety. This study has compared the effect of gabapentin on postoperative pain, operation complications and haemodynamics. This randomized double blinded placebo controlled clinical trial was conducted on 61 patients divided randomly into two groups (30 as cases and 31 as controls). All patients had total abdominal hysterectomy. In the first group, the patients got 100 mg gabapentin in the night and 300 mg gabapentin orally (one capsule) two hours before surgery. The second group got one capsule of multivitamin orally. Then all patients were subjected to the same anaesthesia protocol and total abdominal hysterectomy. During the 24 hours after operation, the patients were assessed according to pain, nausea, vomiting, dizziness, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate (PR) and morphine use at 1, 6, 12 and 24 hours. Mean age and weight of patients were 45.86 +/- 4.06, 48.16 +/- 4.48, 64.56 +/- 13.29 and 68.8 +/- 12.88 in the study population and control groups, respectively. Except in the first hour after operation (p = 0.02), there was no significant differences between the two groups in morphine use. There was no significant correlation between the groups according to postoperative complications and the haemodynamic parameters (PR, SBP and DBP). Results show that gabapentin can decrease the need for morphine use in the first hour after operation only and has no significant effect on operation complications. Thus, we suggest gabapentin for pain management, and not to decrease opium use.


Lifetime implications and cost-effectiveness of using finasteride to prevent prostate cancer.
We estimate the lifetime implications of daily treatment with finasteride following the results of the Prostate Cancer Prevention Trial (PCPT). In this trial, prostate cancer prevalence was reduced by 25%; however, an increase in the number of high-grade tumors among the treatment group necessitates the long-term projection of the likely benefits and costs. We use a Markov decision analysis model with data from the trial, the SEER program, and published literature. The model measures the cost per life-year and cost per quality-adjusted life-year (QALY) gained for a cohort of men age 55 years who initiate preventive treatment with finasteride. Finasteride is associated with a gain of 6 life-years per 1000 men treated at an incremental cost of 1660000 dollars per life-year gained. The quality-adjusted analysis results in 46 QALYs gained per 1000 men treated at an incremental cost of 200000 dollars per QALY gained, due primarily to the favorable effects of finasteride on benign prostatic hyperplasia. Under the assumption that the increase in high-grade tumors observed among finasteride treated men is a pathologic artifact, the incremental costs are 290000 dollars per life-year gained and 130000 dollars per QALY gained. The cost burden associated with finasteride is substantial, while its survival benefit is small and only realized many years after initiating treatment. To achieve an incremental cost below 100000 dollars per QALY gained, the price of finasteride must be reduced by 50% from its current average wholesale price and finasteride must be shown to prevent high-grade as well as low-grade disease.


Wetting of water on hexagonal boron nitride@Rh(111): a QM/MM model based on atomic charges derived for nano-structured substrates.
The wetting of water on corrugated and flat hexagonal boron nitride (h-BN) monolayers on Rh(111) is studied within a hybrid quantum mechanics/molecular mechanics (QM/MM) approach. Water is treated by QM methods, whereas the interactions between liquid and substrate are described at the MM level. The electrostatic properties of the substrate are reproduced by assigning specifically generated partial charges to each MM atom. We propose a method to determine restrained electrostatic potential (RESP) charges that can be applied to periodic systems. Our approach is based on the Gaussian and plane waves algorithm and allows an easy tuning of charges for nano-structured substrates. We have successfully applied it to reproduce the electrostatic potential of the corrugated and flat h-BN/Rh(111) known as nanomesh. Molecular dynamics simulations of water films in contact with these substrates are performed and structural and dynamic properties of the interfaces are analyzed. Based on this analysis and on the interaction energies between water film and substrate, we found that the corrugated nanomesh is slightly more hydrophilic. On a macroscopic scale, we expect a smaller contact angle for a droplet on the corrugated surface.


Confirmational identification of Escherichia coli, a comparison of genotypic and phenotypic assays for glutamate decarboxylase and beta-D-glucuronidase.
Genotypic and phenotypic assays for glutamate decarboxylase (GAD) and beta-D-glucuronidase (GUD) were compared for their abilities to detect various strains of Escherichia coli and to discriminate among other bacterial species. Test strains included nonpathogenic E. coli, three major groups of diarrheagenic E. coli, three other non-coli Escherichia species, and various other gram-negative and -positive bacteria found in water. The genotypic assays were performed with hybridization probes generated by PCR amplification of 670- and 623-bp segments of the gadA/B (GAD) and uidA (GUD) genes, respectively. The GAD enzymes catalyze the alpha-decarboxylation of L-glutamic acid to yield gamma-aminobutyric acid and carbon dioxide, which are detected in the phenotypic assay by a pH-sensitive indicator dye. The phenotypic assay for GUD involves the transformation of 4-methylumbelliferyl-beta-D-glucuronide to the fluorogenic compound 4-methylumbelliferone. The GAD phenotypic assay detected the majority of the E. coli strains tested, whereas a number of these strains, including all representatives of the O157:H7 serotype and several nonpathogenic E. coli strains, gave negative results in the GUD assay. Both phenotypic assays detected some but not all strains from each of the four Shigella species. A strain of Citrobacter freundii was also detected by the GUD assay but not by the GAD assay. All E. coli and Shigella strains were detected with both the gadA/B and uidA probes. A few Escherichia fergusonii strains gave weak hybridization signals in response to both probes at 65 degrees C but not at 68 degrees C. None of the other bacterial species tested were detected by either probe. These results were consistent with previous reports which have indicated that the GAD phenotypic assay detects a wider range of E. coli strains than does the GUD assay and is also somewhat more specific for this species. The genotypic assays for the two enzymes were found to be equivalent in both of these respects and superior to both of the phenotypic assays in terms of the range of E. coli strains and isolates detected.


Historical concepts of interactions, synergism and antagonism between nutrition and infection.
In the 1950s textbooks of nutrition made little or no mention of a relation to infection. The same was true for treatises on infectious disease. Relevant studies in experimental animals and a number of classical clinical observations were available pointing out the role of infection in precipitating nutritional disorders. However, clinicians and nutritionists did not recognize the importance of the relationship. The field and metabolic studies of the Institute of Nutrition of Central America and Panama (INCAP) in the 1950s demonstrated that malnutrition and infection in humans are generally synergistic. These studies stimulated the review of available evidence that resulted in the 1968 WHO monograph on "Interactions of Nutrition and Infection." It provided extensive evidence for the role of infections in precipitating clinical malnutrition and for the impact of malnutrition on morbidity and mortality from infection. The high frequency of diarrhea in underprivileged young children led to intensive studies in many countries of its effect on nutritional status and to recognition of the high prevalence of "weanling diarrhea." The effects of infection on nutritional status were then extensively and elegantly investigated at Fort Detrick, MD, and hormonal and cytokine mechanisms identified. The subsequent explosion in knowledge of cell-mediated immune mechanisms has led to an understanding of how malnutrition lowers this resistance. Today, recognition of the synergistic relationship between nutrition and infection influences most public health interventions to prevent malnutrition.


White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease.
White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.


Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.
Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease. Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49). Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.).


Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development.
The Tet family of enzymes (Tet1/2/3) converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Mouse embryonic stem cells (mESCs) highly express Tet1 and have an elevated level of 5hmC. Tet1 has been implicated in ESC maintenance and lineage specification in vitro but its precise function in development is not well defined. To establish the role of Tet1 in pluripotency and development, we have generated Tet1 mutant mESCs and mice. Tet1(-/-) ESCs have reduced levels of 5hmC and subtle changes in global gene expression, and are pluripotent and support development of live-born mice in tetraploid complementation assay, but display skewed differentiation toward trophectoderm in vitro. Tet1 mutant mice are viable, fertile, and grossly normal, though some mutant mice have a slightly smaller body size at birth. Our data suggest that Tet1 loss leading to a partial reduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic and postnatal development.


Direct medical cost of influenza-related hospitalizations among severe acute respiratory infections cases in three provinces in China.
Influenza-related hospitalizations impose a considerable economic and social burden. This study aimed to better understand the economic burden of influenza-related hospitalizations among patients in China in different age and risk categories. Laboratory-confirmed influenza-related hospitalizations between December 2009 and June 2011 from three hospitals participating in the Chinese Severe Acute Respiratory Infections (SARI) sentinel surveillance system were included in this study. Hospital billing data were collected from each hospital's Hospital Information System (HIS) and divided into five cost categories. Demographic and clinical information was collected from medical records. Mean (range) and median (interquartile range [IQR]) costs were calculated and compared among children (≤15 years), adults (16-64 years) and elderly (≥65 years) groups. Factors influencing cost were analyzed. A total of 106 laboratory-confirmed influenza-related hospitalizations were identified, 60% of which were children. The mean (range) direct medical cost was $1,797 ($80-$27,545) for all hospitalizations, and the median (IQR) direct medical cost was $231 ($164), $854 ($890), and $2,263 ($7,803) for children, adults, and elderly, respectively. Therapeutics and diagnostics were the two largest components of direct medical cost, comprising 57% and 23%, respectively. Cost of physician services was the lowest at less than 1%. Direct medical cost of influenza-related hospitalizations imposes a heavy burden on patients and their families in China. Further study is needed to provide more comprehensive evidence on the economic burden of influenza. Our study highlights the need to increase vaccination rate and develop targeted national preventive strategies.


Urinary Biomarkers in Women with Refractory Urgency Urinary Incontinence Randomized to Sacral Neuromodulation versus OnabotulinumtoxinA Compared to Controls.
We measured urinary biomarker levels in women with refractory urgency urinary incontinence and controls at baseline and 6 months after treatment with sacral neuromodulation or intradetrusor injection of onabotulinumtoxinA. We also assessed the association of baseline biomarkers with posttreatment urgency urinary incontinence episodes and overactive bladder symptom bother outcomes. First morning urine samples were collected from consented trial participants and age matched women without urgency urinary incontinence. Biomarkers reflecting general inflammation, neuroinflammation, afferent neurotransmitters and tissue remodeling were measured using standardized enzyme-linked immunosorbent assay and activity assays as appropriate. Symptom bother was assessed by the overactive bladder questionnaire and urgency urinary incontinence episodes were determined by bladder diary. Linear models were used to examine differences in mean biomarker levels and the change in urgency urinary incontinence episodes and symptom bother between baseline and 6 months. Modest evidence of a potential association was represented by p ≤0.01 and p ≤0.004 represented moderate evidence of an association with outcomes. Baseline biomarker levels differed little between cases and controls except tropoelastin (p = 0.001) and N-terminal telopeptide collagen type 1 (p <0.001). Changes in biomarker levels 6 months after intervention included decreases in collagenase (p <0.001) in both treatment groups and increases in interleukin-8 (p = 0.002) and matrix metalloprotease-9 (p <0.001) in the onabotulinumtoxinA group. Higher baseline calcitonin gene-related peptide across both treatments (p = 0.007) and nerve growth factor in the onabotulinumtoxinA arm (p = 0.007) were associated with less reduction in overactive bladder symptom bother. Refractory urgency urinary incontinence is a complex condition. These data suggest that matrix remodeling and neuropeptide mediation may be involved in its pathophysiological mechanisms and response to treatment.


Natural polyphenols in preclinical models of epilepsy.
Natural polyphenols are being tested both in preclinical and clinical settings for the treatment of different neurological disorders. The article describes the outcome of three polyphenols, resveratrol, epigallocatechin gallate, and quercetin, in preclinical animal models of epilepsy (both acute and chronic) and epileptogenesis. In theory, the antioxidant and neuroprotective properties of these natural polyphenols might be valuable in the management of acute seizures and the prevention of epileptogenesis. It is fascinating to observe that these polyphenols have a capacity to alter various signaling processes involved in the pathogenesis of epilepsy. The antiepileptic or antiseizure potential with these molecules delivers a mixed outcome. Some studies have demonstrated the usefulness of these molecules in preclinical models of epilepsy; however, contrary to the findings also exist. These molecules have poor bioavailability that may remain as the limiting factor in their clinical effects. The use of nanotechnology and other techniques have been tested to enhance bioavailability and brain penetration. There are no randomized double-blinded clinical studies establishing their antiepileptic effects in humans. It is concluded that more preclinical mechanism-based studies are needed to deliver a more certain picture regarding the use of natural polyphenols in the treatment of epilepsy.


Brain Plasticity following Intensive Bimanual Therapy in Children with Hemiparesis: Preliminary Evidence.
Neuroplasticity studies examining children with hemiparesis (CH) have focused predominantly on unilateral interventions. CH also have bimanual coordination impairments with bimanual interventions showing benefits. We explored neuroplasticity following hand-arm bimanual intensive therapy (HABIT) of 60 hours in twelve CH (6 females, mean age 11 ± 3.6 y). Serial behavioral evaluations and MR imaging including diffusion tensor (DTI) and functional (fMRI) imaging were performed before, immediately after, and at 6-week follow-up. Manual skills were assessed repeatedly with the Assisting Hand Assessment, Children's Hand Experience Questionnaire, and Jebsen-Taylor Test of Hand Function. Beta values, indicating the level of activation, and lateralization index (LI), indicating the pattern of brain activation, were computed from fMRI. White matter integrity of major fibers was assessed using DTI. 11/12 children showed improvement after intervention in at least one measure, with 8/12 improving on two or more tests. Changes were retained in 6/8 children at follow-up. Beta activation in the affected hemisphere increased at follow-up, and LI increased both after intervention and at follow-up. Correlations between LI and motor function emerged after intervention. Increased white matter integrity was detected in the corpus callosum and corticospinal tract after intervention in about half of the participants. Results provide first evidence for neuroplasticity changes following bimanual intervention in CH.


Dorsal root potentials after C-fiber stimulation.
A pure volley from C-fibers, set up by electrical stimulation of a cutaneous nerve and subsequent selective blocking of the A-fibers, generates in the cat spinal cord a dorsal root potential (C-DRP). Its polarity is the same as that of the dorsal root potential elicited by stimulation of the A-fibers (A-DRP), thus probably providing presynaptic inhibition of primary afferents. The size of the C-DRP increases in proportion to the size of the C-volley. A preceding A-DRP reduces the C-DRP.


Thyroid nodules, polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan.
Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-1962). Cases with thyroid nodules (n = 907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, P = 0.03) and GFRA1 -193C>G (rs not assigned, P = 0.05) and decreased risk with XRCC1 R194W (rs1799782, P trend = 0.03) and TGFB1 T263I (rs1800472, P = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n = 25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% CI 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT P value = 0.02). Polymorphisms in RET signaling, DNA repair and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways such as genes in double-strand break repair, apoptosis and genes related to proliferation should also be pursued.


Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is an aggressive cancer, and is the third leading cause of cancer death worldwide. Standard therapy is ineffective partly because HCC is intrinsically resistant to conventional chemotherapy. Its poor prognosis and limited treatment options make it critical to develop novel and selective chemotherapeutic agents. Since the Wnt/beta-catenin pathway is essential in HCC carcinogenesis, we studied the inhibition of Wnt-1-mediated signaling as a potential molecular target in HCC. We demonstrated that Wnt-1 is highly expressed in human hepatoma cell lines and a subgroup of human HCC tissues compared to paired adjacent non-tumor tissues. An anti-Wnt-1 antibody dose-dependently decreased viability and proliferation of Huh7 and Hep40 cells over-expressing Wnt-1 and harboring wild type beta-catenin, but did not affect normal hepatocytes with undetectable Wnt-1 expression. Apoptosis was also observed in Huh7 and Hep40 cells after treatment with anti-Wnt-1 antibody. In these two cell lines, the anti-Wnt-1 antibody decreased beta-catenin/Tcf4 transcriptional activities, which were associated with down-regulation of the endogenous beta-catenin/Tcf4 target genes c-Myc, cyclin D1, and survivin. Intratumoral injection of anti-Wnt-1 antibody suppressed in vivo tumor growth in a Huh7 xenograft model, which was also associated with apoptosis and reduced c-Myc, cyclin D1, and survivin expressions. Our results suggest that Wnt-1 is a survival factor for HCC cells, and that the blockade of Wnt-1-mediated signaling may offer a potential pathway-specific therapeutic strategy for the treatment of a subgroup of HCC that over-expresses Wnt-1.


Model SNP development for complex genomes based on hexaploid oat using high-throughput 454 sequencing technology.
Genetic markers are pivotal to modern genomics research; however, discovery and genotyping of molecular markers in oat has been hindered by the size and complexity of the genome, and by a scarcity of sequence data. The purpose of this study was to generate oat expressed sequence tag (EST) information, develop a bioinformatics pipeline for SNP discovery, and establish a method for rapid, cost-effective, and straightforward genotyping of SNP markers in complex polyploid genomes such as oat. Based on cDNA libraries of four cultivated oat genotypes, approximately 127,000 contigs were assembled from approximately one million Roche 454 sequence reads. Contigs were filtered through a novel bioinformatics pipeline to eliminate ambiguous polymorphism caused by subgenome homology, and 96 in silico SNPs were selected from 9,448 candidate loci for validation using high-resolution melting (HRM) analysis. Of these, 52 (54%) were polymorphic between parents of the Ogle1040 × TAM O-301 (OT) mapping population, with 48 segregating as single Mendelian loci, and 44 being placed on the existing OT linkage map. Ogle and TAM amplicons from 12 primers were sequenced for SNP validation, revealing complex polymorphism in seven amplicons but general sequence conservation within SNP loci. Whole-amplicon interrogation with HRM revealed insertions, deletions, and heterozygotes in secondary oat germplasm pools, generating multiple alleles at some primer targets. To validate marker utility, 36 SNP assays were used to evaluate the genetic diversity of 34 diverse oat genotypes. Dendrogram clusters corresponded generally to known genome composition and genetic ancestry. The high-throughput SNP discovery pipeline presented here is a rapid and effective method for identification of polymorphic SNP alleles in the oat genome. The current-generation HRM system is a simple and highly-informative platform for SNP genotyping. These techniques provide a model for SNP discovery and genotyping in other species with complex and poorly-characterized genomes.


The dynamics of interacting folds under biaxial compressive stresses.
The gradual in-plane compression of a solid film bonded to a soft substrate can lead to surface wrinkling and even to the formation of a network of folds for sufficiently high strain. An understanding of how these folds initiate, propagate, and interact with each other is still lacking. In a previous study, we developed an experimental system to observe the wrinkle-to-fold transition of layered elastic materials under biaxial compressive stresses. Here we focus on the dynamic interaction of a pair of propagating folds under biaxial compression. We find experimentally that their behavior is mediated through their tips and depends on the separation of the tips and their angle of interception. When the angle is lower than 45°, the two folds either form a unique fold by the coalescence of their tips when close enough, or bend their trajectories to intersect each other and form a lenticular region in analogy with cracks. When the angle is higher then 45°, the folds simply intersect and form a T-like junction. We rationalize this behavior by conducting numerical simulations to visualize the stress field around the two tips and find that the initial geometric position of the tips primarily determines the final state of the folds.


Tuning the magnetism of two-dimensional hematene by ferroelectric polarization.
Magnetism in two-dimensional (2D) materials, that is, a 2D version of the magnetism of three-dimensional bulk materials, and the associated novel physics have recently been the focus of many spintronics researchers. Here we investigate the manipulation of 2D magnetism at the interfaces of ferromagnetic/ferroelectric hematene/BaTiO3(001) heterostructures (HSs) fabricated via a precisely chosen sequence. By introducing four types of interfaces of 2D hematene and three-dimensional BaTiO3 that induce different oxygen environments, the control of magnetism is directly demonstrated from first-principles. An obvious 2D electron gas originates from the Fe-3d and O-2p hybridization; the electron gas is sensitive to the interfacial atomic displacements. Robust control of both the direction and magnitude of the net magnetization has been realized for an Fe/TiO2 terminated bilayer HS. The electron occupancies of the dxy and dxz orbitals and changes to the Fe-O bond play a key role in determining the magnetism of our systems. Our work not only demonstrates the technique's potential for manipulating magnetism in 2D hematene, but also sheds light on the underlying mechanism and the fundamental properties of hematene HSs.


Distinct Neural Suppression and Encoding Effects for Conceptual Novelty and Familiarity.
Like yin and yang, novelty and familiarity are typically described as separate-yet-complementary aspects of an experience, two ends of a single continuum. However, novelty and familiarity are also multifaceted. For instance, novelty can sometimes result in enhanced mnemonic performance, whereas at other times familiarity is better remembered. As previous investigations focused primarily on the experimental aspect of novelty, the mechanisms supporting conceptual novelty (the novel combination of two previously unrelated existing concepts) remain unclear. Importantly, conceptual novelty can be recognized as such only when compared with preexperimental familiar knowledge, regardless of experimental status. Here we applied a combined repetition suppression/subsequent memory fMRI paradigm, focusing on the conceptual aspect of novelty and familiarity as the subject matter. Conceptual novelty was characterized by sustained neural activity; familiarity, on the other hand, exhibited repetition effects in multiple cortical regions, a subset of which was modulated by successful encoding. Subsequent memory of novelty was associated only with activation differences in a distinct set of regions, including the hippocampus and medial cortical regions. These results suggest that conceptual novelty (a) does not (easily) trigger the repetition suppression phenomenon but requires sustained neural recruitment and (b) activates dedicated encoding mechanisms. Conceptual familiarity, in contrast, allows rapid neural processing that depends upon existing neural representations. Overall, these findings challenge the definition of novelty as a unitary concept. Furthermore, they bear important implications for research into the neural bases of knowledge representation and recognition memory.


Exclusive breastfeeding in first-time mothers in rural Kenya: a longitudinal observational study of feeding patterns in the first six months of life.
Exclusive breastfeeding up to 6 months of age is recommended by the World Health Organization as the optimal mode of infant feeding, providing adequate nutrition for the baby and protection against infectious diseases. Breastfeeding can be adversely affected by individual, cultural and socio-economic factors. The study aimed to explore barriers of exclusive breastfeeding in the first 6 months of life among first-time mothers in rural Kenya. An observational longitudinal design aimed to provide rich data on breastfeeding behaviour. Twenty pregnant first-time mothers were recruited through antenatal clinics and snowballing. Mothers were visited nine times at home from late pregnancy, at 1 week and 2 weeks post-delivery, then monthly until the baby was aged 6 months. Visits were conducted between November 2016 and April 2018. At the first visit, participants were asked about breastfeeding intentions and infant feeding education received. At each postnatal visit, direct observation of breastfeeding, a recorded semi-structured interview on feeding, mother's and baby's health was performed. Interviews were transcribed, checked, content was grouped into categories and analyzed using a qualitative descriptive approach. Most participants were adolescent (75%) and unmarried (65%). All 20 mothers intended to and did breastfeed, however additional fluids and semi-solids were commonly given. Only two mothers exclusively breastfed from birth up to 6 months of age. Prelacteal feeds, home remedies and traditional medicine were given by over a third of mothers in the first week of life. Concern over babies' bowel habits and persistent crying perceived as abdominal colic led to several mothers receiving advice to give gripe water and traditional remedies. Early introduction of maize porridge from 3 months of age because of perceived hunger of the child was recommended by other family members. Breastfeeding observation showed persistent problems with positioning and attachment of infants. Exclusive breastfeeding from birth to 6 months was uncommon. Prioritization of capacity to detect mothers with breastfeeding problems and provide breastfeeding education and support is necessary, particularly during the antenatal and early postnatal period. It is important to engage with other women resident in the household who may offer conflicting feeding advice.


Tear function and ocular surface changes with topical mitomycin (MMC) treatment for primary corneal intraepithelial neoplasia.
To evaluate the tear function and ocular surface alterations in patients with primary CIN before and after treatment with topical mitomycin (MMC). We describe seven patients with unilateral CIN treated with 0.04% topical MMC three times daily until full eradication of the lesion. The patients underwent tear and ocular surface examinations including Cochet-Bonnet corneal sensitivity measurements, tear film break-up time (BUT), Schirmer test, and Rose-Bengal staining before, at the time of resolution of the CIN, and at the final follow-up. Conjunctival impression cytology was performed before treatment and at the last visit. The mean pretreatment corneal sensitivity was 30.3 +/- 7.4 mm and improved to 55 +/- 5 mm at the final visit (P < 0.05). There were no aqueous-deficient eyes. The BUT values and Rose-Bengal staining scores also showed significant improvement at the last follow-up compared with the pretreatment values (P < 0.05). Initial impression cytology specimens showed goblet cell loss, higher grades of squamous metaplasia, areas of isolated keratinized, binucleated, and actively mitotic disfigured epithelial cells in all patients. The mean goblet cell density and squamous metaplasia grade were observed to improve significantly at the last visit (P < 0.05). MMC-induced cytologic changes were seen to persist long after cessation of treatment in some patients. All eyes remained free of recurrence and complications during the follow-up period. We found 0.04% topical MMC treatment tid until full eradication to be effective in the management of CIN. The ocular surface disease of CIN was characterized by disturbance of tear film stability, goblet cell loss, and increased squamous metaplasia in all patients. Impression cytology proved useful in attaining the diagnosis of CIN, evaluating the effect of treatment, and showing MMC-related long-term changes on the ocular surface.


Anatomic runoff score predicts cardiovascular outcomes in patients with lower extremity peripheral artery disease undergoing revascularization.
Although the presence, extent, and severity of obstruction in patients with lower extremity peripheral artery disease (LE PAD) affect their functional status, quality of life, and treatment, it is not known if these factors are associated with future cardiovascular events. We empirically created an anatomic runoff score (ARS) to approximate the burden of LE PAD and determined its association with clinical outcomes. We evaluated all patients with LE PAD and bilateral angiography undergoing revascularization in a community-based clinical study. Primary clinical outcomes of interest were (1) a composite of all-cause death, myocardial infarction (MI), and stroke and (2) amputation-free survival. Cox proportional hazards models were created to identify predictors of clinical outcomes. We evaluated 908 patients undergoing angiography, and a total of 260 (28.0%) patients reached the composite end point (45 MI, 63 stroke, and 152 death) during the study period. Anatomic runoff score ranged from 0 to 15 (mean 4.7; SD 2.5) with higher scores indicating a higher burden of disease, and an optimal cutpoint analysis classified patients into low ARS (<5) and high ARS (≥5). The unadjusted rates of the primary composite end point and amputation-free survival were nearly 2-fold higher in patients with a high ARS when compared with patients with a low ARS. The most significant predictors of the composite end point (death/MI/stroke) were age (δ 10 years; hazard ratio [HR] 1.53; CI 1.32-1.78; P < .001), diabetes mellitus (HR 1.65; CI 1.26-2.18; P < .001), glomerular filtration rate <30 (HR 2.23; CI 1.44-3.44; P < .001), statin use (HR 0.66; CI 0.48-0.88; P < .001), and ARS (δ 2 points; HR 1.21; CI 1.08-1.35; P < .001). After adjustment for clinical factors, the LE PAD ARS was an independent predictor of future cardiovascular morbidity and mortality in a broadly representative patient population undergoing revascularization for symptomatic PAD. A clinically useful anatomic scoring system, if validated, may assist clinicians in risk stratification during the course of clinical decision making.


Network-level accident-mapping: Distance based pattern matching using artificial neural network.
The objective of an accident-mapping algorithm is to snap traffic accidents onto the correct road segments. Assigning accidents onto the correct segments facilitate to robustly carry out some key analyses in accident research including the identification of accident hot-spots, network-level risk mapping and segment-level accident risk modelling. Existing risk mapping algorithms have some severe limitations: (i) they are not easily 'transferable' as the algorithms are specific to given accident datasets; (ii) they do not perform well in all road-network environments such as in areas of dense road network; and (iii) the methods used do not perform well in addressing inaccuracies inherent in and type of road environment. The purpose of this paper is to develop a new accident mapping algorithm based on the common variables observed in most accident databases (e.g. road name and type, direction of vehicle movement before the accident and recorded accident location). The challenges here are to: (i) develop a method that takes into account uncertainties inherent to the recorded traffic accident data and the underlying digital road network data, (ii) accurately determine the type and proportion of inaccuracies, and (iii) develop a robust algorithm that can be adapted for any accident set and road network of varying complexity. In order to overcome these challenges, a distance based pattern-matching approach is used to identify the correct road segment. This is based on vectors containing feature values that are common in the accident data and the network data. Since each feature does not contribute equally towards the identification of the correct road segments, an ANN approach using the single-layer perceptron is used to assist in "learning" the relative importance of each feature in the distance calculation and hence the correct link identification. The performance of the developed algorithm was evaluated based on a reference accident dataset from the UK confirming that the accuracy is much better than other methods.


A framework for characterizing eHealth literacy demands and barriers.
Consumer eHealth interventions are of a growing importance in the individual management of health and health behaviors. However, a range of access, resources, and skills barriers prevent health care consumers from fully engaging in and benefiting from the spectrum of eHealth interventions. Consumers may engage in a range of eHealth tasks, such as participating in health discussion forums and entering information into a personal health record. eHealth literacy names a set of skills and knowledge that are essential for productive interactions with technology-based health tools, such as proficiency in information retrieval strategies, and communicating health concepts effectively. We propose a theoretical and methodological framework for characterizing complexity of eHealth tasks, which can be used to diagnose and describe literacy barriers and inform the development of solution strategies. We adapted and integrated two existing theoretical models relevant to the analysis of eHealth literacy into a single framework to systematically categorize and describe task demands and user performance on tasks needed by health care consumers in the information age. The method derived from the framework is applied to (1) code task demands using a cognitive task analysis, and (2) code user performance on tasks. The framework and method are applied to the analysis of a Web-based consumer eHealth task with information-seeking and decision-making demands. We present the results from the in-depth analysis of the task performance of a single user as well as of 20 users on the same task to illustrate both the detailed analysis and the aggregate measures obtained and potential analyses that can be performed using this method. The analysis shows that the framework can be used to classify task demands as well as the barriers encountered in user performance of the tasks. Our approach can be used to (1) characterize the challenges confronted by participants in performing the tasks, (2) determine the extent to which application of the framework to the cognitive task analysis can predict and explain the problems encountered by participants, and (3) inform revisions to the framework to increase accuracy of predictions. The results of this illustrative application suggest that the framework is useful for characterizing task complexity and for diagnosing and explaining barriers encountered in task completion. The framework and analytic approach can be a potentially powerful generative research platform to inform development of rigorous eHealth examination and design instruments, such as to assess eHealth competence, to design and evaluate consumer eHealth tools, and to develop an eHealth curriculum.


Nonparametric graphical model for counts.
Although multivariate count data are routinely collected in many application areas, there is surprisingly little work developing flexible models for characterizing their dependence structure. This is particularly true when interest focuses on inferring the conditional independence graph. In this article, we propose a new class of pairwise Markov random field-type models for the joint distribution of a multivariate count vector. By employing a novel type of transformation, we avoid restricting to non-negative dependence structures or inducing other restrictions through truncations. Taking a Bayesian approach to inference, we choose a Dirichlet process prior for the distribution of a random effect to induce great flexibility in the specification. An efficient Markov chain Monte Carlo (MCMC) algorithm is developed for posterior computation. We prove various theoretical properties, including posterior consistency, and show that our COunt Nonparametric Graphical Analysis (CONGA) approach has good performance relative to competitors in simulation studies. The methods are motivated by an application to neuron spike count data in mice.


Accelerating Monte Carlo Bayesian Prediction via Approximating Predictive Uncertainty Over the Simplex.
Estimating the predictive uncertainty of a Bayesian learning model is critical in various decision-making problems, e.g., reinforcement learning, detecting the adversarial attack, self-driving car. As the model posterior is almost always intractable, most efforts were made on finding an accurate approximation to the true posterior. Even though a decent estimation of the model posterior is obtained, another approximation is required to compute the predictive distribution over the desired output. A common accurate solution is to use Monte Carlo (MC) integration. However, it needs to maintain a large number of samples, and evaluate the model repeatedly, and average multiple model outputs. In many real-world cases, this is computationally prohibitive. In this work, assuming that the exact posterior or a decent approximation is obtained, we propose a generic framework to approximate the output probability distribution induced by the model posterior with a parameterized model and in an amortized fashion. The aim is to approximate the predictive uncertainty of a specific Bayesian model, meanwhile alleviating the heavy workload of MC integration at testing time. The proposed method is universally applicable to Bayesian classification models that allow for posterior sampling. Theoretically, we show that the idea of amortization incurs no additional costs on approximation performance. Empirical results validate the strong practical performance of our approach.


Reproducibility-optimized test statistic for ranking genes in microarray studies.
A principal goal of microarray studies is to identify the genes showing differential expression under distinct conditions. In such studies, the selection of an optimal test statistic is a crucial challenge, which depends on the type and amount of data under analysis. While previous studies on simulated or spike-in datasets do not provide practical guidance on how to choose the best method for a given real dataset, we introduce an enhanced reproducibility-optimization procedure, which enables the selection of a suitable gene- anking statistic directly from the data. In comparison with existing ranking methods, the reproducibilityoptimized statistic shows good performance consistently under various simulated conditions and on Affymetrix spike-in dataset. Further, the feasibility of the novel statistic is confirmed in a practical research setting using data from an in-house cDNA microarray study of asthma-related gene expression changes. These results suggest that the procedure facilitates the selection of an appropriate test statistic for a given dataset without relying on a priori assumptions, which may bias the findings and their interpretation. Moreover, the general reproducibilityoptimization procedure is not limited to detecting differential expression only but could be extended to a wide range of other applications as well.


A Systematic Search and Review of Adult-Targeted Overweight and Obesity Prevention Mass Media Campaigns and Their Evaluation: 2000-2017.
Mass media campaigns are a commonly used strategy in public health. However, no review has assessed whether the design and evaluation of overweight and obesity campaigns meets best practice recommendations. This study aimed to fill this gap. We systematically searched five databases for peer-reviewed articles describing adult-targeted obesity mass media campaigns published between 2000 and 2017, complemented by reference list searches and contact with authors and agencies responsible for the campaigns. We extracted data on campaign design, implementation, and evaluation from eligible publications and conducted a qualitative review of 29 publications reporting on 14 campaigns. We found a need for formative research with target audiences to ensure campaigns focus on the most salient issues. Further, we noted that most campaigns targeted individual behaviors, despite calls for campaigns to also focus upstream and to address social determinants of obesity. Television was the dominant communication channel but, with the rapid advance of digital media, evaluation of other channels, such as social media, is increasingly important. Finally, although evaluation methods varied in quality, the evidence suggests that campaigns can have an impact on intermediate outcomes, such as knowledge and attitudes. However, evidence is still limited as to whether campaigns can influence behavior change.


Impact of caregiver literacy on children's oral health outcomes.
The objective of this study was to examine the relationship of primary caregivers' literacy with children's oral health outcomes. We performed a cross-sectional study of children who were aged < or =6 years and presented for an initial dental appointment in the teaching clinics at the University of North Carolina at Chapel Hill School of Dentistry. Caregiver literacy was measured using the Rapid Estimate of Adult Literacy in Dentistry (REALD-30). The outcome measures included oral health knowledge, oral health behaviors, primary caregiver's reports of their child's oral health status, and the clinical oral health status of the child as determined by a clinical examination completed by trained, calibrated examiners. Among the 106 caregiver-child dyads enrolled, 59% of the children were male, 52% were white, and 86% of caregivers were the biological mothers. The bivariate results showed no significant relationships between literacy and oral health knowledge (P = .16) and behaviors (P = .24); however, there was an association between literacy and oral health status (P < .05). The multivariate analysis controlled for race and income; this analysis revealed a significant relationship between caregiver literacy scores and clinical oral health status as determined by using a standardized clinical examination. Caregivers of children with mild to moderate treatment needs were more likely to have higher REALD-30 scores than those with severe treatment needs (odds ratio: 1.14 [95% confidence interval: 1.05-1.25]; P = .003). Caregiver literacy is significantly associated with children's dental disease status.


Use of allografts in spinal surgery.
This is a review of 118 patients operated between January 1989 and February 1999, 78 for posterior fusions and 40 for anterior spinal reconstructions. For posterior fusion, meticulous preparation of the fusion bed was essential. The author strongly advocated using autografts from spinous processes for achieving facet joint fusion. Deep frozen allografts were used as a 50% allograft-autograft mixture. Good results were achieved -- no infection in all cases and implant failure with clinical non-union in only 5 cases. Massive anterior spinal reconstruction following corpectomy was performed in 34 cases. Allografts used included 15 femoral cortical rings, 11 tibial rings and 3 humeral cortical rings. The author advocated the use of an allograft-autograft composite by packing the medullary canal of the allograft with autografts. Deep-frozen cortical rings have been used (25 cases). Recently, more freeze-dried cortical rings made available were used (9 cases). The results of massive reconstructions were good. There was no infection and no implant failure in all cases. Both deep-frozen and freeze-dried cortical allografts were strong enough to withstand loads taken by the reconstructed spine.


Modeled impact of anthropogenic warming on the frequency of intense Atlantic hurricanes.
Several recent models suggest that the frequency of Atlantic tropical cyclones could decrease as the climate warms. However, these models are unable to reproduce storms of category 3 or higher intensity. We explored the influence of future global warming on Atlantic hurricanes with a downscaling strategy by using an operational hurricane-prediction model that produces a realistic distribution of intense hurricane activity for present-day conditions. The model projects nearly a doubling of the frequency of category 4 and 5 storms by the end of the 21st century, despite a decrease in the overall frequency of tropical cyclones, when the downscaling is based on the ensemble mean of 18 global climate-change projections. The largest increase is projected to occur in the Western Atlantic, north of 20 degrees N.


Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs.
Although improved epicardial blood flow (as assessed with either TIMI flow grades or TIMI frame count) has been related to reduced mortality after administration of thrombolytic drugs, the relationship of myocardial perfusion (as assessed on the coronary arteriogram) to mortality has not been examined. A new, simple angiographic method, the TIMI myocardial perfusion (TMP) grade, was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI (Thrombolysis In Myocardial Infarction) 10B trial, and its relationship to mortality was examined. TMP grade 0 was defined as no apparent tissue-level perfusion (no ground-glass appearance of blush or opacification of the myocardium) in the distribution of the culprit artery; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature (blush or a stain was present on the next injection); TMP grade 2 blush clears slowly (blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase); and TMP grade 3 indicates that blush begins to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). There was a mortality gradient across the TMP grades, with mortality lowest in those patients with TMP grade 3 (2.0%), intermediate in TMP grade 2 (4.4%), and highest in TMP grades 0 and 1 (6.0%; 3-way P=0.05). Even among patients with TIMI grade 3 flow in the epicardial artery, the TMP grades allowed further risk stratification of 30-day mortality: 0.73% for TMP grade 3; 2.9% for TMP grade 2; 5.0% for TMP grade 0 or 1 (P=0.03 for TMP grade 3 versus grades 0, 1, and 2; 3-way P=0.066). TMP grade 3 flow was a multivariate correlate of 30-day mortality (OR 0.35, 95% CI 0.12 to 1.02, P=0.054) in a multivariate model that adjusted for the presence of TIMI 3 flow (P=NS), the corrected TIMI frame count (OR 1.02, P=0.06), the presence of an anterior myocardial infarction (OR 2.3, P=0.03), pulse rate on admission (P=NS), female sex (P=NS), and age (OR 1.1, P<0.001). Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery. Patients with both normal epicardial flow (TIMI grade 3 flow) and normal tissue level perfusion (TMP grade 3) have an extremely low risk of mortality.


The influence of tinnitus acceptance on the quality of life and psychological distress in patients with chronic tinnitus.
Recent findings show the importance of acceptance in the treatment of chronic tinnitus. So far, very limited research investigating the different levels of tinnitus acceptance has been conducted. The aim of this study was to investigate the quality of life (QoL) and psychological distress in patients with chronic tinnitus who reported different levels of tinnitus acceptance. The sample consisted of outpatients taking part in a tinnitus coping group (n = 97). Correlations between tinnitus acceptance, psychological distress, and QoL were calculated. Receiver operating characteristic (ROC) curves were used to calculate a cutoff score for the German "Tinnitus Acceptance Questionnaire" (CTAQ-G) and to evaluate the screening abilities of the CTAQ-G. Independent sample t-tests were conducted to compare QoL and psychological distress in patients with low tinnitus acceptance and high tinnitus acceptance. A cutoff point for CTAQ-G of 62.5 was defined, differentiating between patients with "low-to-mild tinnitus acceptance" and "moderate-to-high tinnitus acceptance." Patients with higher levels of tinnitus acceptance reported a significantly higher QoL and lower psychological distress. Tinnitus acceptance plays an important role for patients with chronic tinnitus. Increased levels of acceptance are related to better QoL and less psychological distress.


Multifocal Osteonecrosis in the Foot and Ankle After Extracorporeal Membrane Oxygenation: A Case Report.
Osteonecrosis is acknowledged as a relatively uncommon disorder caused by various factors, including autoimmune diseases, drug-induced diseases, inherited metabolic disorders, coagulation disorders, and underlying malignancies. To our knowledge, no previous research has investigated osteonecrosis stemming from extracorporeal membrane oxygenation. Herein, we report a rare case of postperipheral venoarterial extracorporeal membrane oxygenation-induced multifocal osteonecrosis in the foot and ankle that demonstrated a low serpiginous peripheral signal on T1-weighted images and a double-line sign on fat-suppressed or T2-weighted magnetic resonance images. Conservative treatment was applied, and the patient was mostly recuperated after 6 months.


The experience of implementing evidence-based practice change: a qualitative analysis.
The Oncology Nursing Society (ONS) and ONS Foundation worked together to develop the Institute for Evidence-Based Practice Change (IEBPC) program to facilitate the implementation of evidence-based practice (EBP) change in nursing. This analysis describes the experience of 19 teams of nurses from various healthcare settings who participated in the IEBPC program. Qualitative analysis of verbatim narratives of activities and observations during the process of implementing an EBP project was used to identify key themes in the experience. EBP implementation enabled participants to learn about their own practice and to experience empowerment through the evidence, and it ignited the spirit of inquiry, team work, and multidisciplinary collaboration. Experiences and lessons learned from nurses implementing EBP can be useful to others in planning EBP implementation.