Cost-Effectiveness Analysis of Human Papillomavirus Vaccination in Adolescent Girls in Taiwan
Objective: Three vaccines are available to Taiwanese young girls for cervical cancer (CC) prevention. Here we evaluate the cost-effectiveness of the two-dose (2D) AS04-adjuvanted HPV-16/18 vaccine (2D-AS04-HPV- 16/18v)+screening compared with a screening programme alone, with 2D human papillomavirus 6/11/16/18 vaccine (2D-4vHPVv)+screening, and with 2D/three-dose (3D) human papillomavirus 6/11/16/18/31/33/45/52/58 vaccine (9vHPVv)+screening, for Taiwan universal mass vaccination. Methods: A static Markov cohort model simulated the natural history of human papillomavirus (HPV) infection and CC screening for a 12-year-old cohort of Taiwanese girls (N=120,000). The model ran in 1-year cycles over the cohort's lifetime. Vaccine efficacy irrespective of HPV type was considered in the analysis for each vaccine. Input data were obtained from published literature, local databases, government reports and websites, and expert opinion. The analysis incorporated direct medical costs only, with an annual discount rate of 3.0%. The threshold was determined as 1 Gross Domestic Product per capita (New Taiwan dollar [NT$] 727,818; year 2016). Results: The 2D-AS04-HPV-16/18v+screening yielded 0.0365 quality-adjusted life year (QALY) gained at an additional cost of NT$ 5,770 per person compared with the screening programme alone. This resulted in an incremental cost-effectiveness ratio well below the threshold. Compared with 2D-4vHPVv+screening and 2D/3D-9vHPVv+screening, discounted results demonstrated additional QALYs gained at lower cost for 2D-AS04-HPV- 16/18v+screening, making it dominant over both 2D-4vHPVv+screening and 2D/3D-9vHPVv+screening. Conclusions: Vaccinating Taiwanese girls with 2D-AS04-HPV-16/18v in addition to screening to prevent CC is cost-effective compared with using a screening programme alone and the dominant option compared with 2D-4vHPVv+screening and 2D/3D-9vHPVv+screening.


Elevated serum iron concentration in adolescent alcohol users.
Alcohol is a frequently abused drug among adolescents. In adults, alcohol alters iron metabolism, predisposing to excess hepatic iron storage and, possibly, liver damage. The purpose of this study was to determine whether alcohol is associated with an elevated serum iron concentration and transferrin saturation in adolescents, and to determine the contribution of oral contraceptive use to these abnormalities. Adolescents (591 male and 614 female) aged 16 to 19 years, who participated in the first National Health and Nutrition Examination Survey from 1971 to 1973, were grouped according to their reported frequency of alcohol intake. Drinking frequency was associated with serum iron concentrations in boys and girls, and with total iron-binding capacity, transferrin saturation, and hemoglobin concentration in boys. Alcohol use was associated with an elevated serum iron concentration only in oral contraceptive nonusers. Adolescents who use alcohol have an elevated serum iron concentration, and male alcohol users have an increased transferrin saturation as well. These abnormalities may be precursors of hepatic iron overload and chronic liver damage.


AN EXPERIMENTAL STUDY OF OPSONIC IMMUNITY TO STAPHYLOCOCCUS AUREUS.
1. The administration of Staphylococcus aureus, killed by heat (vaccine), produces a high degree of opsonic immunity in rabbits. 2. Such increase of opsonin affords protection against living virulent staphylococcus in direct proportion to the amount of opsonins present in the serum and complete recovery may follow subsequent inoculation, if the opsonic power be high. 3. Frequent administration of vaccines may produce a diminution of the opsonic power of the serum. 4. Immune opsonins are most active against the homologous strain of Staphylococcus aureus, but are only slightly less active against heterologous strains. 5. Infections of the human body by Staphylococcus aureus may cause great increase of opsonins. 6. Vaccines prepared from Staphylococcus aureus may produce a high degree of opsonic immunity in man.


Picosecond all-optical switching in hydrogenated amorphous silicon microring resonators.
We utilize cross-phase modulation to observe all-optical switching in microring resonators fabricated with hydrogenated amorphous silicon (a-Si:H). Using 2.7-ps pulses from a mode-locked fiber laser in the telecom C-band, we observe optical switching of a cw telecom-band probe with full-width at half-maximum switching times of 14.8 ps, using approximately 720 fJ of energy deposited in the microring. In comparison with telecom-band optical switching in undoped crystalline silicon microrings, a-Si:H exhibits substantially higher switching speeds due to reduced impact of free-carrier processes.


The host response: Toll-like receptor expression in periprosthetic tissues as a biomarker for deep joint infection.
Toll-like receptors (TLRs) 1 and 6 are consistent molecular indicators of the host inflammatory response against bacterial infection. Our aims were to determine whether TLR elevation could be detected in infected periprosthetic tissues and to assess the utility of these biomarkers as tests for detecting a periprosthetic joint infection. Fifty-nine patients undergoing revision total joint arthroplasty (twenty-seven hips and thirty-two knees) were prospectively evaluated for periprosthetic joint infection according to currently recommended diagnostic criteria. Nine patients were excluded because of insufficient work-up, leaving fifty available for study. Of these, twenty-one were categorized as infected and twenty-nine as noninfected. Periprosthetic tissues were collected intraoperatively, and total RNA was extracted by standard techniques. Expression of TLR messenger RNAs was assessed by first-strand complementary DNA synthesis from 1 μg of total RNA followed by real-time PCR (polymerase chain reaction). Results were normalized relative to the housekeeping gene GAPDH (glyceraldehyde 3-phosphate dehydrogenase). Expression of TLRs 1, 6, and 10 in the infected and noninfected groups was compared with use of the Student t test. The receiver operating characteristic curve, area under the curve (AUC), sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated to determine the accuracy of each TLR for predicting periprosthetic joint infection at its optimal diagnostic threshold. Mean TLR1 mRNA expression was significantly elevated in infected compared with noninfected samples (0.600 compared with 0.005, p = 0.0003); the same was true of TLR6 (0.208 compared with 0.0165, p = 0.0059) but not of TLR10 (0.00019 compared with 0.00014, p = 0.6238). The AUC was 0.995 for TLR1, 0.883 for TLR6, and 0.546 for TLR10. The optimal threshold for diagnosing periprosthetic joint infection was 0.0924 for TLR1 (sensitivity = 95.2%, specificity = 100%, LR+ = 13.80, LR- = 0.91) and 0.0215 for TLR6 (sensitivity = 85.7%, specificity = 82.8%, LR+ = 4.98, LR- = 0.83). In our pilot study, TLR1 expression in periprosthetic tissues most accurately predicted periprosthetic joint infection. This measure of the host response may be particularly helpful in detecting culture-negative infections and avoiding false positives resulting from contamination. Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.


RNA/DNA co-analysis from human saliva and semen stains--results of a third collaborative EDNAP exercise.
A third collaborative exercise on RNA/DNA co-analysis for body fluid identification and STR profiling was organized by the European DNA Profiling Group (EDNAP). Twenty saliva and semen stains, four dilution series (10-0.01 μl saliva, 5-0.01 μl semen) and, optionally, bona fide or mock casework samples of human or non-human origin were analyzed by 20 participating laboratories using an RNA extraction or RNA/DNA co-extraction method. Two novel mRNA multiplexes were used: a saliva triplex (HTN3, STATH and MUC7) and a semen pentaplex (PRM1, PRM2, PSA, SEMG1 and TGM4). The laboratories used different chemistries and instrumentation and a majority (16/20) were able to successfully isolate and detect mRNA in dried stains. The simultaneous extraction of RNA and DNA from individual stains not only permitted a confirmation of the presence of saliva/semen (i.e. tissue/fluid source of origin), but allowed an STR profile of the stain donor to be obtained as well. The method proved to be reproducible and sensitive, with as little as 0.05 μl saliva or semen, using different analysis strategies. Additionally, we demonstrated the ability to positively identify the presence of saliva and semen, as well as obtain high quality DNA profiles, from old and compromised casework samples. The results of this collaborative exercise involving an RNA/DNA co-extraction strategy support the potential use of an mRNA based system for the identification of saliva and semen in forensic casework that is compatible with current DNA analysis methodologies.


The riddle of formycin A insulinotropic action.
Formycin A augments insulin release evoked by glucose (5.6 mm or more), this effect not being rapidly reversible. The mechanism responsible for the insulinotropic action of formycin A was investigated in isolated pancreatic islets. It could not be ascribed to facilitation of glucose metabolism. On the contrary, formycin A inhibited glucose oxidation, lowered ATP content, and impaired glucose-stimulated protein biosynthesis. The insulinotropic action of formycin A was apparently attributable to its conversion to formycin A 5'-triphosphate, both this process and the secretory response to formycin A being abolished by the inhibitor of adenosine kinase 5-iodotubercidin. In agreement with the latter view, adenosine receptor antagonists such as 8-cyclopentyl-1, 3-dipropylxanthine and 3,7-dimethyl-1-propargylxanthine failed to suppress and, instead, augmented the insulinotropic action of formycin A. Unexpectedly, however, formycin A failed to decrease 86Rb efflux, this coinciding with a low efficiency of formycin A 5'-triphosphate to inhibit KATP-channel activity in excised membranes and with the fact that formycin A increased gliben-clamide-stimulated insulin release. The secretory response to formycin A represented a Ca2+-dependent process suppressed in the absence of extracellular Ca2+ or presence of verapamil and associated with an increased net uptake of 45Ca. Nevertheless, the view that formycin A exerts any major effect upon intracellular Ca2+ redistribution, protein kinase C activity, or cyclic AMP net production also met with objections such as the minor secretory effect of formycin A in islets exposed to a high concentration of K+ in the presence of a diazoxide analog, the resistance of formycin A insulinotropic action to bisindolylmaleimide, the poor increase of cyclic AMP content in formycin A-stimulated islets, and the pronounced enhancement by forskolin or theophylline of insulin release from islets exposed to formycin A. It is concluded, therefore, that the mechanism of action of formycin A in the pancreatic beta-cell remains to be elucidated.


Droplet aerodynamics, cellular uptake, and efficacy of a nebulizable corticosteroid nanosuspension are superior to a micronized dosage form.
Inhaled corticosteroids are considered to be an effective prophylactic against the morbid symptoms of several lung diseases, but scope remains for improvement in drug delivery technology to benefit bioavailability and treatment compliance. To ascertain whether dosage form might influence bioavailability, the emission characteristics and efficacy of a nanoparticulate budesonide formulation (Nanagel®) were compared with those of a proprietary micronized suspension (Pulmicort®) when delivered as a nebulized aerosol to human airway epithelial cells in a culture model. Having the visual appearance of a clear solution, Nanagel® was delivered by both jet and vibrating mesh nebulizers as an increased fine particle fraction and with a smaller mass median aerodynamic diameter (MMAD) compared to the micronized suspension. Quantitative high performance liquid chromatography (HPLC) analysis of cultured epithelia one hour after treatment with Nanagel® revealed a significantly greater cellular accumulation of budesonide when compared with Pulmicort® for an equivalent dose, a differential which persisted 24 and 48 h later. A quantitative in vitro assay measuring the activity of enzymes involved in superoxide production revealed that stressed HaCaT cells (a long-lived, spontaneously immortalized human keratinocyte line) treated with Nanagel® continued to show significantly greater attenuation of inflammatory response compared with Pulmicort®-treated cells 24 h after the application of an equivalent budesonide dose. The present in vitro findings suggest that formulation of inhalable drugs such as budesonide as aerosolized nanoparticulate, rather than microparticulate, suspensions can enhance bioavailability with concomitant improvements in efficacy.


Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis.
To evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib. Phase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05). We identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15-161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)). Within the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.


Caregivers of people with multiple sclerosis: experiences of support.
The aim of this phenomenological study was to gain an understanding of the experiences of a group of caregivers of people with multiple sclerosis (MS). Sixteen caregivers from Northern Ireland and the Republic of Ireland participated in focus group interviews. The theme of support, either sought or received, emerged as a major aspect of the experiences described. Caregivers' feelings about, and experiences of, support appeared to change over time. Four common phases that caregivers experienced in relation to support were identified as: 'rejecting', 'resisting, 'seeking' and 'accepting' support. This paper will present and discuss these four phases. The study findings highlight the complexity of issues surrounding a caregiver's decision to seek and accept support. It is hoped that the phases identified within this study are useful in depicting how caregivers of people with MS may progress through stages in their desire for, and acceptance of support. Findings from this study are useful to healthcare professionals who work with people with MS and their caregivers by increasing awareness that a caregiver's attitude toward and acceptance of support changes over time.


Opioid desensitization: interactions with G-protein-coupled receptors in the locus coeruleus.
In rat locus coeruleus (LC) neurons, alpha 2 adrenoceptors, mu-opioid and somatostatin receptors all activate the same potassium conductance. Chronic treatment with morphine causes a loss of sensitivity that is specific to the mu-opioid response, with no change in the alpha 2 adrenoceptor-mediated response. Acute desensitization induced by opioid, somatostatin, and alpha 2-adrenoceptor agonists was studied in brain slices of rat LC using intracellular recording. A supramaximal concentration of the opioid agonist Met5-enkephalin induced a profound homologous desensitization but little heterologous desensitization to an alpha 2-adrenoceptor agonist (UK 14304) or somatostatin. All desensitized currents showed partial recovery. A supramaximal concentration of UK14304 caused a relatively small amount of desensitization. Although little interaction was observed among inhibitory G-protein-coupled receptors, activation of an excitatory receptor had marked effects on inhibitory responses. Muscarinic agonists, which produce an inward current in LC neurons, reduced the magnitude of agonist-induced outward currents and increased both the rate and amount of opioid desensitization. Muscarinic activation did not alter desensitization of alpha 2-adrenoceptor responses. Acute desensitization shares several characteristics with the tolerance induced by chronic morphine treatment of animals.


Spinal manipulation for primary and secondary dysmenorrhoea.
Dysmenorrhoea refers to the occurrence of painful menstrual cramps of uterine origin and is a common gynaecological condition. One possible treatment is spinal manipulation therapy. One hypothesis is that mechanical dysfunction in certain vertebrae causes decreases spinal mobility. This could affect the sympathetic nerve supply to the blood vessels supplying the pelvic viscera, leading to dysmenorrhoea as a result of vasoconstriction. Manipulation of these vertebrae increases spinal mobility and may improve pelvic blood supply. Another hypothesis is that dysmenorrhoea is referred pain arising from musculoskeletal structures that share the same pelvic nerve pathways. The character of pain from musculoskeletal dysfunction can be very similar to gynaecological pain as it can present as cyclic pain altered by hormonal influences associated with menstruation. To determine the safety and efficacy of spinal manipulative interventions for the treatment of primary or secondary dysmenorrhoea when compared to each other, placebo, no treatment, or other medical treatment. We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched April 2006), CENTRAL (The Cochrane Library 2006, Issue 1), MEDLINE (1966 to March 2006), EMBASE (1980 to April 2006), CINAHL (1982 to March 2006), AMED (1985 to April 2006), Biological Abstracts (1969 to March 2006), PsycINFO (1806 to April 2006), and SPORTDiscus (1830 to April 2006). Attempts were also made to identify trials from the metaRegister of Controlled Trials and the citation lists of review articles and included trials. In most cases the first or corresponding author of each included trial was contacted for additional information. Any randomised controlled trials (RCTs) including spinal manipulative interventions (for example chiropractic, osteopathy, or manipulative physiotherapy) versus each other, placebo, no treatment, or other medical treatment were considered. Exclusion criteria were: mild or infrequent dysmenorrhoea or dysmenorrhoea from an intrauterine device (IUD). Four trials of high velocity, low amplitude manipulation (HVLA), and one of the Toftness manipulation technique were included. Quality assessment and data extraction were performed independently by two review authors. Meta analysis was performed using odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Data unsuitable for meta-analysis were reported as descriptive data and were also included for discussion. The outcome measures were pain relief or pain intensity (dichotomous, visual analogue scales, descriptive) and adverse effects. Results from the four trials of high velocity, low amplitude manipulation suggest that the technique was no more effective than sham manipulation for the treatment of dysmenorrhoea, although it was possibly more effective than no treatment. Three of the smaller trials indicated a difference in favour of HVLA, however the one trial with an adequate sample size found no difference between HVLA and sham treatment. There was no difference in adverse effects experienced by participants in the HVLA or sham treatment. The Toftness technique was shown to be more effective than sham treatment by one small trial, but no strong conclusions could be made due to the small size of the trial and other methodological considerations. Overall there is no evidence to suggest that spinal manipulation is effective in the treatment of primary and secondary dysmenorrhoea. There is no greater risk of adverse effects with spinal manipulation than there is with sham manipulation.


BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.
Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.


Cyclic nucleotide phosphodiesterase 1 and vascular aging.
VSMCs (vascular smooth muscle cells) play critical roles in arterial remodelling with aging, hypertension and atherosclerosis. VSMCs exist in diverse phenotypes and exhibit phenotypic plasticity, e.g. changing from a quiescent/contractile phenotype to an active myofibroblast-like, often called 'synthetic', phenotype. Synthetic VSMCs are able to proliferate, migrate and secrete ECM (extracellular matrix) proteinases and ECM proteins. In addition, they produce pro-inflammatory molecules, providing an inflammatory microenvironment for leucocyte penetration, accumulation and activation. The aging VSMCs have also shown changes in cellular phenotype, responsiveness to contracting and relaxing mediators, replicating potential, matrix synthesis, inflammatory mediators and intracellular signalling. VSMC dysfunction plays a key role in age-associated vascular remodelling. Cyclic nucleotide PDEs (phosphodiesterases), by catalysing cyclic nucleotide hydrolysis, play a critical role in regulating the amplitude, duration and compartmentalization of cyclic nucleotide signalling. Abnormal alterations of PDEs and subsequent changes in cyclic nucleotide homoeostasis have been implicated in a number of different diseases. In the study published in the latest issue of Clinical Science, Bautista Niño and colleagues have shown that, in cultured senescent human VSMCs, PDE1A and PDE1C mRNA levels are significantly up-regulated and inhibition of PDE1 activity with vinpocetine reduced cellular senescent makers in senescent VSMCs. Moreover, in the premature aging mice with genomic instability (Ercc1(d/-)), impaired aortic ring relaxation in response to SNP (sodium nitroprusside), an NO (nitric oxide) donor, was also largely improved by vinpocetine. More interestingly, using data from human GWAS (genome-wide association studies), it has been found that PDE1A single nucleotide polymorphisms is significantly associated with diastolic blood pressure and carotid intima-media thickening, two hallmarks of human vascular dysfunction in aging. These findings establish a strong relationship between PDE1 expression regulation and vascular abnormalities in aging.


Children's Depression Inventory in Estonia. Single items and factor structure by age and gender.
The aim of study was to estimate the score of symptoms of depression with the Children's Depression Inventory (CDI) among Estonian schoolchildren aged 7-13-year-old, according to age and gender differences, and to identify the components in factor analysis characterising self-reported childhood symptoms of depression. The applicability of the CDI in 7-year-old children was also estimated. The number of subjects in the study was 725 (342 girls and 383 boys), and the mean age was 10.2 (SD 1.7). The mean total score of the CDI for the whole sample was 9.96 (SD = 6.3, range 0-39, median 9.0). The mean scores of symptoms of depression among children did not differ by gender or age. There were no significant differences in the CDI mean scores between 7-year-old compared to older schoolchildren in the present study. Factor analysis obtained five factors: anhedonia, ineffectiveness, negative self-esteem, negative mood and interpersonal problems. Significant gender and age differences were found: girls reported more symptoms of anhedonia and negative self-esteem, and boys reported more symptoms of ineffectiveness. Younger children reported more symptoms of anhedonia and ineffectiveness, and older children negative self-esteem. The study serves as baseline data before intervention of the EC project "European Alliance Against Depression".


Outcomes of living donor liver transplantation for hepatitis C virus-positive recipients in Japan: results of a nationwide survey.
A nationwide survey of living donor liver transplantation (LDLT) for hepatitis C virus (HCV)-positive recipients was performed in Japan. A total of 514 recipients are reported and included in the study. The cumulative patient survival rate at 5 and 10 years was 72% and 63%, respectively. Of the 514 recipients, 142 patients (28%) died until the end of the observation, among which the leading cause was recurrent hepatitis C (42 cases). According to Cox regression multivariate analysis, donor age (>40), non-right liver graft, acute rejection episode, and absence of a sustained virologic response were independent prognostic factors. Of the 514 recipients, 361 underwent antiviral treatment mainly with pegylated-interferon and ribavirin (preemptive treatment in 150 patients and treatment for confirmed recurrent hepatitis in 211). The dose reduction rate and discontinuation rate were 40% and 42%, respectively, with a sustained virologic response rate of 43%. In conclusion, patient survival of HCV-positive recipients after LDLT was good, with a 10-year survival of 63%. Right liver graft might be preferable for HCV-positive recipients in an LDLT setting.


Pre-travel health care of immigrants returning home to visit friends and relatives.
Immigrants returning home to visit friends and relatives (VFR travelers) are at higher risk of travel-associated illness than other international travelers. We evaluated 3,707 VFR and 17,507 non-VFR travelers seen for pre-travel consultation in Global TravEpiNet during 2009-2011; all were traveling to resource-poor destinations. VFR travelers more commonly visited urban destinations than non-VFR travelers (42% versus 30%, P < 0.0001); 54% of VFR travelers were female, and 18% of VFR travelers were under 6 years old. VFR travelers sought health advice closer to their departure than non-VFR travelers (median days before departure was 17 versus 26, P < 0.0001). In multivariable analysis, being a VFR traveler was an independent predictor of declining a recommended vaccine. Missed opportunities for vaccination could be addressed by improving the timing of pre-travel health care and increasing the acceptance of vaccines. Making pre-travel health care available in primary care settings may be one step to this goal.


DEOP: a database on osmoprotectants and associated pathways.
Microorganisms are known to counteract salt stress through salt influx or by the accumulation of osmoprotectants (also called compatible solutes). Understanding the pathways that synthesize and/or breakdown these osmoprotectants is of interest to studies of crops halotolerance and to biotechnology applications that use microbes as cell factories for production of biomass or commercial chemicals. To facilitate the exploration of osmoprotectants, we have developed the first online resource, 'Dragon Explorer of Osmoprotection associated Pathways' (DEOP) that gathers and presents curated information about osmoprotectants, complemented by information about reactions and pathways that use or affect them. A combined total of 141 compounds were confirmed osmoprotectants, which were matched to 1883 reactions and 834 pathways. DEOP can also be used to map genes or microbial genomes to potential osmoprotection-associated pathways, and thus link genes and genomes to other associated osmoprotection information. Moreover, DEOP provides a text-mining utility to search deeper into the scientific literature for supporting evidence or for new associations of osmoprotectants to pathways, reactions, enzymes, genes or organisms. Two case studies are provided to demonstrate the usefulness of DEOP. The system can be accessed at. Database URL: http://www.cbrc.kaust.edu.sa/deop/


Aggregation properties of the chromonic liquid crystal benzopurpurin 4B.
Optical polarization, absorption, and scattering studies along with confocal microscopy reveal that Benzopurpurin 4B forms aggregates of micrometer size at very low concentrations in aqueous solution. A chromonic liquid crystal phase is stable at room temperature down to concentrations as low as 0.4 wt %, which can only be possible if the aggregates contain an ample amount of water. The kinetics of aggregate formation are extremely slow, with changes going on for days before equilibrium is reached. The stacking free energy change is estimated to be 10.3 +/- 0.4 k(B)T, which is in the higher range of values for recently studied chromonic liquid crystals. However, the very low concentration of the liquid crystal phase puts it in a different class, probably more similar to Scheibe or Jelly aggregates than the typical chromonic systems that are formed by simple stacks of molecules.


Reevaluation of the role of parallel fiber synapses in delay eyeblink conditioning in mice using Cbln1 as a tool.
The delay eyeblink conditioning (EBC) is a cerebellum-dependent type of associative motor learning. However, the exact roles played by the various cerebellar synapses, as well as the underlying molecular mechanisms, remain to be determined. It is also unclear whether long-term potentiation (LTP) or long-term depression (LTD) at parallel fiber (PF)-Purkinje cell (PC) synapses is involved in EBC. In this study, to clarify the role of PF synapses in the delay EBC, we used mice in which a gene encoding Cbln1 was disrupted (cbln1(-/-) mice), which display severe reduction of PF-PC synapses. We showed that delay EBC was impaired in cbln1(-/-) mice. Although PF-LTD was impaired, PF-LTP was normally induced in cbln1(-/-) mice. A single recombinant Cbln1 injection to the cerebellar cortex in vivo completely, though transiently, restored the morphology and function of PF-PC synapses and delay EBC in cbln1(-/-) mice. Interestingly, the cbln1(-/-) mice retained the memory for at least 30 days, after the Cbln1 injection's effect on PF synapses had abated. Furthermore, delay EBC memory could be extinguished even after the Cbln1 injection's effect were lost. These results indicate that intact PF-PC synapses and PF-LTD, not PF-LTP, are necessary to acquire delay EBC in mice. In contrast, extracerebellar structures or remaining PF-PC synapses in cbln1(-/-) mice may be sufficient for the expression, maintenance, and extinction of its memory trace.


Chronic hepatitis virus infection increases the risk of pancreatic cancer: a meta-analysis.
Several reports have inconsistently demonstrated that there is an association between hepatitis B virus (HBV) or hepatitis C virus (HCV) infections and pancreatic cancer (PC). The aim of the present meta-analysis is to assess this possible relationship. Studies were identified by searching available database from January 2000 to July 2012. Possible associations between PC risk and hepatitis B surface antigen (HBsAg) and its antibody (HBsAb), hepatitis B e antigen (HBeAg) and its antibody (HBeAb), anti-HBcAg antibody (HBcAb), and HCV antibody (anti-HCV) were evaluated. Eight case-control and two cohort studies were included, and their quality scores were assessed by the modified Newcastle-Ottawa Quality Assessment Scale (NOS). We found that HBsAg and anti-HCV seropositivity significantly increased risk of PC (OR=1.28, 95% CI: 1.11-1.48 and OR=1.21, 95% CI: 1.02-1.44). The presence of HBsAb was associated with a statistically significant decrease in the risk of PC (OR=0.40, 95% CI: 0.20-0.79) and HBeAb (OR=0.62, 95% CI: 0.39-0.99). HBsAg-/HBcAb+/HBsAb- or HBsAg-/HBcAb+/HBsAb+ profile was not related to PC risk (OR=1.57, 95% CI: 0.83-2.98 and OR=1.24, 95% CI: 0.72-2.14). HBV/HCV infection increases the risk of PC. HBsAb and HBeAb seropositivity may be the protective factors against PC. It is still uncertain whether serological pattern of past exposure to HBV with or without natural immunity is associated with an enhanced probability of this malignancy.


Antiangiogenic agents for nonmalignant brain tumors.
Objective To assess the treatment response and side effects for the use of antiangiogenic agents such as vascular endothelial growth factor (VEGF) inhibitors for patients with vestibular schwannomas and meningiomas. Design and Methods Retrospective review of eight male and two female patients (ages 14 to 70, mean 36 years), treated with bevacizumab (9) or pazopanib (1). Six patients had neurofibromatosis type 2 (NF2) with bilateral vestibular schwannomas and meningiomas, and the four others had aggressive recurrent meningiomas. Results During treatment (range 4 to 21 months, mean 9.1) with antiangiogenic agents, two patients with an atypical meningioma and radiation necrosis had dramatic partial response, the six NF2 patients had stable or slightly improved disease, and two meningioma patients had disease progression. Hearing was stable in three of the NF2 patients and was improved in three NF2 patients (one of whom received a cochlear implant). Minor toxicities included epistaxis, nausea, diarrhea, weight loss, and abdominal pain. No grade 3 or 4 toxicities were observed. Conclusion Antiangiogenic agents appear to be safe for the treatment of patients with nonmalignant brain tumors, and in select cases may be efficacious.


The GPR88 receptor agonist 2-PCCA does not alter the behavioral effects of methamphetamine in rats.
GPR88 is a novel orphan G protein-coupled receptor that is primarily located at the striatum. Genetic knockout studies reveal phenotypes of increased dopamine D(2) receptor sensitivity in mice, suggesting that GPR88 receptors may be involved in the modulation of dopaminergic system. However, there is no study that examines the pharmacological effects of GPR88 receptor ligands in in vivo preparations. This study examined the effects of a GPR88 receptor agonist, (1R, 2R)-2-pyridin-2-yl-cyclopropane carboxylic acid ((2S, 3S)-2-amino-3-methyl-pentyl)-(4'-propylbiphenyl-4-yl)-amide (2-PCCA), on the motor activity in rats and on methamphetamine-induced hyperactivity and discriminative stimulus effects. 2-PCCA (0.1-3.2mg/kg) dose-dependently decreased the locomotor activity in rats and, when studied in combination with 1.0mg/kg methamphetamine, also dose-dependently decreased methamphetamine-induced hyperactivity. However, the dose of 2-PCCA that significantly attenuated methamphetamine-induced hyperactivity was also the dose that by itself markedly decreased the baseline locomotor activity. In rats discriminating 0.32mg/kg methamphetamine, 2-PCCA (1-3.2mg/kg) itself did not produce methamphetamine-like discriminative stimulus effects and, when studied in combination, did not alter the discriminative stimulus effects of methamphetamine. Together, these data have provided the first line of evidence that activation of GPR88 receptors does not alter the behavioral effects of methamphetamine. The potential implications of these findings are also discussed.


A comparison of P-wave duration and dispersion in patients with short-term and long-term atrial fibrillation.
This study compared P-wave duration and dispersion (PD) in patients with short-term (<or=48 hours) and long-term (>48 hours) atrial fibrillation (AF) after cardioversion. We studied 96 consecutive patients with short-term (group A; n:51, age: 61 +/- 11 years) and long-term AF (group B; n:45, age: 64 +/- 10 years). P-wave measurements were calculated from 12-lead electrocardiogram. There was no difference related to clinical characteristics. Left atrial dimension was significantly higher in group B (P =.003). P maximum (124 +/- 12 vs. 113 +/- 11 ms, P =.001) and PD (57 +/- 8 vs. 49 +/- 9 ms, P =.001) were also significantly longer in group B compared with group A, but P minimum did not. In univariate analysis, PD were related to AF duration (P =.002) and left atrial size (P =.02). This relation remained in multivariate analysis (P =.01, P =.02, respectively). P maximum >112 ms and PD >47 ms had accuracy values of 74% and 83% respectively for separating group B. Our results suggest that P wave duration and dispersion is prolonged in patients with long-term AF compared to short-term AF.


Efficient interfacing photonic and long-range dielectric-loaded plasmonic waveguides.
Long-range dielectric-loaded surface plasmon-polariton waveguides (LR-DLSPPWs) operating at telecom wavelengths are efficiently (end-fire) interfaced with photonic waveguides by taking advantage of very similar lateral mode field profiles in these waveguide configurations. The LR-DLSPPWs are formed by 1-μm-high and 1-μm-wide polymer ridges fabricated atop 15-nm-thin and 500-nm-wide gold stripes supported by a 289-nm-thick ormoclear polymer deposited on a low-index (1.34) layer of cytop, whereas gold stripes are absent in the photonic waveguide configuration that is identical to the plasmonic one in all other respects. The coupling efficiency between LR-DLSPPWs and photonic waveguides is numerically estimated to be 97%, decreasing by only a few percents for non-centered gold stripes (as long as a gold stripe is kept inside the polymer ridge). The fabricated LR-DLSPPWs coupled to photonic waveguides are first characterized using amplitude- and phase-resolved near-field imaging of propagating radiation that reveals very similar mode field distributions in these waveguides as well as their efficient interfacing. The coupling efficiency is then experimentally characterized using the cutback approach resulting in an average level of 75% per interface, while the LR-DLSPPW mode propagation length is estimated to be on average 0.3 mm. Possible reasons for differences between experimental and simulation results are discussed, indicating that a 3-nm-thin titanium layer (used for improving adhesion between gold and ormoclear) introduces substantial mode absorption. The results obtained open new perspectives for realization of hybrid photonic-plasmonic components and circuits.


Reassortment and modification of hemagglutinin cleavage motif of avian/WSN influenza viruses generated by reverse genetics that correlate with attenuation.
Avian influenza associated with H9N2 and H5N1 subtypes of avian influenza viruses (AIVs) has raised great concerns in China. To study this problem, reverse genetics has been employed. Three reassortants, rgH9N2, rgH5N1 and rgH5N2, were prepared and compared. Their hemagglutinin (HA) and neuraminidase (NA) genes originated from Chinese AIV isolates of H9N2 or H5N1 subtype, while the rest of their genes were derived from A/WSN/33(H1N1) virus (WSN). In the H5 HA reassortants, the multibasic cleavage site was converted to a monobasic one. The results demonstrated that the reassortants did not produce CPE on MDCK cells in the absence of trypsin, showed egg-adaptation phenotype and stability of HA and NA during consecutive egg passages, and were not lethal to chickens and mice. However, the rgH5N1 reassortant exhibited a residual virulence in terms of lethality to chick embryos and pathogenesis in chickens. It can be concluded that (i) the genetic modification of H5 HA attenuated the H5 reassortants, (ii) the presence of internal WSN proteins contributed to the attenuated properties of the reassortants independently on H5 HA, and (iii) also the overall genome composition contributed to virulence differences. This report provides further contribution of reverse genetics to the knowledge of virulence of influenza viruses.


Cyclophosphamide: effect on experimental allergic encephalomyelitis in Lewis rats.
Lewis rats sensitized to spinal cord in adjuvant and exhibiting advanced clinical paralytic signs of experimental allergic encephalomyelitis were treated with cyclophosphamide (5 milligrams per kilogram) daily. Of 30 treated animals, 21 recovered rapidly and appeared clinically well within 7 to 12 days. This immunosuppressive agent may prove therapeutically useful in the treatment of autoimmune diseases.


Hidden in the Middle: Culture, Value and Reward in Bioinformatics.
Bioinformatics - the so-called shotgun marriage between biology and computer science - is an interdiscipline. Despite interdisciplinarity being seen as a virtue, for having the capacity to solve complex problems and foster innovation, it has the potential to place projects and people in anomalous categories. For example, valorised 'outputs' in academia are often defined and rewarded by discipline. Bioinformatics, as an interdisciplinary bricolage, incorporates experts from various disciplinary cultures with their own distinct ways of working. Perceived problems of interdisciplinarity include difficulties of making explicit knowledge that is practical, theoretical, or cognitive. But successful interdisciplinary research also depends on an understanding of disciplinary cultures and value systems, often only tacitly understood by members of the communities in question. In bioinformatics, the 'parent' disciplines have different value systems; for example, what is considered worthwhile research by computer scientists can be thought of as trivial by biologists, and vice versa. This paper concentrates on the problems of reward and recognition described by scientists working in academic bioinformatics in the United Kingdom. We highlight problems that are a consequence of its cross-cultural make-up, recognising that the mismatches in knowledge in this borderland take place not just at the level of the practical, theoretical, or epistemological, but also at the cultural level too. The trend in big, interdisciplinary science is towards multiple authors on a single paper; in bioinformatics this has created hybrid or fractional scientists who find they are being positioned not just in-between established disciplines but also in-between as middle authors or, worse still, left off papers altogether.


Evaluation of a theory-informed implementation intervention for the management of acute low back pain in general medical practice: the IMPLEMENT cluster randomised trial.
This cluster randomised trial evaluated an intervention to decrease x-ray referrals and increase giving advice to stay active for people with acute low back pain (LBP) in general practice. General practices were randomised to either access to a guideline for acute LBP (control) or facilitated interactive workshops (intervention). We measured behavioural predictors (e.g. knowledge, attitudes and intentions) and fear avoidance beliefs. We were unable to recruit sufficient patients to measure our original primary outcomes so we introduced other outcomes measured at the general practitioner (GP) level: behavioural simulation (clinical decision about vignettes) and rates of x-ray and CT-scan (medical administrative data). All those not involved in the delivery of the intervention were blinded to allocation. 47 practices (53 GPs) were randomised to the control and 45 practices (59 GPs) to the intervention. The number of GPs available for analysis at 12 months varied by outcome due to missing confounder information; a minimum of 38 GPs were available from the intervention group, and a minimum of 40 GPs from the control group. For the behavioural constructs, although effect estimates were small, the intervention group GPs had greater intention of practising consistent with the guideline for the clinical behaviour of x-ray referral. For behavioural simulation, intervention group GPs were more likely to adhere to guideline recommendations about x-ray (OR 1.76, 95%CI 1.01, 3.05) and more likely to give advice to stay active (OR 4.49, 95%CI 1.90 to 10.60). Imaging referral was not statistically significantly different between groups and the potential importance of effects was unclear; rate ratio 0.87 (95%CI 0.68, 1.10) for x-ray or CT-scan. The intervention led to small changes in GP intention to practice in a manner that is consistent with an evidence-based guideline, but it did not result in statistically significant changes in actual behaviour. Australian New Zealand Clinical Trials Registry ACTRN012606000098538.


Complementation of an Escherichia coli adhE mutant by the Entamoeba histolytica EhADH2 gene provides a method for the identification of new antiamebic drugs.
The pathogenic protozoan parasite Entamoeba histolytica, the cause of amebic dysentery and amebic liver abscess, is an obligate anaerobe, and derives energy from the fermentation of glucose to ethanol with pyruvate and acetyl coenzyme A as intermediates. We have isolated EhADH2, a key enzyme in this pathway, that is a NAD+- and Fe2+-dependent bifunctional enzyme with acetaldehyde dehydrogenase and alcohol dehydrogenase activities. EhADH2 is the only known eukaryotic member of a newly defined family of prokaryotic multifunctional enzymes, which includes the Escherichia coli AdhE enzyme, an enzyme required for anaerobic growth of E. coli. Because of the critical role of EhADH2 in the amebic fermentation pathway and the lack of known eukaryotic homologues of the EhADH2 enzyme, EhADH2 represents a potential target for antiamebic chemotherapy. However, screening of compounds for antiamebic activity is hampered by the cost of large scale growth of Ent. histolytica, and difficulties in quantitating drug efficacy in vitro. To approach this problem, we expressed the EhADH2 gene in a mutant strain of E. coli carrying a deletion of the adhE gene. Expression of EhADH2 restored the ability of the mutant E. coli strain to grow under anaerobic conditions. By screening compounds for the ability to inhibit the anaerobic growth of the E. coli/EhADH2 strain, we have developed a rapid assay for identifying compounds with anti-EhADH2 activity. Using bacteria to bypass the need for parasite culture in the initial screening process for anti-parasitic agents could greatly simplify and reduce the cost of identifying new therapeutic agents effective against parasitic diseases.


Rapid calculation of standardized placental volume at 11 to 13 weeks and the prediction of small for gestational age babies.
Fetal growth restriction is one of the greatest risk factors for stillbirth. This pilot cohort study examined whether rapid placental volume (PlaV) calculation at 11 to 13 + 6 weeks can predict the small for gestational age (cSGA) baby. Women with singleton pregnancies were recruited (N = 145), a static three-dimensional (3-D) volume was captured, and the placental volume was computed using a semi-automated technique. Regression analysis explored the relationships between customized birth weight, placental quotient (PQ), standardized placental volume (sPlaV), and other predictors of SGA (including pregnancy-associated protein and uterine artery pulsatility index (PI). The results were examined using receiver-operating characteristic (ROC) curve analysis in the total population and then in the 2 subgroups whose members were classified as low risk or high risk at booking. Both PQ and sPlaV were significantly different for cSGA pregnancies compared to appropriate for gestational age (AGA) babies (p = 0.003 and <0.001, respectively) but only sPlaV was normally distributed. The independent predictors of birth weight (sPlaV, pregnancy associated protein, and nuchal translucency) were combined to produce a predictive model for cSGA. The ROC curves for prediction of cSGA in all 143 women gave areas under the curve of 0.77 (0.66 to 0.87) for sPlaV alone and 0.80 (0.69 to 0.92) for the combined model. When this was applied to the low-risk group, the areas under the curve were 0.82 (0.69 to 0.94) and 0.84 (0.72 to 0.95), respectively. For the high-risk group, the areas under the curve were 0.67 (0.45 to 0.86) for sPlaV alone and 0.76 (0.55 to 0.96) for the combined model. The use of this rapid-image analysis technique and dimensionless index to correct for gestation brings the possibility of an early combined screening test for the cSGA baby a step closer.


Autofermentation of Chamomile Ligulate Flowers Promote Antitumor Effects in vitro.
In the frame of this paper, the enzyme-assisted hydrolysis coupled with ultrasound and Soxhlet extraction was applied in order to get extracts of chamomile ligulate flowers (CLF). Obtained extracts were characterized in terms to their apigenin and apigenin glucoside composition, as well as antiproliferative potential against tumour cells. Antioxidant activity was determined by two different assays based on different mechanisms showing that autofermented extracts have higher reduction potential. Autofermented extracts prepared by ultrasound and Soxhlet extraction had a stronger impact on the treated carcinoma (HeLa and NCI-H358) and leukemia (K562) cells' growth reduction in comparison to the native extracts, 30-35% greater inhibition at the lowest concentration (0.01 mg/mL), in two observed time points (48 and 72 h). Leukemia cells are more sensitive to all tested extracts. The autofermented CLF extracts with highest antiproliferative efficacy induced morphological changes and apoptosis in the HeLa cells. Obtained results clearly showed that the combination of enzymatic hydrolysis with cavitation phenomenon results in extracts with higher apigenin content and increased biological potential.


Deep resequencing unveils genetic architecture of ADIPOQ and identifies a novel low-frequency variant strongly associated with adiponectin variation.
Increased adiponectin levels have been shown to be associated with a lower risk of type 2 diabetes. To understand the relations between genetic variation at the adiponectin-encoding gene, ADIPOQ, and adiponectin levels, and subsequently its role in disease, we conducted a deep resequencing experiment of ADIPOQ in 14,002 subjects, including 12,514 Europeans, 594 African Americans, and 567 Indian Asians. We identified 296 single nucleotide polymorphisms (SNPs), including 30 amino acid changes, and carried out association analyses in a subset of 3,665 subjects from two independent studies. We confirmed multiple genome-wide association study findings and identified a novel association between a low-frequency SNP (rs17366653) and adiponectin levels (P = 2.2E-17). We show that seven SNPs exert independent effects on adiponectin levels. Together, they explained 6% of adiponectin variation in our samples. We subsequently assessed association between these SNPs and type 2 diabetes in the Genetics of Diabetes Audit and Research in Tayside Scotland (GO-DARTS) study, comprised of 5,145 case and 6,374 control subjects. No evidence of association with type 2 diabetes was found, but we were also unable to exclude the possibility of substantial effects (e.g., odds ratio 95% CI for rs7366653 [0.91-1.58]). Further investigation by large-scale and well-powered Mendelian randomization studies is warranted.


The capability set for work: development and validation of a new questionnaire.
The aim of this study was to develop a questionnaire to measure work capabilities based on Amartya Sen's capability approach and evaluate its validity. The development of the questionnaire was based on a combination of qualitative and quantitative methods: interviews, literature study, and an expert meeting. Additionally, in a survey, the validity was evaluated by means of hypotheses testing (using correlations and regression analyses). The questionnaire consists of a set of seven capability aspects for work. For each aspect, it is determined whether it is part of a worker's capability set, ie, when the aspect is considered valuable, is enabled in work, and is realized. The capability set was significantly correlated with work role functioning-flexibility demands (-0,187), work ability (-0.304), work performance (-0.282), worked hours (-0.073), sickness absence (yes/no) (0.098), and sickness absence days (0.105). The capability set and the overall capability item are significantly associated with all work outcomes (P<0.010). The new capability set for work questionnaire appears to be a valid instrument to measure work capabilities. The questionnaire is unique because the items include the valued aspects of work and incorporate whether a worker is able to achieve what (s)he values in his/her work. The questionnaire can be used to evaluate the capability set of workers in organizations to identify aspects that need to be addressed in interventions.


High-dose benzodiazepine dependence: a qualitative study of patients' perception on cessation and withdrawal.
Benzodiazepine withdrawal syndrome has been reported following attempts to withdraw even from low or therapeutic doses and has been compared to barbiturate and alcohol withdrawal. This experience is known to deter patients from future cessation attempts. Research on other psychotropic substances shows that the reasons and motivations for withdrawal attempts - as well as the experiences surrounding those attempts - at least partially predict future efforts at discontinuation as well as relapse. We therefore aimed to qualitatively explore what motivates patients to discontinue this medication as well as to examine their experiences surrounding previous and current withdrawal attempts and treatment interventions in order to positively influence future help-seeking behavior and compliance. To understand these patients better, we conducted a series of 41 unstructured, narrative, in-depth interviews among adult Swiss patients with a long-term dependent use of benzodiazepines in doses equivalent to more than 40 mg diazepam per day and/or otherwise problematic use (mixing benzodiazepines, escalating dosage, recreational use or illegal purchase). Mayring's qualitative content analysis was used to evaluate findings. These high-dose benzodiazepine-dependent patients decision to change consumption patterns were affected by health concerns, the feeling of being addicted and social factors. Discontinuation attempts were frequent and not very successful with fast relapse. Withdrawal was perceived to be a difficult, complicated, and highly unpredictable process. The first attempt at withdrawal occurred at home and typically felt better than at the clinic. Inpatient treatment was believed to be more effective with long term treatment (approaches) than short term. Patients preferred gradual reduction of usage to abrupt cessation (and had experienced both). While no clear preferences for withdrawal were found for benzodiazepines with specific pharmacokinetic properties, participants frequently based their decision to participate in treatment on the availability of their preferred brand name and furthermore discarding equivalent dosage rationales. Our findings provide greater understanding of the factors that motivate high-dose benzodiazepine-dependent individuals to stop taking these medications, and how they experience withdrawal and treatment strategies. They underscore how patients' perceptions of treatment approaches contribute to compliant or non-compliant behavior.


Commentary: What are the benefits of training deaf and hard-of-hearing doctors?
Deaf and hard-of-hearing (DHoH) individuals are underrepresented among physicians and physicians-in-training, yet this group is frequently overlooked in the diversity efforts of many medical training programs. The inclusion of DHoH individuals, with their diverse backgrounds, experiences, and struggles, contributes to medical education and health care systems in a variety of ways, including (1) a richer medical education experience for students and faculty resulting in greater disability awareness and knowledge about how to interact with and care for DHoH individuals and their families, (2) the provision of empathetic care desired by many patients and their families, including individuals who have a disability or chronic condition, and (3) the promotion of a more supportive and accessible professional environment for physicians, including older physicians in practice and as educators, who are experiencing age-associated decreased hearing acuity or other acquired disabilities.Today, many qualified DHoH individuals face barriers to pursuing medical careers even while physicians who become DHoH can continue to practice medicine. These barriers still exist two decades after the implementation of the Americans with Disabilities Act of 1990 and despite technological advancements and changing attitudes. In light of the findings by Moreland and colleagues, the authors of this commentary discuss reasons to include DHoH individuals in the physician workforce, explain why this group remains underrepresented among physicians, and suggest ways that medical schools and training programs can ensure fair application processes and inclusive educational opportunities for work with DHoH students who are interested in health care careers.


Vibrational coherence and quantum yield of retinal-chromophore-inspired molecular switches.
UV-Vis transient absorption (TA) spectroscopy is used to carry out a systematic investigation of the ultrafast C[double bond, length as m-dash]C double photoisomerization dynamics and quantum yield of each isomer of a set of six chromophores based on the same retinal-inspired, indanylidene pyrrolinium (IP) molecular framework. All compounds undergo a sub-picosecond photoisomerization, and can be categorized within two photoisomerization scenarios. Scenario I corresponds to compounds which display the signatures of a vibrationally coherent reactive motion through the conical intersection, with different degrees of vibrational coherence. Qualitatively distinct TA signatures are observed for other compounds which are therefore proposed to obey scenario II, referring to an intermediate regime between scenario I and a thermally-equilibrated, fully stochastic photoreaction. Remarkably, the photoisomerization scenario is observed to correlate with the computed distortion from planarity of the ground state equilibrium geometry, reflecting the torsional strain that would be released after photoexcitation. The most planar compounds - i.e. those having a C[double bond, length as m-dash]C double bond pre-twist of less than 10° - obey scenario II, while compounds obeying scenario I have larger pre-twists. The most pre-twisted compounds (>15°) show pronounced oscillatory signatures of a reaction-induced, low-frequency vibrational wavepacket observed in the S0 photoproduct and assigned to the torsion mode of the reaction coordinate, thus mimicking the vibrationally coherent photoisomerization dynamics of the rhodopsin protein. Importantly, the systematic comparison of all photoisomerization quantum yields does however not reveal any correlation with observables such as excited state life time, vibrational coherence, absorption wavelengths or degree of pre-twisting.


Activities of branched-chain 2-oxo acid dehydrogenase and its components in skin fibroblasts from normal and classical-maple-syrup-urine-disease subjects.
1. Comparisons of the activity and kinetics of the branched-chain 2-oxo acid dehydrogenase in cultured skin fibroblasts from normal and classical maple-syrup-urine-disease (MSUD) subjects provide a kinetic explanation for the enzyme defect. 2. In the intact cell assays, normal fibroblasts demonstrated hyperbolic kinetics with 3-methyl-2-oxo[1-14C]butyrate as a substrate. Intact fibroblasts from four classical MSUD patients showed no decarboxylation over a substrate concentration range of 0.25 to 5.0 mM, and thiamin (4 mM) was without effect. 3. The overall reaction of the multienzyme complex was efficiently reconstituted by using a disrupted-cell system. Normals again showed typical hyperbolic kinetics at the 2-oxo acid concentrations of 0.1 to 5 mM. The Vmax. and apparent Km values were 0.10 +/- 0.02 m-unit/mg of protein and 0.05-0.1 mM respectively, with 3-methyl-2-oxobutyrate. In contrast, classical MSUD patients exhibited sigmoidal kinetics (Hill coefficient, 2.5) with activity approaching 40-60% of the normal value at 5 mM substrate. The K0.5 values from the Hill plots for MSUD patients were 4-7 mM. 4. The E1 (branched-chain 2-oxo acid decarboxylase) component of the multienzyme complex was measured in disrupted-particulate preparations. Normals again showed hyperbolic kinetics with the 2-oxo acid, whereas MSUD preparations exhibited sigmoidal kinetics with the activity of E1 strictly dependent on substrate concentration. Apparent Km or K0.5 were 0.1 and 1.0 mM for normal and MSUD subjects respectively. 5. Measurements of E2 (dihydrolipoyl transacylase) and E3 (dihydrolipoyl dehydrogenase) in MSUD preparations showed them to be in the normal range. 6. The above data suggest a defect in the E1 step of branched-chain 2-oxo acid dehydrogenase in classical MSUD patients.


Minimization of dynamic effects in the evolution of dihydrofolate reductase.
Protein isotope labeling is a powerful technique to probe functionally important motions in enzyme catalysis and can be applied to investigate the conformational dynamics of proteins. Previous investigations have indicated that dynamic coupling is detrimental to catalysis by dihydrofolate reductase (DHFR) from the mesophile Escherichia coli (EcDHFR). Comparison of DHFRs from organisms adapted to survive at a wide range of temperatures suggests that dynamic coupling in DHFR catalysis has been minimized during evolution; it arises from reorganizational motions needed to facilitate charge transfer events. Contrary to the behaviour observed for the DHFR from the moderate thermophile Geobacillus stearothermophilus (BsDHFR), the chemical transformation catalyzed by the cold-adapted bacterium Moritella profunda (MpDHFR) is only weakly affected by protein isotope substitutions at low temperatures, but the isotopically substituted enzyme is a substantially inferior catalyst at higher, non-physiological temperatures. QM/MM studies revealed that this behaviour is caused by the enzyme's structural sensitivity to temperature changes, which enhances unfavorable dynamic coupling at higher temperatures by promoting additional recrossing trajectories on the transition state dividing surface. We postulate that these motions are minimized by fine-tuning DHFR flexibility through optimization of the free energy surface of the reaction, such that a nearly static reaction-ready configuration with optimal electrostatic properties is maintained under physiological conditions.


Serpentine stability to mantle depths and subduction-related magmatism.
Results of high-pressure experiments on samples of hydrated mantle rocks show that the serpentine mineral antigorite is stable to approximately 720 degrees C at 2 gigapascals, to approximately 690 degrees C at 3 gigapascals, and to approximately 620 degrees C at 5 gigapascals. The breakdown of antigorite to forsterite plus enstatite under these conditions produces 13 percent H(2)O by weight to depths of 150 to 200 kilometers in subduction zones. This H(2)O is in an ideal position for ascent into the hotter, overlying mantle where it can cause partial melting in the source region for calc-alkaline magmas at a depth of 100 to 130 kilometers and a temperature of approximately 1300 degrees C. The breakdown of antigorite in hydrated mantle produces an order of magnitude more H(2)O than does the dehydration of altered oceanic crust.


Lactate and Pyruvate Are Major Sources of Energy for Stallion Sperm with Dose Effects on Mitochondrial Function, Motility, and ROS Production.
Stallion sperm rely primarily on oxidative phosphorylation for production of ATP used in sperm motility and metabolism. The objective of the study was to identify which substrates included in Biggers, Whitten, and Whittingham (BWW) media are key to optimal mitochondrial function through measurements of sperm motility parameters, mitochondrial oxygen consumption, and cellular reactive oxygen species (ROS) production. It was expected that mitochondrial substrates, pyruvate and lactate, would support sperm motility and mitochondrial function better than the glycolytic substrate, glucose, due to direct utilization within the mitochondria. Measurements were performed after incubation in modified BWW media with varying concentrations of lactate, pyruvate, and glucose. The effects of media and duration of incubation on sperm motility, ROS production, and oxygen consumption were determined using a linear mixed-effects model. Duplicate ejaculates from four stallions were used in three separate experiments to determine the effects of substrate availability and concentration on sperm motility and mitochondrial function and the relationship of oxygen consumption with cellular ROS production. The present results indicate that lactate and pyruvate are the most important sources of energy for stallion sperm motility and velocity, and elicit a dose-dependent response. Additionally, lactate and pyruvate are ideal for maximal mitochondrial function, as sperm in these media operate at a very high level of their bioenergetic capability due to the high rate of energy metabolism. Moreover, we found that addition of glucose to the media is not necessary for short-term storage of equine sperm, and may even result in reduction of mitochondrial function. Finally, we have confirmed that ROS production can be the result of mitochondrial dysfunction as well as intense mitochondrial activity.


Apolipoprotein E polymorphism and Alzheimer disease: The Indo-US Cross-National Dementia Study.
The APOE*E4 allele of the gene for apolipoprotein E (APOE) has been reported as a risk factor for Alzheimer disease (AD) to varying degrees in different ethnic groups. To compare APOE*E4-AD epidemiological associations in India and the United States in a cross-national epidemiological study. Case-control design within 2 cohort studies, using standardized cognitive screening and clinical evaluation to identify AD and other dementias and polymerase chain reaction to identify APOE genotyping. Rural community samples, aged 55 years or older (n=4450) in Ballabgarh, India, and 70 years or older (n=886) in the Monongahela Valley region of southwestern Pennsylvania. Criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association for probable and possible AD and Clinical Dementia Rating (CDR) scale for dementia staging. Frequency of APOE*E4 was significantly lower (P<.001) in Ballabgarh vs the Monongahela Valley (0.07 vs 0.11). Frequency of probable or possible AD, with CDR of at least 1.0, in the Indian vs US samples, was as follows: aged 55 to 69 years, 0.1% (Indian sample only); aged 70 to 79 years, 0.7% vs 3.1%; aged 80 years or older, 4.0% vs 15.7%. Among those aged 70 years or older, adjusted odds ratios (95% confidence interval) for AD among carriers of APOE*E4 vs noncarriers were 3.4 (1.2-9.3) and 2.3 (1.3-4.0) in the Indian and US samples, respectively, and not significantly different between cohorts (P=. 20). This first report of APOE*E4 and AD from the Indian subcontinent shows very low prevalence of AD in Ballabgarh, India, but association of APOE*E4 with AD at similar strength in Indian and US samples. Arch Neurol. 2000.


Juvenile hormone regulates extreme mandible growth in male stag beetles.
The morphological diversity of insects is one of the most striking phenomena in biology. Evolutionary modifications to the relative sizes of body parts, including the evolution of traits with exaggerated proportions, are responsible for a vast range of body forms. Remarkable examples of an insect trait with exaggerated proportions are the mandibular weapons of stag beetles. Male stag beetles possess extremely enlarged mandibles which they use in combat with rival males over females. As with other sexually selected traits, stag beetle mandibles vary widely in size among males, and this variable growth results from differential larval nutrition. However, the mechanisms responsible for coupling nutrition with growth of stag beetle mandibles (or indeed any insect structure) remain largely unknown. Here, we demonstrate that during the development of male stag beetles (Cyclommatus metallifer), juvenile hormone (JH) titers are correlated with the extreme growth of an exaggerated weapon of sexual selection. We then investigate the putative role of JH in the development of the nutritionally-dependent, phenotypically plastic mandibles, by increasing hemolymph titers of JH with application of the JH analog fenoxycarb during larval and prepupal developmental periods. Increased JH signaling during the early prepupal period increased the proportional size of body parts, and this was especially pronounced in male mandibles, enhancing the exaggerated size of this trait. The direction of this response is consistent with the measured JH titers during this same period. Combined, our results support a role for JH in the nutrition-dependent regulation of extreme mandible growth in this species. In addition, they illuminate mechanisms underlying the evolution of trait proportion, the most salient feature of the evolutionary diversification of the insects.


Technical, economic and environmental assessment of sludge treatment wetlands.
Sludge treatment wetlands (STW) emerge as a promising sustainable technology with low energy requirements and operational costs. In this study, technical, economic and environmental aspects of STW are investigated and compared with other alternatives for sludge management in small communities (<2000 population equivalent). The performance of full-scale STW was characterised during 2 years. Sludge dewatering increased total solids (TS) concentration by 25%, while sludge biodegradation lead to volatile solids around 45% TS and DRI(24h) between 1.1 and 1.4 gO(2)/kgTS h, suggesting a partial stabilisation of biosolids. In the economic and environmental assessment, four scenarios were considered for comparison: 1) STW with direct land application of biosolids, 2) STW with compost post-treatment, 3) centrifuge with compost post-treatment and 4) sludge transport to an intensive wastewater treatment plant. According to the results, STW with direct land application is the most cost-effective scenario, which is also characterised by the lowest environmental impact. The life cycle assessment highlights that global warming is a significant impact category in all scenarios, which is attributed to fossil fuel and electricity consumption; while greenhouse gas emissions from STW are insignificant. As a conclusion, STW are the most appropriate alternative for decentralised sludge management in small communities.


Treated and untreated rock dust: Quartz content and physical characterization.
Rock dusting is used to prevent secondary explosions in coal mines, but inhalation of rock dusts can be hazardous if the crystalline silica (e.g., quartz) content in the respirable fraction is high. The objective of this study is to assess the quartz content and physical characteristics of four selected rock dusts, consisting of limestone or marble in both treated (such as treatment with stearic acid or stearates) and untreated forms. Four selected rock dusts (an untreated and treated limestone and an untreated and treated marble) were aerosolized in an aerosol chamber. Respirable size-selective sampling was conducted along with particle size-segregated sampling using a Micro-Orifice Uniform Deposit Impactor. Fourier Transform Infrared spectroscopy and scanning electron microscopy with energy-dispersive X-ray (SEM-EDX) analyses were used to determine quartz mass and particle morphology, respectively. Quartz percentage in the respirable dust fraction of untreated and treated forms of the limestone dust was significantly higher than in bulk samples, but since the bulk percentage was low the enrichment factor would not have resulted in any major change to conclusions regarding the contribution of respirable rock dust to the overall airborne quartz concentration. The quartz percentage in the marble dust (untreated and treated) was very low and the respirable fractions showed no enrichment. The spectra from SEM-EDX analysis for all materials were predominantly from calcium carbonate, clay, and gypsum particles. No free quartz particles were observed. The four rock dusts used in this study are representative of those presented for use in rock dusting, but the conclusions may not be applicable to all available materials.


A radiation hybrid map of chromosome 1D reveals synteny conservation at a wheat speciation locus.
The species cytoplasm specific (scs) genes affect nuclear-cytoplasmic interactions in interspecific hybrids. A radiation hybrid (RH) mapping population of 188 individuals was employed to refine the location of the scs (ae) locus on Triticum aestivum chromosome 1D. "Wheat Zapper," a comparative genomics tool, was used to predict synteny between wheat chromosome 1D, Oryza sativa, Brachypodium distachyon, and Sorghum bicolor. A total of 57 markers were developed based on synteny or literature and genotyped to produce a RH map spanning 205.2 cR. A test-cross methodology was devised for phenotyping of RH progenies, and through forward genetic, the scs (ae) locus was pinpointed to a 1.1 Mb-segment containing eight genes. Further, the high resolution provided by RH mapping, combined with chromosome-wise synteny analysis, located the ancestral point of fusion between the telomeric and centromeric repeats of two paleochromosomes that originated chromosome 1D. Also, it indicated that the centromere of this chromosome is likely the result of a neocentromerization event, rather than the conservation of an ancestral centromere as previously believed. Interestingly, location of scs locus in the vicinity of paleofusion is not associated with the expected disruption of synteny, but rather with a good degree of conservation across grass species. Indeed, these observations advocate the evolutionary importance of this locus as suggested by "Maan's scs hypothesis."


Global cardiovascular device innovation: Japan-USA synergies: Harmonization by Doing (HBD) program, a consortium of regulatory agencies, medical device industry, and academic institutions.
Global medical devices have become more popular, but investment money for medical device development is not easily available in the market. Worldwide health-care budget constraints mean that efficient medical device development has become essential. To achieve efficient development, globalization is a key to success. Spending large amounts of money in different regions for medical device development is no longer feasible. In order to streamline processes of global medical device development, an academic, governmental, and industrial consortium, called the Harmonization by Doing program, has been set up. The program has been operating between Japan and the USA since 2003. The program has 4 working groups: (1) Global Cardiovascular Device Trials; (2) Study on Post-Market Registry; (3) Clinical Trials; and (4) Infrastructure and Methodology Regulatory Convergence and Communication. Each working group has as its goals the achievement of speedy and efficient medical device development in Japan and the USA. The program has held multiple international meetings to deal with obstacles against efficient medical device development. This kind of program is very important to deliver novel medical devices. Involvement of physicians in this type of activity is also very helpful to achieve these goals.


Gibberellin 20-oxidase gene OsGA20ox3 regulates plant stature and disease development in rice.
Gibberellin (GA) 20-oxidase (GA20ox) catalyses consecutive steps of oxidation in the late part of the GA biosynthetic pathway. A T-DNA insertion mutant (17S-14) in rice, with an elongated phenotype, was isolated. Analysis of the flanking sequences of the T-DNA insertion site revealed that an incomplete T-DNA integration resulted in enhanced constitutively expression of downstream OsGA20ox3 in the mutant. The accumulation of bioactive GA(1) and GA(4) were increased in the mutant in comparison with the wild-type plant. Transgenic plants overexpressing OsGA20ox3 showed phenotypes similar to those of the 17S-14 mutant, and the RNA interference (RNAi) lines that had decreased OsGA20ox3 expression exhibited a semidwarf phenotype. Expression of OsGA20ox3 was detected in the leaves and roots of young seedlings, immature panicles, anthers, and pollens, based on β-glucuronidase (GUS) activity staining in transgenic plants expressing the OsGA20ox3 promoter fused to the GUS gene. The OsGA20ox3 RNAi lines showed enhanced resistance against rice pathogens Magnaporthe oryzae (causing rice blast) and Xanthomonas oryzae pv. oryzae (causing bacterial blight) and increased expression of defense-related genes. Conversely, OsGA20ox3-overexpressing plants were more susceptible to these pathogens comparing with the wild-type plants. The susceptibility of wild-type plants to X. oryzae pv. oryzae was increased by exogenous application of GA(3) and decreased by S-3307 treatment. Together, the results provide direct evidence for a critical role of OsGA20ox3 in regulating not only plant stature but also disease resistance in rice.


The effect of green coffee extract supplementation on blood pressure: A systematic review and meta-analysis of randomized controlled trials.
Given the proliferation in studies investigating green coffee bean extract (GCBE) supplementation, the purpose of this study was to determine the efficacy and effectiveness of GCBE supplementation on indices of blood pressure. The literature search was performed in four databases, namely, PubMed/Medline, Scopus, the Cochrane Library, and Google Scholar, to identify clinical trials that examined the effects of green coffee supplements on systolic blood pressure (SBP) and diastolic blood pressure (DBP) up to February 2019. Mean change and standard deviation (SD) of the outcome measures were used to estimate the mean difference between the intervention group and the control group at follow-up. Nine studies reported SBP and DBP as an outcome measure. Results revealed significant reduction in SBP (weighted mean difference: -3.093 mmHg, 95% confidence interval [CI]: -3.914, -2.273; I2 = 0.0%) and DBP (-2.170 mmHg, 95% CI: -2.749, -1.590; I2 = 46.5%) after green coffee supplementation with low heterogeneity among the studies. In addition, in subgroup analysis, a significant reduction in SBP and DBP in studies with hypertensive patients, green coffee dosage <400 mg, and administered for 4 weeks was identified. The results of the current meta-analysis study support the use of GCBE supplementation for the improvement of blood pressure indices, with subgroup analysis highlighting improvements in hypertensive patients.


The Distribution of the Asymptotic Number of Citations to Sets of Publications by a Researcher or from an Academic Department Are Consistent with a Discrete Lognormal Model.
How to quantify the impact of a researcher's or an institution's body of work is a matter of increasing importance to scientists, funding agencies, and hiring committees. The use of bibliometric indicators, such as the h-index or the Journal Impact Factor, have become widespread despite their known limitations. We argue that most existing bibliometric indicators are inconsistent, biased, and, worst of all, susceptible to manipulation. Here, we pursue a principled approach to the development of an indicator to quantify the scientific impact of both individual researchers and research institutions grounded on the functional form of the distribution of the asymptotic number of citations. We validate our approach using the publication records of 1,283 researchers from seven scientific and engineering disciplines and the chemistry departments at the 106 U.S. research institutions classified as "very high research activity". Our approach has three distinct advantages. First, it accurately captures the overall scientific impact of researchers at all career stages, as measured by asymptotic citation counts. Second, unlike other measures, our indicator is resistant to manipulation and rewards publication quality over quantity. Third, our approach captures the time-evolution of the scientific impact of research institutions.


Professionally perceived effectiveness of psychosocial interventions for existential suffering of terminally ill cancer patients.
Although integrated care for existential suffering is an essential part of palliative care, little is known about its concept and efficacy as perceived by professionals. A questionnaire survey was carried out to 1) explore the underlying structure of psychosocial interventions recommended by specialists, 2) identify the professionally perceived effectiveness of each intervention for specific existential distress, and 3) examine the effects of specialty on their recommendations. A questionnaire with three scenarios representing terminally ill cancer patients with uncertainty-related anxiety, guilt feelings, and dependency-related meaninglessness was mailed to 701 Japanese psychiatrists, 118 psychologists, and 372 palliative care nurses. A total of 456 responses were obtained (response rate = 38%). Recommended psychosocial interventions were classified into six subcategories: 'a supportive-expressive approach,' 'providing comfortable environments,' 'meaning-centered approach,' 'being,' 'education and coping skills training,' and 'a religious approach.' A 'supportive-expressive approach' was consistently recommended in all vignettes. On the other hand, 'providing comfortable environments' was most recommended for patients with uncertainty-related anxiety, and a 'meaning-centered approach' and 'being' were most recommended for patients feeling dependency-related meaninglessness. Psychiatrists estimated the effectiveness of psychopharmacological treatment significantly higher than psychologists and nurses, while nurses evaluated efficacy of all other interventions significantly higher than psychiatrists and psychologists. Experts evaluated a variety of clinical interventions as effective in palliating existential suffering, although the perceived levels of efficacy of each intervention differed according to the nature of suffering and their specialties. To effectively alleviate existential suffering in terminally ill cancer patients, an integrated care by an interdisciplinary team is necessary.


Differential Role of B Cells and IL-17 Versus IFN-γ During Early and Late Rejection of Pig Islet Xenografts in Mice.
Xenogeneic islet transplantation is an emerging therapeutic option for diabetic patients. However, immunological tolerance to xenogeneic islets remains a challenge. The current study used a pig-to-mouse discordant xenogeneic islet transplant model to examine antidonor xenogeneic immune responses during early and late rejection and to determine experimental therapeutic interventions that promote durable pig islet xenograft survival. We found that during early acute rejection of pig islet xenografts, the rejecting hosts exhibited a heavy graft infiltration with B220 B cells and a robust antipig antibody production. In addition, early donor-stimulated IL-17 production, but not IFN-γ production, dominated during early acute rejection. Recipient treatment with donor apoptotic 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide-treated splenocytes significantly inhibited antidonor IL-17 response, and when combined with B cell depletion and a short course of rapamycin led to survival of pig islet xenografts beyond 100 days in approximately 65% recipients. Interestingly, treated recipients in this model experienced late rejection between 100 and 200 days posttransplant, which coincided with B cell reconstitution and an ensuing emergence of a robust antidonor IFN-γ, but not IL-17, response. These findings reveal that early and late rejection of pig islet xenografts may be dominated by different immune responses and that maintenance of long-term xenogeneic tolerance will require strategies that target the temporal sequence of antixenogeneic immune responses.


Life Course Perspective: evidence for the role of nutrition.
The "Life Course Perspective" proposes that environmental exposures, including biological, physical, social, and behavioral factors, as well as life experiences, throughout the entire life span, influence health outcomes in current and future generations. Nutrition, from preconception to adulthood, encompasses all of these factors and has the potential to positively or negatively shape the individual or population health trajectories and their intergenerational differences. This paper applies the T2E2 model (timing, timeline, equity and environment), developed by Fine and Kotelchuck, as an overlay to examine advances in nutritional science, as well as the complex associations between life stages, nutrients, nutrigenomics, and access to healthy foods, that support the life course perspective. Examples of the application of nutrition to each of the four constructs are provided, as well as a strong recommendation for inclusion of nutrition as a key focal point for all health professionals as they address solutions to optimize health outcomes, both domestically and internationally. The science of nutrition provides strong evidence to support the concepts of the life course perspective. These findings lend urgency to the need to improve population health across the life span and over generations by ensuring ready access to micronutrient-dense foods, opportunities to balance energy intake with adequate physical activity and the need for biological, social, physical, and macro-level environments that support critical phases of human development. Recommendations for the application of the life course perspective, with a focus on the emerging knowledge of nutritional science, are offered in an effort to improve current maternal and child health programs, policies, and service delivery.


Studies on the use of non-Rayleigh statistics for ultrasonic tissue characterization.
The research groups at Drexel University and Thomas Jefferson University had proposed the use of non-Rayleigh statistics for tissue characterization. Previous work based on the hypothesis that the envelope of the backscattered echosignal from abnormal regions of the tissue is more likely to be K-distributed than Rayleigh distributed, used the parameter of the K-distribution, M, to distinguish between regions containing benign or malignant masses and normal ones. In this work the B-scan breast images of 19 patients were studied using this approach. Previous studies have also been extended to exploit the existence of non-uniform phase characteristics of the echosignal from scatterers with some regular spacings, such as those in a periodic or quasi-periodic alignment. Computer simulations were carried out to show that the phase statistics deviate significantly from uniform in the range of (0, 2 pi) if the imaging region contained a number of periodically aligned (regular lattice) scatterers along with a collection of randomly distributed scatterers resulting in a quasi-periodic arrangement. This methodology was then applied to B-scan images of the breasts to distinguish between benign and malignant masses. If benign lesions show some sort of quasi-periodic or regular structures in the tissue, they will present non-uniform phase characteristics while more randomly structured malignant masses will have uniform phase characteristics. It is seen that the K-distribution may be used to identify the abnormal regions in the breast images and information on the phase may be used to further separate the abnormal regions into benign and malignant ones.


The genome of Polaromonas naphthalenivorans strain CJ2, isolated from coal tar-contaminated sediment, reveals physiological and metabolic versatility and evolution through extensive horizontal gene transfer.
We analysed the genome of the aromatic hydrocarbon-degrading, facultatively chemolithotrophic betaproteobacterium, Polaromonas naphthalenivorans strain CJ2. Recent work has increasingly shown that Polaromonas species are prevalent in a variety of pristine oligotrophic environments, as well as polluted habitats. Besides a circular chromosome of 4.4 Mb, strain CJ2 carries eight plasmids ranging from 353 to 6.4 kb in size. Overall, the genome is predicted to encode 4929 proteins. Comparisons of DNA sequences at the individual gene, gene cluster and whole-genome scales revealed strong trends in shared heredity between strain CJ2 and other members of the Comamonadaceae and Burkholderiaceae. blastp analyses of protein coding sequences across strain CJ2's genome showed that genetic commonalities with other betaproteobacteria diminished significantly in strain CJ2's plasmids compared with the chromosome, especially for the smallest ones. Broad trends in nucleotide characteristics (GC content, GC skew, Karlin signature difference) showed at least six anomalous regions in the chromosome, indicating alteration of genome architecture via horizontal gene transfer. Detailed analysis of one of these anomalous regions (96 kb in size, containing the nag-like naphthalene catabolic operon) indicates that the fragment's insertion site was within a putative MiaB-like tRNA-modifying enzyme coding sequence. The mosaic nature of strain CJ2's genome was further emphasized by the presence of 309 mobile genetic elements scattered throughout the genome, including 131 predicted transposase genes, 178 phage-related genes, and representatives of 12 families of insertion elements. A total of three different terminal oxidase genes were found (putative cytochrome aa(3)-type oxidase, cytochrome cbb(3)-type oxidase and cytochrome bd-type quinol oxidase), suggesting adaptation by strain CJ2 to variable aerobic and microaerobic conditions. Sequence-suggested abilities of strain CJ2 to carry out nitrogen fixation and grow on the aromatic compounds, biphenyl and benzoate, were experimentally verified. These new phenotypes and genotypes set the stage for gaining additional insights into the physiology and biochemistry contributing to strain CJ2's fitness in its native habitat, contaminated sediment.


Compassion Competence in Nurses.
The purpose of study was to identify the attributes of the concept of compassion competence for nurses. A hybrid model was used to develop the concept, which included fieldwork performed. The concept of compassion competence was found to possess 3 dimensions: (a) acquisition of a wealth of knowledge; (b) development of skills of emotional communication, sensitivity, insight, and self-regulation; and (c) development of attitudes of respect and empathy, and maintenance of occupational distance. Compassion competence could be useful for developing ways to enhance the knowledge, skills, and attitudes required for nurses to provide compassionate care in various nursing practices.


Evidence-based medicine.
Evidence-based medicine, whose philosophical origins extend back to mid-19th century Paris and earlier, is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that we individual clinicians acquire through clinical experience and clinical practice. Increased expertise is reflected in many ways, but especially in more effective and efficient diagnosis and in the more thoughtful identification and compassionate use of individual patients' predicaments, rights, and preferences in making clinical decisions about their care. By best available external clinical evidence we mean clinically relevant research, often from the basic sciences of medicine, but especially from patient centered clinical research into the accuracy and precision of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens. External clinical evidence both invalidates previously accepted diagnostic tests and treatment and replaces them with new ones that are more powerful, more accurate, more efficacious, and safer. Good doctors use both individual clinical expertise and the best available external evidence, and neither alone is enough. Without clinical expertise, practice risks becoming tyrannized by external evidence, for even excellent external evidence may be inapplicable to or inappropriate for an individual patient. Without current best external evidence, practice risks becoming rapidly out of date, to the detriment of patients. The practice of evidence-based medicine is a process of life-long, self-directed learning in which caring for our own patients creates the need for clinically important information about diagnosis, prognosis, therapy, and other clinical and health care issues, and in which we (1) convert these information needs into answerable questions; (2) track down, with maximum efficiency, the best evidence with which to answer them (whether from the clinical examination, the diagnostic laboratory from research evidence, or other sources); (3) critically appraise that evidence for its validity (closeness to the truth) and usefulness (clinical applicability); (4) integrate this appraisal with our clinical expertise and apply it in practice; and (5) evaluate our performance.


From fatty liver to fibrosis: a tale of "second hit".
Although much is known about how fat accumulates in the liver, much remains unknown about how this causes sustained hepatocellular injury. The consequences of injury are recognized as nonalcoholic steatohepatitis (NASH) and progressive fibrosis. The accumulation of fat within the hepatocytes sensitizes the liver to injury from a variety of causes and the regenerative capacity of a fatty liver is impaired. An additional stressor is sometimes referred to as a "second hit" in a paradigm that identifies the accumulation of fat as the "first hit". Possible candidates for the second hit include increased oxidative stress, lipid peroxidation and release of toxic products such as malondialdehyde and 4-hydroxynonenal, decreased antioxidants, adipocytokines, transforming growth factor (TGF)-β, Fas ligand, mitochondrial dysfunction, fatty acid oxidation by CYPs (CYP 2E1, 4A10 and 4A14), and peroxisomes, excess iron, small intestinal bacterial overgrowth, and the generation of gut-derived toxins such as lipopolysaccharide and ethanol. Oxidative stress is one of the most popular proposed mechanisms of hepatocellular injury. Previous studies have specifically observed increased plasma and tissue levels of oxidative stress markers and lipid peroxidation products, with reduced hepatic and plasma levels of antioxidants. There is also some indirect evidence of the benefit of antioxidants such as vitamin E, S-adenosylmethionine, betaine, phlebotomy to remove iron, and N-acetylcysteine in NASH. However, a causal relationship or a pathogenic link between NASH and oxidative stress has not been established so far. A number of sources of increased reactive oxygen species production have been established in NASH that include proinflammatory cytokines such as tumor necrosis factor (TNF)-α, iron overload, overburdened and dysfunctional mitochondria, CYPs, and peroxisomes. Briefly, the pathogenesis of NASH is multifactorial and excess intracellular fatty acids, oxidant stress, ATP depletion, and mitochondrial dysfunction are important causes of hepatocellular injury in the steatotic liver.