Effect of erythropoiesis-stimulating agent policy decisions on off-label use in myelodysplastic syndromes.
Erythropoiesis-stimulating agents (ESAs) are widely used to treat anemia associated with myelodysplastic syndromes (MDS) as an off-label indication. In early 2007, the U.S. Food and Drug Administration (FDA) released safety alerts and mandated label changes, and the Centers for Medicare & Medicaid Services (CMS) implemented a National Coverage Determination (NCD) in August 2007, dramatically restricting ESA coverage based on specific clinical parameters in non-MDS patients. We sought to determine the effect on ESA use in MDS, examining both treatment initiation and concordance with guidelines designed to target patients most likely to benefit from therapy. We determined receipt of ESA within 6 months of diagnosis. For ESA recipients, we operationalized three National Comprehensive Cancer Network guidelines: serum erythropoietin determination before ESA initiation, transfusion-independent at ESA initiation, and initial ESA treatment episode of >= 8 weeks. Logistic regression models tested the effect of time (half-year increments pre-post the August '07 CMS NCD implementation), controlling for demographics and health status. 17,491 (61.1%) of 28,627 beneficiaries with MDS received ESAs. ESA use increased prior to the reference period (Jan.-July 2007), but declined beginning in August 2007, the date of NCD implementation (marginal probability =-0.05, p-value<0.01). Concordance with treatment guidelines changed during the observation period, with increased rates of serum erythropoietin levels, but declined in the other two guidelines. These results suggest a mixed pattern of change in the face of the FDA safety warnings and CMS NCD in MDS and highlight the importance of monitoring for unintended consequences of policy changes.


The hypothalamic-pituitary-testicular axis and the testicular function are modulated after silver nanoparticle exposure.
Silver nanoparticles (AgNPs) are widely used in industrial and medical applications and humans may be exposed through different routes, increasing the risk of toxicity. We investigated the transcript expression of genes involved in the regulation of the hypothalamic-pituitary-testicular (HPT) axis and the parameters associated with sperm functionality after prepubertal exposure. AgNPs modulated the transcript expression of genes involved in the control of the HPT axis and spermatogenesis in the groups treated with lower doses, while the functional parameters related to sperm and puberty were affected in the groups administered higher doses. These results suggest that the HPT axis is disrupted by AgNPs during the prepubertal and pubertal periods, which are highly susceptible windows for the endocrine-disrupting chemical activity.


Contribution of the drought tolerance-related stress-responsive NAC1 transcription factor to resistance of barley to Ramularia leaf spot.
NAC proteins are plant transcription factors that are involved in tolerance to abiotic and biotic stresses, as well as in many developmental processes. Stress-responsive NAC1 (SNAC1) transcription factor is involved in drought tolerance in barley and rice, but has not been shown previously to have a role in disease resistance. Transgenic over-expression of HvSNAC1 in barley cv. Golden Promise reduced the severity of Ramularia leaf spot (RLS), caused by the fungus Ramularia collo-cygni, but had no effect on disease symptoms caused by Fusarium culmorum, Oculimacula yallundae (eyespot), Blumeria graminis f. sp. hordei (powdery mildew) or Magnaporthe oryzae (blast). The HvSNAC1 transcript was weakly induced in the RLS-susceptible cv. Golden Promise during the latter stages of R. collo-cygni symptom development when infected leaves were senescing. Potential mechanisms controlling HvSNAC1-mediated resistance to RLS were investigated. Gene expression analysis revealed no difference in the constitutive levels of antioxidant transcripts in either of the over-expression lines compared with cv. Golden Promise, nor was any difference in stomatal conductance or sensitivity to reactive oxygen species-induced cell death observed. Over-expression of HvSNAC1 delayed dark-induced leaf senescence. It is proposed that mechanisms controlled by HvSNAC1 that are involved in tolerance to abiotic stress and that inhibit senescence also confer resistance to R. collo-cygni and suppress RLS symptoms. This provides further evidence for an association between abiotic stress and senescence in barley and the development of RLS.


Characteristics of adolescents who intervene to stop the risky and dangerous behavior of their friends.
Adolescents value protecting friends from harm and report that they do intervene as bystanders in friends' risky and dangerous behavior. Moreover intervention can be effective in reducing such behaviors. The Protection-Risk Framework was used to explain bystander intervention. There were 962 students from 13 Australian high schools (mean age at time 1=13.44 years) surveyed in their 9th grade and again 1-year later when students were in 10th grade. We found that protective factors of self-efficacy, support, prosocial models, social control, and ease of opportunity related to greater intervening behavior after 12-months. Among those who reported that they had intervened in a 3-month period, a cumulative measure of protective factors was associated with their reports of intervening. Risk factors were non-significant predictors after accounting for earlier, time 1, bystander intervening behavior and demographic factors. The findings highlight potential mechanisms to promote adolescents' looking out for their friends and provide an assessment over time of bystander behavior. The theory-guided inquiry into such behavior provides a foundation on which to better develop our understanding of benefits to adolescent friendship in the injury field.


Characterization of a low-speckle laser line generator.
The goal of our investigation is to design a low-speckle laser line generator based on partial spatially coherent laser light. Low speckle is achieved by exploiting a regime of strongly reduced spatial coherence of a broad-area vertical-cavity surface-emitting laser, which is used as the line generator's light source. A comparative experimental study of different optical configurations is conducted, leading to the design of an optimal optical system. The results of our study are also valid for other sources of partial spatially coherent emission.


Sex knowledge and sexual attitudes among medical and nursing students.
The aim of this study was to assess the relationship between background and sociodemographic variables, attitudes toward controversial aspects of human sexuality and sex knowledge among medical and nursing students. The study design was a questionnaire-based survey of medical and nursing students in Western Australia. Participants were first- through fifth-year medical students at the University of Western Australia and first- through third-year undergraduate nursing students at Edith Cowan University. Outcome measures were students' attitudes toward controversial aspects of human sexuality expressed on a five-point Likert scale and a modified version of the Kinsey Institute/Roper Organization National Sex Knowledge Test. A significant relationship was found between certain background and sociodemographic variables, sexual attitudes and sex knowledge. The background variable most strongly related to both attitudes and knowledge was frequency of attendance at religious services of any religious denomination during the past month, with those attending three or more times more likely to express negative attitudes and have lower sex knowledge scores. Lower sex knowledge was related to negative attitudes toward gay/lesbian/bisexual behaviour, masturbation, premarital sex and contraception. Other important background and sociodemographic variables related to negative attitudes were: never having experienced sexual intercourse; right-wing political orientation; lower family income; gender and ethnicity. Negative attitudes toward controversial aspects of human sexuality and lower sex knowledge scores among medical and nursing students can be predicted on the basis of background and sociodemographic variables. Education aimed at increasing sex knowledge and modifying negative attitudes may increase students' ability to function more effectively as sexual history takers and sex counsellors.


High levels of N-palmitoylethanolamide and N-stearoylethanolamide in microdialysate samples from myalgic trapezius muscle in women.
N-acylethanolamines (NAEs) are endogenous compounds that regulate inflammation and pain. These include the cannabinoid ligand anandamide (AEA) and the peroxisome proliferator-activated receptor-α ligand palmitoylethanolamide (PEA). Little is known as to the levels of NAEs in pain states in human, particularly in the skeletal muscle. The aim of this study was to investigate the levels of these lipid mediators in muscle dialysate from women with chronic neck-/shoulder pain compared to healthy controls. Eleven women with chronic neck-/shoulder pain and eleven healthy women participated in this study. All participants went through microdialysis procedures in the trapezius muscle. Muscle dialysate samples were collected during four hours and analysed by nano liquid chromatography tandem mass spectrometry (nLC-MS/MS). We were able to detect AEA, PEA, N-stearoylethanolamine (SEA) and 2-arachidonoylglycerol (2-AG) in a single chromatographic run. Of the NAEs studied, PEA and SEA were clearly detectable in the muscle microdialysate samples. The muscle dialysate levels of PEA and SEA were significantly higher in myalgic subjects compared to healthy controls. This study demonstrates that microdialysis in combination with mass spectrometry can be used for analysing NAE's in human muscle tissue regularly over time. Furthermore the significant group differences in the concentration of PEA and SEA in this study might fill an important gap in our knowledge of mechanisms in chronic myalgia in humans. In the long run this expanded understanding of nociceptive and anitinociceptive processes in the muscle may provide a base for ameliorating treatment and rehabilitation of pain.


Flunixin pharmacokinetics and serum thromboxane inhibition in the dog.
Flunixin meglumine administered orally to beagle dogs at doses of 0.55, 1.10 or 1.65 mg/kg bodyweight was rapidly absorbed to produce maximum mean plasma concentrations of 2.40 +/- 0.70, 4.57 +/- 1.12 and 7.42 +/- 2.07 micrograms/ml, respectively. Thereafter, the plasma concentrations of flunixin fell rapidly to values less than 0.10 micrograms/ml from 24 hours after drug administration at all dosage levels. The maximum mean inhibition of serum thromboxane B2 was 91.5 per cent after the lowest dose of flunixin and 98.8 per cent for both the intermediate and high dose rates. At plasma concentrations of flunixin above 2 micrograms/ml there was more than 90 per cent inhibition of thromboxane.


Outcomes of renal transplantation in patients with major lower limb amputation.
The impact of severe peripheral vascular disease on graft survival in patients undergoing renal transplantation is poorly defined. The aim of our study is to establish outcomes in renal transplant recipients who have severe peripheral vascular disease necessitating major lower limb amputation. Data for patients undergoing renal transplantation from January 2001-December 2010 was extracted from a regional transplantation database. Patients undergoing lower limb amputation pre- and post-transplantation were identified and outcome measures including delayed graft function, biopsy-proven acute rejection, serum creatinine level at 1 year, and graft loss and recipient survival at 1 year and long-term were compared with patients who did not undergo amputation. Student t and Pearson's chi-squared tests were used to compare patients with and without amputation and Kaplan-Meier curves were used for survival analysis. A P value < .05 is considered statistically significant. A total of 762 patients underwent renal transplantation. Four (0.5%) patients had an amputation before transplantation and 16 (2.1%) underwent amputation after transplantation. Serum creatinine levels at 1 year were significantly higher in patients who had amputation after transplantation (308.5 ± 60.8 μmol/l vs 177.6 ± 6.4 μmol/l; P = .03). During longer follow-up (mean: 2053.1 ± 58.3 days), patients who underwent amputation after transplantation had a higher rate of graft loss (P < .01) and higher death rate (P < .01). The requirement for amputation after renal transplantation is associated with poor long-term graft and patient survival and higher serum creatinine levels at 1 year. Patients at increased risk of severe peripheral vascular disease should be identified and measures taken to reduce the long-term risk.


Achieving Logical Equivalence between SNOMED CT and ICD-10-PCS Surgical Procedures.
Surgical procedures are coded in SNOMED CT in the electronic health record and in ICD-10-PCS in administrative systems. We compared the logical definitions of SNOMED CT concepts to the ICD-10-PCS axial components to identify overlap and gaps. The biggest discrepancy was in the surgical approach which was specified in all ICD-10-PCS codes but only in 8.7% of SNOMED CT surgical procedures. Among the top 100 commonly used ICD-10-PCS codes, 25% could be matched fully in meaning and logical definition to pre-coordinated SNOMED CT concepts. Using post-coordination, it was possible to represent the full meaning of 86% of ICD-10-PCS codes. Logical mapping between SNOMED CT and ICD-10-PCS is feasible but will be more productive if more SNOMED CT concepts can become fully-defined. Short of full logical matching, partial logical matches can also be useful in suggesting candidate maps for expert review and to support interactive post-coordination.


Acupuncture and self acupuncture for long-term treatment of vasomotor symptoms in cancer patients--audit and treatment algorithm.
Since hormone replacement therapy given for long periods is now recognised to produce serious side effects, patients with troublesome vasomotor symptoms are increasingly using non-hormonal treatment including acupuncture. Several randomised controlled trials have shown that acupuncture reduces menopausal symptoms in patients experiencing the normal climacteric. It may have this effect by raising serotonin levels which alter the temperature set point in the hypothalamus. Vasomotor symptoms can be extreme in breast cancer patients and patients with prostate cancer who are undergoing anticancer therapy. The safety of some herbal medicines and phytoestrogens has been questioned, as they could potentially interfere adversely with the bioavailability of tumouricidal drugs. A previous study reports short term benefit from acupuncture, and the aim of this report is to describe our approach to long term treatment. After piloting several approaches, six weekly treatments were given initially at LI4, TE5, LR3 and SP6 and two upper sternal points, but avoiding any limb with existing lymphoedema or prone to developing it. If there were no contraindications, patients were given clear instructions on how to perform self acupuncture using either semi-permanent needles or conventional needling at SP6, weekly for up to six years, for long term maintenance. A retrospective audit of electronic records was carried out by a doctor not involved in treatment. A total of 194 patients were treated, predominantly with breast and prostate cancer. One hundred and eighty two patients were female. The number of pre-treatment hot flushes per day was estimated by the patient: in the 159 cases providing adequate records, the mean was 16 flushes per day. Following treatment, 114 (79%) gained a 50% or greater reduction in hot flushes and 30 (21%) a less than 50% reduction. Treatment was abandoned in those who responded poorly or not at all. The duration of treatment varied from one month to over six years with a mean duration of nine months. Seventeen patients (9%) experienced minor side effects over the six year period, mostly minor rashes; one patient described leg swelling but this was likely to be due to a concurrent fracture. Acupuncture including self acupuncture is associated with long-term relief of vasomotor symptoms in cancer patients. Treatment is safe and costs appear to be low. An algorithm is presented to guide clinical use. We recommend the use of self acupuncture with needles at SP6 in preference to semi-permanent needles in the first instance, but poor responders use indwelling studs if they fail to respond adequately to self acupuncture with regular needles. Point location may be of less importance than the overall 'dose', and an appropriate minimum dose may be required to initiate the effect.


Correlates of immune protection following cutaneous immunization with an attenuated Burkholderia pseudomallei vaccine.
Infections with the Gram-negative bacterium Burkholderia pseudomallei (melioidosis) are associated with high mortality, and there is currently no approved vaccine to prevent the development of melioidosis in humans. Infected patients also do not develop protective immunity to reinfection, and some individuals will develop chronic, subclinical infections with B. pseudomallei. At present, our understanding of what constitutes effective protective immunity against B. pseudomallei infection remains incomplete. Therefore, we conducted a study to elucidate immune correlates of vaccine-induced protective immunity against acute B. pseudomallei infection. BALB/c and C57BL/6 mice were immunized subcutaneously with a highly attenuated, Select Agent-excluded purM deletion mutant of B. pseudomallei (strain Bp82) and then subjected to intranasal challenge with virulent B. pseudomallei strain 1026b. Immunization with Bp82 generated significant protection from challenge with B. pseudomallei, and protection was associated with a significant reduction in bacterial burden in lungs, liver, and spleen of immunized mice. Humoral immunity was critically important for vaccine-induced protection, as mice lacking B cells were not protected by immunization and serum from Bp82-vaccinated mice could transfer partial protection to nonvaccinated animals. In contrast, vaccine-induced protective immunity was found to be independent of both CD4 and CD8 T cells. Tracking studies demonstrated uptake of the Bp82 vaccine strain predominately by neutrophils in vaccine-draining lymph nodes and by smaller numbers of dendritic cells (DC) and monocytes. We concluded that protection following cutaneous immunization with a live attenuated Burkholderia vaccine strain was dependent primarily on generation of effective humoral immune responses.


Interactions between a small chronic increase in diel water temperature and exposure to a common environmental contaminant on development of Arizona tiger salamander larvae.
Global climate change leading to increased temperatures may affect shifts in physiological processes especially in ectothermic organisms. Temperature-dependent shifts in developmental rate in particular, may lead to life-long changes in adult morphology and physiology. Combined with anthropogenic changes in the chemical environment, changes in developmental outcomes may affect adult functionality. The purpose of this study is to determine 1) if small increases in diel water temperature affect the development of Arizona tiger salamander (Ambystoma tigrinum nebulosum) larvae, and 2) if this change interacts with exposure to the common environmental thyroid disrupting compound, perchlorate. Larvae between Watson and Russell developmental stages 8-13 were exposed to ammonium perchlorate (AP) at doses of 0, 20 or 200ppb and then raised at either ambient or a 0.9°C elevated above ambient temperature for 81days in outdoor enclosures. During the first 5 treatment weeks, AP treatment induced slower development and smaller snout-vent length (SVL) of exposed larvae, but only in the elevated temperature group. During the later stages of development, the small increase in temperature, regardless of AP treatment, tended to decrease the time to metamorphosis and resulted in a significantly smaller body mass and worse body condition. Our results suggest that even small diel water temperature increases can affect the developmental process of salamanders and this shift in the water temperature may interact with a common environmental contaminant.


Analyses of the 1990 chest health survey of china clay workers.
During 1990 all present and retired china clay workers in the United Kingdom were invited to take part in a chest health survey. A total of 4401 china clay workers participated representing over 70% of current employees and 17% of pensioners. The survey consisted of a chest x ray film, lung function measurements, and a questionnaire on respiratory symptoms and smoking habits. The chest x ray films were read by three readers to the International Labour Office (ILO) 1980 classification. Full details of occupational history for each participant were available and for each employee an estimate of total exposure to china clay dust was derived from representative dust concentrations for each location and job. These were based on measured dust concentrations after 1978 and on estimates before 1978. Analyses of the data were carried out to investigate the relations between exposure, x ray film category, lung function, and respiratory symptoms. The percentage of people with small opacities greater than major x ray film category 1 was 0.8% (lower than in previous studies). Dust concentrations have been reduced in recent years, averaging 1.7 mg m-3 for dryers in 1990 compared with 3.5 mg m-3 in 1978. The lower effect of exposure after 1971, compared with earlier exposure, was confirmed by the analyses. After 1971 the milling of dried china clay (Atritor mills) was found to be the occupation with the highest effect on x ray film category. The relation between total exposure to china clay dust and x ray film category is such that a typical non-smoker worker employed in the most dusty of current occupations may expect to reach the lower limit of category 1 after about 42 years continuous employment in that job at current exposures. Both forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were found (as in other studies) to decline with age, more rapidly for smokers than non-smokers at the rates for FVC of 0.035 l/y and 0.033 l/y, whereas for FEV1 the rates are 0.039 l/y for smokers and 0.034 l/y for non-smokers. Changes in x ray film category are also related to lung function , a change of one major category being equivalent to about six years of aging in its effect on FEV1.


Application of Gene Expression Trajectories Initiated from ErbB Receptor Activation Highlights the Dynamics of Divergent Promoter Usage.
Understanding how cells use complex transcriptional programs to alter their fate in response to specific stimuli is an important question in biology. For the MCF-7 human breast cancer cell line, we applied gene expression trajectory models to identify the genes involved in driving cell fate transitions. We modified trajectory models to account for the scenario where cells were exposed to different stimuli, in this case epidermal growth factor and heregulin, to arrive at different cell fates, i.e. proliferation and differentiation respectively. Using genome-wide CAGE time series data collected from the FANTOM5 consortium, we identified the sets of promoters that were involved in the transition of MCF-7 cells to their specific fates versus those with expression changes that were generic to both stimuli. Of the 1,552 promoters identified, 1,091 had stimulus-specific expression while 461 promoters had generic expression profiles over the time course surveyed. Many of these stimulus-specific promoters mapped to key regulators of the ERK (extracellular signal-regulated kinases) signaling pathway such as FHL2 (four and a half LIM domains 2). We observed that in general, generic promoters peaked in their expression early on in the time course, while stimulus-specific promoters tended to show activation of their expression at a later stage. The genes that mapped to stimulus-specific promoters were enriched for pathways that control focal adhesion, p53 signaling and MAPK signaling while generic promoters were enriched for cell death, transcription and the cell cycle. We identified 162 genes that were controlled by an alternative promoter during the time course where a subset of 37 genes had separate promoters that were classified as stimulus-specific and generic. The results of our study highlighted the degree of complexity involved in regulating a cell fate transition where multiple promoters mapping to the same gene can demonstrate quite divergent expression profiles.


Differential electrophysiological response during rest, self-referential, and non-self-referential tasks in human posteromedial cortex.
The electrophysiological basis for higher brain activity during rest and internally directed cognition within the human default mode network (DMN) remains largely unknown. Here we use intracranial recordings in the human posteromedial cortex (PMC), a core node within the DMN, during conditions of cued rest, autobiographical judgments, and arithmetic processing. We found a heterogeneous profile of PMC responses in functional, spatial, and temporal domains. Although the majority of PMC sites showed increased broad gamma band activity (30-180 Hz) during rest, some PMC sites, proximal to the retrosplenial cortex, responded selectively to autobiographical stimuli. However, no site responded to both conditions, even though they were located within the boundaries of the DMN identified with resting-state functional imaging and similarly deactivated during arithmetic processing. These findings, which provide electrophysiological evidence for heterogeneity within the core of the DMN, will have important implications for neuroimaging studies of the DMN.


Inhibition of circulating dipeptidyl peptidase 4 activity in patients with metastatic prostate cancer.
Cancer is responsible for many deaths and is a major source of healthcare expenditures. The identification of new, non-invasive biomarkers might allow improvement of the direct diagnostic or prognostic ability of already available tools. Here, we took the innovative approach of interrogating the activity of exopeptidases in the serum of cancer patients with the aim of establishing a distinction based on enzymatic function, instead of simple protein levels, as a means to biomarker discovery. We first analyzed two well-characterized mouse models of prostate cancer, each with a distinct genetic lesion, and established that broad exopeptidase and targeted aminopeptidase activity tests reveal proteolytic changes associated with tumor development. We also describe new peptide-based freeze-frame reagents uniquely suited to probe the altered balance of selected aminopeptidases, as opposed to the full array of exopeptidases, and/or their modulators in patient serum or plasma. One particular proteolytic activity was impaired in animals with aggressive disease relative to cancer-free littermates. We identified the protease in question as dipeptidyl peptidase 4 (DPP4) by analyzing selected knockout mice and evaluating the effect of specific inhibitors. DPP4 activity was also reduced in the sera of patients with metastatic prostate cancer relative to patients with localized disease or healthy controls. However, no significant differences in DPP4 serum levels were observed, which established the loss of activity as the result of impaired enzymatic function. Biochemical analysis indicated that reduced activity was the result not of post-translational modifications or allosteric changes, but instead of a low-molecular-weight inhibitor. After we adjusted for age and total prostate-specific antigen, reduced DPP4 activity remained a significant predictor of cancer status. The results of this proof-of-principle study suggest that DPP4 activity might be a potential blood-based indicator of the presence of metastatic cancer of prostatic origin, either by itself or, more likely, as a means to improve the sensitivity and specificity of existing markers.


A profile of children's physical activity data from the 2012 and 2015 health survey for England.
Low childhood physical activity levels constitute an important modifiable risk for adult non-communicable disease incidence and subsequent socio-economic burden, but few publications have explored age and sex related patterns within the UK population. The aims were to profile child physical activity data from the Health Survey for England from 2012 (1,732 respondents) and 2015 (5,346 respondents). Reported physical activity episodes were converted to metabolic equivalents with reference to child-specific compendiums. Physical activity levels were aggregated for each domain, and again to produce total physical activity estimates. Contributions from each domain to total physical activity were explored, stratifying for age, sex, socio-economic deprivation, ethnicity, and weight status. Further analyses were run stratifying for physical activity levels. Few differences were detected between the survey iterations. Boys reported higher absolute levels of physical activity at all ages and across all domains. For boys and girls, informal activity reduces with age. For boys this reduction is largely mitigated by increased formal sport, but this is not the case for girls. Absolute levels of school activity and active travel remained consistent regardless of total physical activity, thereby comprising an increasingly important proportion of total physical activity for less active children. We recommend a specific focus on establishing and maintaining girl's participation in formal sport thorough their teenage years, and a recognition and consolidation of the important role played by active travel and school-based physical activity for the least active children.


Attendance Behavior of Ex-members in Fitness Clubs: A Retrospective Study Applying the Stages of Change.
The transtheoretical model of behavior change (TTM) is often used to understand and predict health-related behavior. The objective of this study is to apply the TTM's stages of change to examine patterns of attendance behavior at fitness clubs. A retrospective study was performed to study the later stages of change, using attendance data of members who cancelled their membership in 2012 in two European fitness chains, including 259,355 ex-members of 267 clubs. A sample of 400 was selected at random for analyses, M age = 32.1 yr. (SD = 10.9; 64% males) and 34.7 yr. (SD = 11.0; 51% males) for BasicFit and HealthCity. Regular attendance behavior was defined by at least four visits per month. In the past, all ex-members had purchased a membership and by that were considered to have entered the preparation stage, but 19.5% had never attended the club in 24 months. Of the ex-members, 10% demonstrated regular attendance behavior for six months, and 2.3% had regular attendance for 24 months. 49% did not attend the club for one full month but started regular attendance again. Significant positive correlations were found in attendance behavior between the 6th and 12th months (r = .61), and the 12th and 24th months (r = .45), suggesting that ex-members who attended for more than six months were more likely to have maintained their attendance behavior. With only 10% of the members demonstrating regular attendance behavior, it is evident that appropriate strategies have to be developed to improve attendance behavior and facilitate exercise behavior in fitness clubs.


Immunization with a hemagglutinin-derived synthetic peptide formulated with a CpG-DNA-liposome complex induced protection against lethal influenza virus infection in mice.
Whole-virus vaccines, including inactivated or live-attenuated influenza vaccines, have been conventionally developed and supported as a prophylaxis. These currently available virus-based influenza vaccines are widely used in the clinic, but the vaccine production takes a long time and a huge number of embryonated chicken eggs. To overcome the imperfection of egg-based influenza vaccines, epitope-based peptide vaccines have been studied as an alternative approach. Here, we formulated an efficacious peptide vaccine without carriers using phosphodiester CpG-DNA and a special liposome complex. Potential epitope peptides predicted from the hemagglutinin (HA) protein of the H5N1 A/Viet Nam/1203/2004 strain (NCBI database, AAW80717) were used to immunize mice along with phosphodiester CpG-DNA co-encapsulated in a phosphatidyl-β-oleoyl-γ-palmitoyl ethanolamine (DOPE):cholesterol hemisuccinate (CHEMS) complex (Lipoplex(O)) without carriers. We identified a B cell epitope peptide (hH5N1 HA233 epitope, 14 amino acids) that can potently induce epitope-specific antibodies. Furthermore, immunization with a complex of the B cell epitope and Lipoplex(O) completely protects mice challenged with a lethal dose of recombinant H5N1 virus. These results suggest that our improved peptide vaccine technology can be promptly applied to vaccine development against pandemic influenza. Furthermore our results suggest that potent epitopes, which cannot be easily found using proteins or a virus as an antigen, can be screened when we use a complex of peptide epitopes and Lipoplex(O).


Size-dependent nucleation kinetics at nonplanar nanowire growth interfaces.
In nanowire growth, kinetic processes at the growth interface can play an important role in governing wire compositions, morphologies, and growth rates. Molecular-dynamics simulations have been undertaken to probe such processes in a system featuring a solid-liquid interface shape characterized by a facet bounded by rough orientations. Simulated growth rates display a dependence on nanowire diameter consistent with a size-dependent barrier for facet nucleation. A theory for the interface mobility is developed, establishing a source for size-dependent growth rates that is an intrinsic feature of systems possessing growth interfaces with faceted and rough orientations.


Murine leukemia virus p12 tethers the capsid-containing pre-integration complex to chromatin by binding directly to host nucleosomes in mitosis.
The murine leukaemia virus (MLV) Gag cleavage product, p12, is essential for both early and late steps in viral replication. The N-terminal domain of p12 binds directly to capsid (CA) and stabilises the mature viral core, whereas defects in the C-terminal domain (CTD) of p12 can be rescued by addition of heterologous chromatin binding sequences (CBSs). We and others hypothesised that p12 tethers the pre-integration complex (PIC) to host chromatin ready for integration. Using confocal microscopy, we have observed for the first time that CA localises to mitotic chromatin in infected cells in a p12-dependent manner. GST-tagged p12 alone, however, did not localise to chromatin and mass-spectrometry analysis of its interactions identified only proteins known to bind the p12 region of Gag. Surprisingly, the ability to interact with chromatin was conferred by a single amino acid change, M63I, in the p12 CTD. Interestingly, GST-p12_M63I showed increased phosphorylation in mitosis relative to interphase, which correlated with an increased interaction with mitotic chromatin. Mass-spectrometry analysis of GST-p12_M63I revealed nucleosomal histones as primary interactants. Direct binding of MLV p12_M63I peptides to histones was confirmed by biolayer-interferometry (BLI) assays using highly-avid recombinant poly-nucleosomal arrays. Excitingly, using this method, we also observed binding between MLV p12_WT and nucleosomes. Nucleosome binding was additionally detected with p12 orthologs from feline and gibbon ape leukemia viruses using both pull-down and BLI assays, indicating that this a common feature of gammaretroviral p12 proteins. Importantly, p12 peptides were able to block the binding of the prototypic foamy virus CBS to nucleosomes and vice versa, implying that their docking sites overlap and suggesting a conserved mode of chromatin tethering for different retroviral genera. We propose that p12 is acting in a similar capacity to CPSF6 in HIV-1 infection by facilitating initial chromatin targeting of CA-containing PICs prior to integration.


Continuous flow synthesis of a carbon-based molecular cage macrocycle via a three-fold homocoupling reaction.
The facile synthesis of the cage molecule (C110H56Br2) via a remarkable three-fold homo-coupling macrocyclization reaction using continuous flow methodology is reported. Synthesis via continuous flow chemistry improves the residence time, safety, and environmental profile of this synthetically challenging reaction. Further, the new cage possesses halogen atoms at its apex that serve to expand the potential reaction space of these intrinsically porous, all carbon-carbon bonded molecular cage molecules.


An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage.
Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.


Plus ça change, plus c'est la meme chose: to the internal market and back in the British National Health Service?
Continuities and changes in policy concerning the organisational structure of the British National Health Service are evident throughout the last decade. This paper presents lessons learned from the internal market experience and discusses the extent to which New Labour policies have taken these into account. The role of decentralised contracts and central government direction in each system is explored. The internal market was less decentralised than expected, and direction from central government continued to be a key element. In the post internal market system, less faith has been placed in the capacity of contracts to improve quality of care, and centralised direction to set and enforce standards has increased. But simultaneously the mechanism of contracting has been retained and it is likely to be extended in increased dealings with the private sector. Efforts are also being made to curtail the high degree of centralisation in the early post internal market years.


Evidence for inhibition mediated by coassembly of GABAA and GABAC receptor subunits in native central neurons.
Fast inhibition in the nervous system is commonly mediated by GABA(A) receptors comprised of 2alpha/2beta/1gamma subunits. In contrast, GABA(C) receptors containing only rho subunits (rho1-rho3) have been predominantly detected in the retina. However, here using reverse transcription-PCR and in situ hybridization we show that mRNA encoding the rho1 subunit is highly expressed in brainstem neurons. Immunohistochemistry localized the rho1 subunit to neurons at light and electron microscopic levels, where it was detected at synaptic junctions. Application of the GABA(C) receptor agonist cis-4-aminocrotonic acid (100-800 microM) requires the rho1 subunit to elicit responses, which surprisingly are blocked independently by antagonists to GABA(A) (bicuculline, 10 microM) and GABA(C) [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA); 40-160 microM] receptors. Responses to GABA(C) agonists were also enhanced by the GABA(A) receptor modulator pentobarbitone (300 microM). Spontaneous and evoked IPSPs were reduced in amplitude but never abolished by TPMPA, but were completely blocked by bicuculline. We therefore tested the hypothesis that GABA(A) and GABA(C) subunits formed a heteromeric receptor. Immunohistochemistry indicated that rho1 and alpha1 subunits were colocalized at light and electron microscopic levels. Electrophysiology revealed that responses to GABA(C) receptor agonists were enhanced by the GABA(A) receptor modulator zolpidem (500 nm), which acts on the alpha1 subunit when the gamma2 subunit is also present. Finally, coimmunoprecipitation indicated that the rho1 subunit formed complexes that also containedalpha1 and gamma2 subunits. Taken together these separate lines of evidence suggest that the effects of GABA in central neurons can be mediated by heteromeric complexes of GABA(A) and GABA(C) receptor subunits.


Prediction of heterodimeric protein complexes from weighted protein-protein interaction networks using novel features and kernel functions.
Since many proteins express their functional activity by interacting with other proteins and forming protein complexes, it is very useful to identify sets of proteins that form complexes. For that purpose, many prediction methods for protein complexes from protein-protein interactions have been developed such as MCL, MCODE, RNSC, PCP, RRW, and NWE. These methods have dealt with only complexes with size of more than three because the methods often are based on some density of subgraphs. However, heterodimeric protein complexes that consist of two distinct proteins occupy a large part according to several comprehensive databases of known complexes. In this paper, we propose several feature space mappings from protein-protein interaction data, in which each interaction is weighted based on reliability. Furthermore, we make use of prior knowledge on protein domains to develop feature space mappings, domain composition kernel and its combination kernel with our proposed features. We perform ten-fold cross-validation computational experiments. These results suggest that our proposed kernel considerably outperforms the naive Bayes-based method, which is the best existing method for predicting heterodimeric protein complexes.


Treating chronic spontaneous urticaria using a brief 'whole person' treatment approach: a proof-of-concept study.
Chronic spontaneous urticaria (CSU) poses problems with respect to high prevalence, reduced quality of life, lack of long term efficacy, and expense of current treatments for severe intractable symptoms. There have been many reports suggesting 'stress' factors may be implicated, but there are no studies that explore the efficacy of treatments including a psychological perspective. A whole person treatment approach (WPTA), which addresses psychological factors has been used, with effect, for 6 years in the Auckland City Hospital Immunology Department. In a pilot study to demonstrate feasibility of recruitment and treatment of CSU patients in a time-limited, whole person treatment approach, within a conventional immunology department, four patients (three CSU and one idiopathic angioedema) were recruited into a brief WPTA course based in non-dualistic concepts of mind and body connectedness, and utilising psychotherapy-derived listening skills for up to 10 h long sessions, once per week. Treatment efficacy rating, using Urticaria Activity Score and the Urticaria Severity Score, and reduction of drug usage, showed patients experienced long term resolution of urticaria and cessation of hospitalisation for angioedema and came off regular antihistamine medication. A clinician treating chronic spontaneous urticaria in an Immunology department, using a whole person treatment paradigm, can safely explore unique meanings and emotional states, in a process acceptable to patients, resulting in a significant clinical benefit for symptoms. A much larger study comparing the outcome of WPTA versus standard treatment alone is warranted.


Antioxidant and pro-oxidant activities of aqueous extracts and crude polyphenolic fractions of rooibos (Aspalathus linearis).
Unfermented rooibos tea is known to contain higher levels of total polyphenols and flavonoids than its fermented counterpart, making it the obvious choice for the preparation of flavonoid-enriched fractions. Evaluation of aqueous extracts and crude polyphenolic fractions of unfermented and fermented rooibos showed anti- and/or pro-oxidant activities, using a linoleic acid-Tween-buffer emulsion for lipid peroxidation and the deoxyribose degradation assay, based on a Fenton reaction model system containing FeCl3-EDTA and H2O2 for the generation of hydroxyl radicals. Except for the ethyl acetate fraction, with the highest total polyphenol (TP) content and offering the least protection presumably due to pro-oxidant activity, the inhibition of lipid peroxidation by the samples correlated moderately with their TP content in a linear relationship (r = 0.896, P < 0.01). Using the deoxyribose degradation assay, the pro-oxidant activity of the aqueous extracts and their crude polymeric fractions (0.1 mg/mL in the reaction mixture) was linear with respect to their dihydrochalcone (aspalathin and nothofagin) (r = 0.977, P = 0.023) and flavonoid (r = 0.971, P = 0.029) content. Pro-oxidant activity was demonstrated for pure aspalathin. Using the same assay, but with ascorbate added to regenerate Fe3+ to Fe2+, the aqueous extract and crude polymeric fraction of fermented rooibos displayed hydroxyl radical scavenging activity. Fermentation (i.e., oxidation) of rooibos decreased the pro-oxidant activity of aqueous extracts, which was contributed to a decrease in their dihydrochalcone content. The in vitro pro-oxidant activity displayed by flavonoid-enriched fractions of rooibos demonstrates that one must be aware of the potential adverse biological properties of potent antioxidant extracts utilized as dietary supplements.


Switching between the forest and the trees: brain systems involved in local/global changed-level judgments.
Visual targets can be coded, in relative terms, at either the local or the global level of stimuli. Previous studies have indicated that targets are identified more slowly when they appear at a new hierarchical level, compared to when they reappear at the same level as in the previous trial. In the present study, we used measures of reaction time and event-related fMRI to investigate factors affecting this switch cost. In particular, we examined the effects of the number of repeated-level trials preceding a switch and whether the cue to switch was either externally or internally mediated. At the behavioral level we found that (1) the time taken to identify a target on a changed-level trial is longer following four repeated-level trials compared to two repeated-level trials, but that runs of six do not produce additional costs over four, and (2) targets can be identified faster following externally cued switches compared to internally mediated switches. We then show that these behavioral effects are associated with distinct patterns of neural activation. Switches performed after two repeated-level trials preferentially activated the precuneus, while those performed after both four and six activated bilateral inferior parietal cortex and motor hand area. Relative to external switches, internal switches activated the putamen, while both kinds of switch conjointly activated the large-scale network proposed to underlie internal/external switches in nonhierarchical tasks. Our data further clarify the mechanisms mediating hierarchical selection.


Chronic replicative stress induced by CCl4 in TRF1 knockout mice recapitulates the origin of large liver cell changes.
Large liver cell changes (LLCC) are characterized by pleomorphic large nuclei frequently found in liver diseases as chronic viral hepatitis and liver cirrhosis. The origin of this lesion remains cryptic, but the presence of LLCC is correlated with an increased risk of hepatocellular carcinoma. Telomeric repeat binding factor 1 (TRF1) is part of the shelterin complex and is essential for telomere protection. Ablation of TRF1 induces telomere fragility and fusions and chromosomal instability. In this study, we addressed the role of TRF1 in liver regeneration generating a mouse model with conditional deletion of TRF1 in the liver. TRF1 deletion has no deleterious effects in liver and leads to increased ploidy of hepatocytes after 2/3 hepatectomy. Mice lacking TRF1 in the liver can survive for over one year without any evidence for altered liver function. Importantly, applying chronic replicative stress by frequent carbon tetrachloride (CCl4) injections, TRF1 deleted mice undergo ploidy changes consistent with endoreduplication and develop LLCC like lesions in the liver positive for p21, Cyclin D1 and PCNA as observed in humans. In summary, we provide mechanistic insight into the role of TRF1 in liver regeneration and provide a mouse model recapitulating the clinical features of LLCC.


Amino acid-linked platinum(II) analogues have altered specificity for RNA compared to cisplatin.
Cisplatin can be modified with various ligands to alter the size and charge distribution of the complex. Several amino acid-linked platinum(II) complexes were synthesized, and a reactivity study with 16S ribosomal RNA was carried out. The amino acid-linked analogues show altered specificity compared to the parental compound cisplatin.


Amplitude and phase analysis in digital dynamic holography.
Lensless in-line digital holographic interferometry has the potential for vibration analysis of objects smaller than 5 mm in diameter. This is particularly useful for dynamic characterization of microelectromechanical systems devices. To achieve this, there is a need to magnify the object wave, which is done using a diverging beam. It is observed that an increase in the object-to-CCD distance increases the sensitivity of the amplitude-modulated time-average fringes. At the same time the effect on phase information that represents the mean static deformation of a vibrating object is studied. It is also observed that a reduction in the object-to-CCD distance increases the phase sensitivity as evidenced by the double-exposure time-average fringes. The experimental observation and a theoretical explanation for this contradictory phenomenon are presented.


Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic.
Recent experiments provide sound arguments in favor of the in vivo expression of the AntiSense Protein (ASP) of HIV-1. This putative protein is encoded on the antisense strand of the provirus genome and entirely overlapped by the env gene with reading frame -2. The existence of ASP was suggested in 1988, but is still controversial, and its function has yet to be determined. We used a large dataset of ∼23,000 HIV-1 and SIV sequences to study the origin, evolution, and conservation of the asp gene. We found that the ASP ORF is specific to group M of HIV-1, which is responsible for the human pandemic. Moreover, the correlation between the presence of asp and the prevalence of HIV-1 groups and M subtypes appeared to be statistically significant. We then looked for evidence of selection pressure acting on asp Using computer simulations, we showed that the conservation of the ASP ORF in the group M could not be due to chance. Standard methods were ineffective in disentangling the two selection pressures imposed by both the Env and ASP proteins-an expected outcome with overlaps in frame -2. We thus developed a method based on careful evolutionary analysis of the presence/absence of stop codons, revealing that ASP does impose significant selection pressure. All of these results support the idea that asp is the 10th gene of HIV-1 group M and indicate a correlation with the spread of the pandemic.


Value-Based Approaches for Emergency Care in a New Era.
Although emergency departments (EDs) play an integral role in the delivery of acute unscheduled care, they have not been fully integrated into broader health care reform efforts. Communication and coordination with the ambulatory environment remain limited, leaving ED care disconnected from patients' longitudinal care. In a value-based environment focused on improving quality, decreasing costs, enhancing population health, and improving the patient experience, this oversight represents a missed opportunity for emergency care. When integrated with primary and subspecialty care, emergency care might meet the needs of patients, providers, and payers more efficiently than yet realized. This article uses the Merit-Based Incentive Payment System from the Medicare Access and CHIP Reauthorization Act as a framework to outline a strategy for improving the value of emergency care, including integrating quality and resource use measures across health care delivery settings and populations, encouraging care coordination from the ED, and implementing robust health information exchange systems.


A serological survey of antibodies to H5, H7 and H9 avian influenza viruses amongst the duck-related workers in Beijing, China.
The continued spread of highly pathogenic avian influenza (HPAI) viruses of H5 and H7 subtypes and low pathogenic avian influenza (LPAI) viruses of H5, H7 and H9 subtypes in birds and the subsequent infections in humans pose an ongoing pandemic threat. It has been proposed that poultry workers are at higher risk of exposure to HPAI or LPAI viruses and subsequently infection due to their repeated exposure to chickens or domestic waterfowl. The aim of this study was to examine the seroprevalence of antibodies against H5, H7 and H9 viruses amongst duck-related workers in Beijing, China and the risk factors associated with seropositivity. In March, 2011, 1741 participants were recruited from (1) commercial duck-breeding farms; (2) private duck-breeding farms; and (3) duck-slaughtering farms. Local villagers who bred ducks in their backyards were also recruited. A survey was administered by face-to-face interview, and blood samples were collected from subjects for antibody testing against H5, H7 and H9 viruses. We found that none of the subjects were seropositive for either H5 or H7 viruses, and only 0.7% (12/1741) had antibody against H9. A statistically significant difference in H9 antibody seroprevalence existed between the various categories of workers (P = 0.005), with the highest figures recorded amongst the villagers (1.7%). Independent risk factors associated with seropositivity toinfection with H9 virus included less frequent disinfection of worksite (OR, 5.13 [95% CI, 1.07-24.58]; P = 0.041; ≤ twice monthly versus>twice monthly) and handling ducks with wounds on hands (OR, 4.13 [95% CI, 1.26-13.57]; P = 0.019). Whilst the risk of infection with H5, H7 and H9 viruses appears to be low among duck-related workers in Beijing, China, ongoing monitoring of infection with the H9 virus is still warranted, especially amongst villagers who breed backyard ducks to monitor for any changes.


NA cohort study of thyroid cancer and other thyroid diseases after the Chernobyl accident: cytohistopathologic correlation and accuracy of fine-needle aspiration biopsy in nodules detected during the first screening in Ukraine (1998-2000).
The Ukrainian American Cohort Study was established to evaluate the risk of thyroid disorders in a group exposed as children and adolescents to 131I by the Chernobyl accident (arithmetic mean thyroid dose, 0.79 grays). Individuals are screened by palpation and ultrasound and are referred to surgery according to fine-needle aspiration biopsy (FNA). However, the accuracy of FNA cytology for detecting histopathologically confirmed malignancy after this level of internal exposure to radioiodines is unknown. During the first screening cycle (1998-2000), 13,243 individuals were examined, 356 individuals with thyroid nodules were referred for FNA, 288 individuals completed the procedure, 85 individuals were referred to surgery, 82 individuals underwent surgery, and preoperative cytology was available for review in 78 individuals. Cytologic interpretation for the nodule that resulted in surgical referral was correlated with final pathomorphology; discrepancies were reviewed retrospectively; and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FNA cytology were calculated. All 24 cytologic interpretations that were definite for papillary thyroid cancer (PTC) were confirmed histopathologically (PPV, 100%); and, of 11 cytologic interpretations that were suspicious for PTC, 10 were confirmed (PPV, 90.9%). Ten of 41 FNAs that were interpreted as either definite or suspect for follicular neoplasm were confirmed as malignant (PPV, 24.4%), including 2 follicular thyroid cancers and 8 PTCs (all but 1 of the follicular or mixed subtypes). Depending on whether a cytologic interpretation of follicular neoplasm was considered "positive" or "negative," the sensitivity was 100% and 77.3%, respectively; similarly, the respective specificity was 17.6% and 97.1%, the respective PPV was 61.1% and 97.1%, and the respective NPV was 100% and 76.7%. Among children and adolescents who were exposed to 131I after the Chernobyl accident and were evaluated 12 to 14 years later, thyroid cytology had a sensitivity and a predictive value similar to those reported in unexposed populations.


Smart capsule for non-invasive sampling and studying of the gastrointestinal microbiome.
Gut microbiota plays an important role in host physiology such as obesity, diabetes, and various neurological diseases. Thus, microbiome sampling is a fundamental approach towards better understanding of possible diseases. However, conventional sampling methods, such as endoscopies or colonoscopies, are invasive and cannot reach the entire small intestine. To address this need, a battery-less 3D-printed sampling capsule, which can collect microbiome samples throughout the entirety of the GI tract was designed. The capsule (9 mm × 15 mm) consists of a 3D printed acrylic housing, a fast-absorbing hydrogel, and a flexible PDMS membrane. Fluids containing samples of the microbial flora within the GI tract enter the device through a sampling aperture on the cap of the device. Once the microbiome enters the housing, the hydrogel absorbs the fluid and swells, effectively protecting the samples within its polymeric matrix, while also pushing on the flexible PDMS membrane to block the sampling aperture from further fluid exchange. The retrieved capsule can be readily disassembled due to the screw-cap design of the capsule and the hydrogel can be removed for further bacterial culture and analysis. As a proof of concept, the capsule's bacterial sampling efficiency and the ability to host microbial samples within the hydrogel in a sealed capsule were validated using a liquid culture containing Escherichia coli. The demonstrated technology provides a promising inexpensive tool for direct sampling and assessment of microbes throughout the GI tract and can enable new insights into the role of diet in mediating host-microbe interactions and metabolism.


Exploration versus exploitation in space, mind, and society.
Search is a ubiquitous property of life. Although diverse domains have worked on search problems largely in isolation, recent trends across disciplines indicate that the formal properties of these problems share similar structures and, often, similar solutions. Moreover, internal search (e.g., memory search) shows similar characteristics to external search (e.g., spatial foraging), including shared neural mechanisms consistent with a common evolutionary origin across species. Search problems and their solutions also scale from individuals to societies, underlying and constraining problem solving, memory, information search, and scientific and cultural innovation. In summary, search represents a core feature of cognition, with a vast influence on its evolution and processes across contexts and requiring input from multiple domains to understand its implications and scope.


Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance.
To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS). Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method. A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation. Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene.


Predictive validity of categorically and dimensionally scored measures of disruptive childhood behaviors.
To examine the predictive validity of categorical and dimensional methods of representing variation in disruptive childhood behaviors. A birth cohort comprising 935 New Zealand children was assessed at age 15 years on measures based on DSM-III-R diagnostic criteria for oppositional defiant disorder, conduct disorder, and attention-deficit hyperactivity disorder. These symptom measures were scored in two ways: (1) as cases or noncases using DSM-III-R diagnostic criteria and (2) as dimensional variables in which the severity of disturbance ranged from none to severe. At age 16 years the cohort was reassessed on a series of measures including substance use behaviors, juvenile offending, and school dropout. The analysis compared the efficacy of the categorically and dimensionally scored measures at age 15 years as predictors of outcomes observed at age 16 years. This comparison showed evidence of continuous and generally linear dose-response functions between symptom severity and outcome risks and that dimensionally scored variables were considerably better predictors of outcome than measures based on a diagnostic classification. These findings support the view that disruptive behavior problems have dimensional properties in which the severity of disturbance ranges from none to severe. While DSM-III-R diagnostic criteria may have considerable value and utility as a means of diagnosing in young people behavior disturbances that merit clinical attention, the routine use of these criteria as a means of describing behavioral variability may result in a system of measurement that produces variables that have less than optimal predictive validity.


Measurements of extrinsic fluorescence in Intralipid and polystyrene microspheres.
The fluorescence of Intralipid and polystyrene microspheres with sphere diameter of 1 µm at a representative lipid and microsphere concentration for simulation of mucosal tissue scattering has not been a subject of extensive experimental study. In order to elucidate the quantitative relationship between lipid and microsphere concentration and the respective fluorescent intensity, the extrinsic fluorescence spectra between 360 nm and 650 nm (step size of 5 nm) were measured at different lipid concentrations (from 0.25% to 5%) and different microsphere concentrations (0.00364, 0.0073, 0.0131 spheres per cubic micrometer) using laser excitation at 355 nm with pulse energy of 2.8 µJ. Current findings indicated that Intralipid has a broadband emission between 360 and 650 nm with a primary peak at 500 nm and a secondary peak at 450 nm while polystyrene microspheres have a single peak at 500 nm. In addition, for similar scattering properties the fluorescence of Intralipid solutions is approximately three-fold stronger than that of the microsphere solutions. Furthermore, Intralipid phantoms with lipid concentrations ~2% (simulating the bottom layer of mucosa) produce up to seven times stronger fluorescent emission than phantoms with lipid concentration ~0.25% (simulating the top layer of mucosa). The fluoresence decays of Intralipid and microsphere solutions were also recorded for estimation of fluorescence lifetime.


Processes toward the end of life and dialysis withdrawal Physicians' and nurses' perspectives.
Nurses and physicians in nephrology settings provide care for patients with end-stage kidney disease receiving hemodialysis treatment along a complex illness trajectory. The aim was to explore physicians' and nurses' perspectives on the trajectories toward the end of life involving decisions regarding hemodialysis withdrawal for patients with end-stage kidney disease. A qualitative research approach was used. Four mixed focus group interviews were conducted with renal physicians (5) and nurses (17) in Sweden. Qualitative content analysis was used to analyse data. Ethical approval was obtained (Dnr 2014/304-31). Findings illuminated multi-faceted, intertwined processes encompassing healthcare professionals, patients, and family members. The analysis resulted in four themes: Complexities of initiating end-of-life conversations, Genuine attentiveness to the patient's decision-making process, The challenge awaiting the family members' processes, and Negotiating different professional responsibilities. Findings showed complexities and challenges when striving to provide good, ethical care which are related to beneficence, nonmaleficence, and self-determination, and which can give rise to moral distress. There are ethical challenges and strains in the dialysis context that healthcare professionals may not always be prepared for. Supporting healthcare professionals in not allowing complexities to hinder the patient's possibilities for shared decision-making seems important. An open and continual communication, including family meetings, from dialysis initiation could serve to make conversations involving decisions about hemodialysis withdrawal a more natural routine, as well as build up a relationship of trust necessary for the advance care planning about the end of life. Healthcare professionals should also receive support in ethical reasoning to meet these challenges and handle potential moral distress in the dialysis context.


Willingness to use and have sex with men taking HIV pre-exposure prophylaxis (PrEP): results of online surveys of Australian gay and bisexual men, 2011-2015.
Assess willingness to use HIV pre-exposure prophylaxis (PrEP), support for others using it and willingness to have sex with partners using PrEP among Australian gay and bisexual men (GBM). National, online cross-sectional surveys of Australian GBM were conducted in 2011, 2013 and 2015. Scales measuring support for and willingness to have sex with men using PrEP were developed in 2015 using factor analysis. Trends and associations with key measures were analysed using multivariate logistic regression. During 2011-2015, 3850 surveys were completed by GBM. Willingness to use PrEP among HIV-negative and untested men did not change between 2011 (28.2%) and 2015 (31.7%, p=0.13). In 2015, willingness to use PrEP was independently associated with younger age, having an HIV-positive regular partner, recent condomless anal intercourse with casual male partners (CAIC), more than 10 male sex partners in the previous 6 months, ever having taken postexposure prophylaxis and having fewer concerns about using PrEP. In 2015, 54.5% of GBM supported other GBM taking PrEP and 39% were willing to have sex with men using PrEP. Support for and willingness to have sex with PrEP users were both associated with being HIV-positive, having a university degree and having two or more male partners in the previous 6 months. Willingness to have sex with men on PrEP was also associated with recent CAIC and using party drugs for sex, but was less likely among men who consistently used or had a positive experience using condoms. Interest in and support for using PrEP are concentrated among men who engage in higher risk practices and who know more about living with HIV. This is consistent with the targeting of PrEP in Australia.


Competencies, Milestones, and a Level of Supervision Scale for Entrustable Professional Activities for Scholarship.
Scholarship is an important element of both undergraduate and graduate medical education, and scholarly activity is required for all pediatric fellows. However, despite the creation of entrustable professional activities (EPAs) for scholarship, the specific progressive levels of performance and the appropriate level of supervision for a given performance level have not been defined. The authors developed competencies and milestones for the scholarship EPA to provide a framework for assessment across the continuum; a level of supervision scale was also developed. The Vitae Researcher Development Framework served as a template to create the competencies and milestones for the scholarship EPA. Beginning in September 2015 and using a modified Delphi approach, three drafts were circulated to individuals with expertise in various types of scholarship until broad agreement was achieved. Then, in October 2016, the Steering Committee of the Subspecialty Pediatrics Investigator Network created a level of supervision scale, modeled after one it had previously developed. Eight competencies were identified as important in making entrustment decisions related to scholarship. For each competency, five milestone levels that span the continuum from novice to expert were created. A supervision scale with five progressive levels of entrustment was also created. Next steps include a study to obtain validity evidence for the supervision scale and determine the correlation between milestone and supervision levels. These competencies, milestones, and supervision levels can potentially serve as a road map for trainees and junior faculty and also play a role in the assessment of physician-scientists.


Effects of sodium polyacrylate on water retention and infiltration capacity of a sandy soil.
Based on the laboratory study, the effects of sodium polyacrylate (SP) was investigated at 5 rates of 0, 0.08, 0.2, 0.5, and 1%, on water retention, saturated hydraulic conductivity(Ks), infiltration characteristic and water distribution profiles of a sandy soil. The results showed that water retention and available water capacity effectively increased with increasing SP rate. The Ks and the rate of wetting front advance and infiltration under certain pond infiltration was significantly reduced by increasing SP rate, which effectively reduced water in a sandy soil leaking to a deeper layer under the plough layer. The effect of SP on water distribution was obviously to the up layer and very little to the following deeper layers. Considering both the effects on water retention and infiltration capacity, it is suggested that SP be used to the sandy soil at concentrations ranging from 0.2 to 0.5%.


Association of Blood Pressure With Cause-Specific Mortality in Mexican Adults.
Elevated blood pressure is a major cause of premature death, but there is little direct evidence demonstrating this association in studies of Hispanic populations. To assess the association between blood pressure and cause-specific mortality in a large cohort of Mexican adults with a high prevalence of uncontrolled diabetes. A total of 159 755 adults aged 35 years or older from 2 districts in Mexico City were recruited to this cohort study between April 1998 and September 2004 and followed up until January 2018. The present analyses focused on 133 613 participants who were aged 35 to 74 years and had no history of chronic disease besides diabetes. Blood pressure. Cox regression, adjusted for confounders, yielded mortality rate ratios (RRs) for deaths of participants occurring between ages 35 and 74 years. Of the 133 613 participants (43 263 [32.4%] men; mean [SD] age, 50 [11] years), 16 911 (12.7%) had self-reported previously diagnosed diabetes (including 8435 [6.3%] with uncontrolled diabetes, defined as hemoglobin A1c ≥9%) and 6548 (4.9%) had undiagnosed diabetes. Systolic blood pressure (SBP) was associated with vascular mortality between ages 35 to 74 years, with each 20 mm Hg lower usual SBP associated with 35% lower vascular mortality (RR, 0.65; 95% CI, 0.61-0.68), including 48% lower stroke mortality (RR, 0.52; 95% CI, 0.47-0.59) and 32% lower ischemic heart disease mortality (RR, 0.68; 95% CI, 0.63-0.74). These RRs were broadly similar in those with and without diabetes. Compared with those without diabetes and SBP less than 135 mm Hg at recruitment, the vascular mortality RR was 2.8 (95% CI, 2.4-3.3) for those without diabetes and SBP of 155 mm Hg or greater, 4.7 (95% CI, 4.1-5.4) for those with uncontrolled diabetes and SBP less than 135 mm Hg, and 8.9 (95% CI, 7.2-11.1) for those with uncontrolled diabetes and SBP of 155 mm Hg or greater. Lower SBP was also associated with decreased kidney-related mortality (RR per 20 mm Hg lower usual SBP, 0.69; 95% CI, 0.64-0.74), decreased mortality from infection (RR, 0.81; 95% CI, 0.71-0.91), and decreased mortality from hepatobiliary disease (RR, 0.87; 95% CI, 0.78-0.98), but not decreased neoplastic or respiratory mortality. SBP was more informative for vascular mortality than other blood pressure measures (eg, compared with SBP, diastolic blood pressure was only two-thirds as informative). Blood pressure was most strongly associated with vascular and kidney-related mortality in this Mexican population, with particularly high absolute excess mortality rates among individuals with diabetes. The findings reinforce the need for more widespread use of blood pressure-lowering medication in Mexico, particularly among those with diabetes.


Non-equivalent loci and mutation-selection balance.
We consider the implications of mutationally non-equivalent loci for large populations of randomly mating diploid organisms under mutation-selection balance. Variation, across loci, of parameters such as the allelic mutational variance and the mutation rate, is shown to reduce the equilibrium genetic variance. This is proved to follow from the genetic variance contributed by a single locus having an underlying convexity. We give approximate results indicating the way small deviations of the mutational parameters, from their mean values, reduce the genetic variance. Numerical estimates of the size of the effect are given for more general variations of the parameters. Variation in the mutation rates has a significantly smaller effect than variation in the mutational variances. Under accepted parameter values, the reduction in genetic variance can be substantial.


Two emerging concepts for elite athletes: the short-term effects of testosterone and cortisol on the neuromuscular system and the dose-response training role of these endogenous hormones.
The aim of this review is to highlight two emerging concepts for the elite athlete using the resistance-training model: (i) the short-term effects of testosterone (T) and cortisol (C) on the neuromuscular system; and (ii) the dose-response training role of these endogenous hormones. Exogenous evidence confirms that T and C can regulate long-term changes in muscle growth and performance, especially with resistance training. This evidence also confirms that changes in T or C concentrations can moderate or support neuromuscular performance through various short-term mechanisms (e.g. second messengers, lipid/protein pathways, neuronal activity, behaviour, cognition, motor-system function, muscle properties and energy metabolism). The possibility of dual T and C effects on the neuromuscular system offers a new paradigm for understanding resistance-training performance and adaptations. Endogenous evidence supports the short-term T and C effects on human performance. Several factors (e.g. workout design, nutrition, genetics, training status and type) can acutely modify T and/or C concentrations and thereby potentially influence resistance-training performance and the adaptive outcomes. This novel short-term pathway appears to be more prominent in athletes (vs non-athletes), possibly due to the training of the neuromuscular and endocrine systems. However, the exact contribution of these endogenous hormones to the training process is still unclear. Research also confirms a dose-response training role for basal changes in endogenous T and C, again, especially for elite athletes. Although full proof within the physiological range is lacking, this athlete model reconciles a proposed permissive role for endogenous hormones in untrained individuals. It is also clear that the steroid receptors (cell bound) mediate target tissue effects by adapting to exercise and training, but the response patterns of the membrane-bound receptors remain highly speculative. This information provides a new perspective for examining, interpreting and utilizing T and C within the elite sporting environment. For example, individual hormonal data may be used to better prescribe resistance exercise and training programmes or to assess the trainability of elite athletes. Possible strategies for acutely modifying the hormonal milieu and, thereafter, the performance/training outcomes were also identified (see above). The limitations and challenges associated with the analysis and interpretation of hormonal research in sport (e.g. procedural issues, analytical methods, research design) were another discussion point. Finally, this review highlights the need for more experimental research on humans, in particular athletes, to specifically address the concept of dual steroid effects on the neuromuscular system.


Lingual Treatment of an Adult Patient with a Simplified Extraction Protocol.
Successful orthodontic treatment of adult cases depends on the biological, mechanical, and esthetic requirements of patients. While customized lingual appliance systems meet the esthetic expectations of the patients, they provide improved patient comfort, have three-dimensional mechanical control, and can be used for the treatment of all types of malocclusions. This report demonstrated the use of fully customized lingual orthodontic brackets for treating an adult case with extraction.


Pathophysiology of Takotsubo Syndrome.
Originally described by Japanese authors in the 1990s, Takotsubo syndrome (TTS) generally presents as an acute myocardial infarction characterized by severe left ventricular dysfunction. TTS, however, differs from an acute coronary syndrome because patients have generally a normal coronary angiogram and left ventricular dysfunction, which extends beyond the territory subtended by a single coronary artery and recovers within days or weeks. The prognosis was initially thought to be benign, but subsequent studies have demonstrated that both short-term mortality and long-term mortality are higher than previously recognized. Indeed, mortality reported during the acute phase in hospitalized patients is ≈4% to 5%, a figure comparable to that of ST-segment-elevation myocardial infarction in the era of primary percutaneous coronary interventions. Despite extensive research, the cause and pathogenesis of TTS remain incompletely understood. The aim of the present review is to discuss the pathophysiology of TTS with particular emphasis on the role of the central and autonomic nervous systems. Different emotional or psychological stressors have been identified to precede the onset of TTS. The anatomic structures that mediate the stress response are found in both the central and autonomic nervous systems. Acute stressors induce brain activation, increasing bioavailability of cortisol and catecholamine. Both circulating epinephrine and norepinephrine released from adrenal medullary chromaffin cells and norepinephrine released locally from sympathetic nerve terminals are significantly increased in the acute phase of TTS. This catecholamine surge leads, through multiple mechanisms, that is, direct catecholamine toxicity, adrenoceptor-mediated damage, epicardial and microvascular coronary vasoconstriction and/or spasm, and increased cardiac workload, to myocardial damage, which has a functional counterpart of transient apical left ventricular ballooning. The relative preponderance among postmenopausal women suggests that estrogen deprivation may play a facilitating role, probably mediated by endothelial dysfunction. Despite the substantial improvement in our understanding of the pathophysiology of TTS, a number of knowledge gaps remain.


Conduct Disorder-Related Hospitalization and Substance Use Disorders in American Teens.
Our study aimed to compare the demographic characteristics of conduct disorder (CD) inpatients versus other psychiatric inpatients in children and adolescents, and assess the association between conduct disorder patients and the spectrum of substance use disorders (SUD). We included 800,614 psychiatric adolescent (12-18 years) inpatients, and this included 8885 inpatients (1.1%) primarily for conduct disorder in the Nationwide Inpatient Sample (2010-2014). ICD-9 codes were used to detect SUD, and a logistic regression model was used to evaluate the odds ratio (OR) for SUD in conduct disorder inpatients. A higher proportion of conduct disorder inpatients were of 12-15 years of age (62.6%), male (64.4%), and White (45.7%). The lower median household income was correlated with a higher prevalence of conduct disorder (36.4%). Among SUD, cannabis use (23.7%) was most prevalent in conduct disorder inpatients followed by tobacco and alcohol use (10.1% each). Conduct disorder inpatients have 1.7-fold higher odds (95% confidence interval (CI) 1.52-1.82) for alcohol use and 1.4-fold higher odds (95% CI 1.31-1.49) for cannabis use compared to the non-conduct disorder inpatients. Cannabis use was seen significantly in adolescents (49.1%, 12-15 years), male (75.6%), and African Americans (45.6%). Conduct disorder inpatients have a higher risk of comorbid SUD compared to other psychiatric illnesses. The most common substance to be abused is cannabis followed by tobacco and alcohol. Varying pattern of substance use was seen by demographics and these predictors may help the clinicians for early diagnosis and treatment to improve overall health-related quality of life.


Mechanism of apoptosis and determination of cellular fate in chromium(VI)-exposed populations of telomerase-immortalized human fibroblasts.
The cellular responses to carcinogen exposure influence cellular fate, which in turn modulates the neoplastic response. Certain hexavalent chromium [Cr(VI)] compounds are implicated as occupational respiratory carcinogens at doses that are both genotoxic and cytotoxic. We examined the mechanism of Cr(VI)-induced apoptosis in normal human fibroblasts (BJ) immortalized by human telomerase gene transfection (BJ-hTERT), and we assessed the spectrum of cumulative cellular fates [(a) regaining of replicative potential; (b) terminal growth arrest; or (c) apoptosis] for a narrow range of increasingly genotoxic doses of Cr(VI). Exposure of BJ-hTERT cells to Cr(VI) resulted in a dose-dependent increase in apoptosis that involved mitochondrial disruption as evidenced by mitochondrial membrane depolarization and cytochrome c release. The initial response to Cr(VI) exposure was inhibition of cell cycle progression. At the lowest dose tested (1 microM; 32% clonogenic survival), the cell cycle inhibition led to terminal growth arrest but no apoptosis. The fraction of terminally growth arrested cells increased as the dose was increased to 3 microM but then decreased at 4, 5, and 6 microM as apoptosis became the predominant cell fate. Our results suggest that cell populations exposed to Cr(VI) have a different spectrum of responses, depending on the extent of DNA damage, and that the regaining of replicative potential after relatively higher genotoxic exposures may be attributable to either escape from, or resistance to, terminal growth arrest or apoptosis.


Exploring meanings of illness causation among those severely affected by multiple sclerosis: a comparative qualitative study of Black Caribbean and White British people.
Illness attributions, particularly for those living with life limiting illnesses, are associated with emotional adjustment or psychological distress. Few studies have examined attributions among people severely affected by multiple sclerosis (PwMS), and specifically among from diverse communities. This study aimed to explore and compare the presence and construction of meanings among Black Caribbean and White British PwMS. Cross sectional qualitative interviews were conducted among Black Caribbean (BC) and White British (WB) PwMS with an EDSS of ≥6.0 (severe disease). Data were analysed using the framework approach. 15 BC and 15 WB PwMS were interviewed. Attributions were complex with most PwMS reporting multiple explanations. Uncertainty, represents the first theme surrounding the aetiology of MS where participants constantly rehearsed the "why me?" question in relation to their illness, a number expressing considerable frustration. The second theme, 'logical and scientific', was voiced more often by WB PwMS and accounts for a range of genetic/viral influences, stress, environmental and lifestyle factors. Third, the 'supernatural' illness attribution theme departs from a biomedical perspective and was reported often among BC PwMS. This theme included the sub-categories of tests of faith and divine punishment, a view although exclusive to BC participants but was sometimes in conflict with notions of modernity. Our findings identify evidence of cross-cultural and intra-group diversity in relation to MS causation. A greater professional awareness of the processes used by PwMS from diverse communities to make sense of their situation will enable health care professionals to facilitate effective support for those in their care and channel relevant psychosocial resources to them. This requires heightened skills in communication and cultural competency.


Parsing brain-behavior heterogeneity in very preterm born children using integrated similarity networks.
Very preterm birth (VPT; ≤32 weeks' gestation) is associated with altered brain development and cognitive and behavioral difficulties across the lifespan. However, heterogeneity in outcomes among individuals born VPT makes it challenging to identify those most vulnerable to neurodevelopmental sequelae. Here, we aimed to stratify VPT children into distinct behavioral subgroups and explore between-subgroup differences in neonatal brain structure and function. 198 VPT children (98 females) previously enrolled in the Evaluation of Preterm Imaging Study (EudraCT 2009-011602-42) underwent Magnetic Resonance Imaging at term-equivalent age and neuropsychological assessments at 4-7 years. Using an integrative clustering approach, we combined neonatal socio-demographic, clinical factors and childhood socio-emotional and executive function outcomes, to identify distinct subgroups of children based on their similarity profiles in a multidimensional space. We characterized resultant subgroups using domain-specific outcomes (temperament, psychopathology, IQ and cognitively stimulating home environment) and explored between-subgroup differences in neonatal brain volumes (voxel-wise Tensor-Based-Morphometry), functional connectivity (voxel-wise degree centrality) and structural connectivity (Tract-Based-Spatial-Statistics). Results showed two- and three-cluster data-driven solutions. The two-cluster solution comprised a 'resilient' subgroup (lower psychopathology and higher IQ, executive function and socio-emotional scores) and an 'at-risk' subgroup (poorer behavioral and cognitive outcomes). No neuroimaging differences between the resilient and at-risk subgroups were found. The three-cluster solution showed an additional third 'intermediate' subgroup, displaying behavioral and cognitive outcomes intermediate between the resilient and at-risk subgroups. The resilient subgroup had the most cognitively stimulating home environment and the at-risk subgroup showed the highest neonatal clinical risk, while the intermediate subgroup showed the lowest clinical, but the highest socio-demographic risk. Compared to the intermediate subgroup, the resilient subgroup displayed larger neonatal insular and orbitofrontal volumes and stronger orbitofrontal functional connectivity, while the at-risk group showed widespread white matter microstructural alterations. These findings suggest that risk stratification following VPT birth is feasible and could be used translationally to guide personalized interventions aimed at promoting children's resilience.


Hydrogen-Rich Water Intake Accelerates Oral Palatal Wound Healing via Activation of the Nrf2/Antioxidant Defense Pathways in a Rat Model.
The wound healing process attempts to restore the integrity and function of the injured tissue. Additionally, proinflammatory cytokines, growth factors, and oxidative stress play important roles in wound healing. The aim of this study was to determine whether hydrogen-rich water intake induces the activation of the Nrf2/antioxidant defense pathway in rat palatal tissue, thereby reducing systemic oxidative stress and proinflammatory cytokine levels and promoting healing-associated genes. A circular excisional wound was created in the oral palatal region, and the wound healing process was observed. The rats were divided into two experimental groups in which either hydrogen-rich water or distilled water was consumed. In the drinking hydrogen-rich water, the palatal wound healing process was accelerated compared to that in the control group. As molecular hydrogen upregulated the Nrf2 pathway, systemic oxidative stresses were decreased by the activation of antioxidant activity. Furthermore, hydrogen-rich water intake reduced proinflammatory cytokine levels and promoted the expression of healing-associated factors in rat palatal tissue. In conclusion, hydrogen-rich water intake exhibited multiple beneficial effects through activation of the Nrf2/antioxidant defense pathway. The results of this study support the hypothesis that oral administration of hydrogen-rich water benefits the wound healing process by decreasing oxidative stress and inflammatory responses.


Adolescent over-general memory, life events and mental health outcomes: Findings from a UK cohort study.
Previous research suggesting that over-general memory (OGM) may moderate the effect of life events on depressive symptoms and suicidality has sampled older adolescents or adults, or younger adolescents in high-risk populations, and has been conducted over relatively short follow-up periods. The authors examined the relationship between OGM at age 13 and life events and mental health outcomes (depression, self-harm, suicidal ideation and planning) at age 16 years within a sample of 5792 adolescents participating in the Avon Longitudinal Study of Parents and Children (ALSPAC), approximately 3800 of whom had also provided data on depression and self-harm. There was no clear evidence of either direct or interactive effects of OGM at age 13 on levels of depression at age 16. Similarly there was no clear evidence of either direct or interactive effects of OGM on suicidal ideation and self-harm. Although there was some evidence that over-general autobiographical memory was associated with reduced risk of suicidal planning and increased risk of self-harm, these associations were absent when confounding variables were taken into account. The findings imply that although OGM is a marker of vulnerability to depression and related psychopathology in high-risk groups, this cannot be assumed to generalise to whole populations.


Chemo- and bioinformatics resources for in silico drug discovery from medicinal plants beyond their traditional use: a critical review.
In silico approaches have been widely recognised to be useful for drug discovery. Here, we consider the significance of available databases of medicinal plants and chemo- and bioinformatics tools for in silico drug discovery beyond the traditional use of folk medicines. This review contains a practical example of the application of combined chemo- and bioinformatics methods to study pleiotropic therapeutic effects (known and novel) of 50 medicinal plants from Traditional Indian Medicine.


The impact of medical school assessment on preparedness for practice.
As assessment is known to drive learning, this paper looks at the relationship between assessment practice across UK medical schools and graduates preparedness for practice. It uses data on written and practical assessment at each medical school and the association with students' self-reported preparedness for working as a foundation doctor on graduation, and in particular the preparation related to clinical skills. A negative correlation (β= -0.003, p < 0.001) was observed between total duration of written assessment and preparedness, while a positive relationship (β = 0.461, p < 0.001) was seen between "adequately prepared" and the proportion of all assessment time focusing on practical skills. This suggests that graduates from medical schools with a greater emphasis on practical skills in their assessment plan are better prepared to practice as a junior doctor on gradation; something that may be of relevance when designing a national licensing examination.


Rural communities' preferences for arsenic mitigation options in Bangladesh.
In the context of arsenic contamination of groundwater in Bangladesh, this paper analyses rural people's preferences for arsenic-free drinking water options. A particular focus is on rural households' willingness to pay for piped water supply which can provide a sustainable solution to the arsenic problem, and how the preference for piped water supply compares with that for various other household/community-based arsenic mitigation technologies. The analysis is based on data collected in a survey of over 2700 households in rural Bangladesh. Six arsenic mitigation technologies were selected for the study: three-kolshi (pitcher) method, activated alumina method (household-based and community-based), dugwell, pond sand filter and deep tubewell (handpump). The survey results indicate that, after taking into consideration the initial and recurring costs, convenience, associated risks and the advantages and disadvantages of each selected technology, the preference of the rural people is overwhelmingly in favor of deep tubewells, followed by the three-kolshi method. The analysis reveals a strong demand for piped water in both arsenic-affected and arsenic-free rural areas, and scope of adequate cost recovery. Between piped water and other arsenic mitigation technologies, the preference of the rural people is found to be predominantly in favor of the former.