Nonstable Staphylococcus aureus Small-Colony Variants Are Induced by Low pH and Sensitized to Antimicrobial Therapy by Phagolysosomal Alkalinization.
Staphylococcus aureus-infected patients treated with antibiotics that are effective in vitro often experience relapse of infection because the bacteria hide in privileged locations. These locations include abscesses and host cells, which contain low-pH compartments and are sites from which nonstable S. aureus small-colony variants (SCVs) are frequently recovered. We assessed the effect of low pH on S. aureus colony phenotype and bacterial growth, using in vitro and in vivo models of long-term infection. We showed that low pH induced nonstable SCVs and nonreplicating persisters that are capable of regrowth. Within host cells, S. aureus was located in phagolysosomes, a low-pH compartment. Therapeutic neutralization of phagolysosomal pH with ammonium chloride, bafilomycin A1, or the antimalaria drug chloroquine reduced SCVs in infected host cells. In a systemic mouse infection model, treatment with chloroquine also reduced SCVs. Our results show that the acidic environment favors formation of nonstable SCVs, which reflect the SCVs found in clinics. They also provide evidence that treatment with alkalinizing agents, together with antibiotics, may provide a novel translational strategy for eradicating persisting intracellular reservoirs of staphylococci. This approach may also be extended to other intracellular bacteria.


Temporal origin of mouse claustrum and development of its cortical projections.
The claustrum is known for its extensive connectivity with many other forebrain regions, but its elongated shape and deep location have made further study difficult. We have sought to understand when mouse claustrum neurons are born, where they are located in developing brains, and when they develop their widespread connections to the cortex. We established that a well-characterized parvalbumin plexus, which identifies the claustrum in adults, is only present from postnatal day (P) 21. A myeloarchitectonic outline of the claustrum can be derived from a triangular fiber arrangement from P15. A dense patch of Nurr1+ cells is present at its core and is already evident at birth. Bromodeoxyuridine birth dating of forebrain progenitors reveals that the majority of claustrum neurons are born during a narrow time window centered on embryonic day 12.5, which is later than the adjacent subplate and endopiriform nucleus. Retrograde tracing revealed that claustrum projections to anterior cingulate (ACA) and retrosplenial cortex (RSP) follow distinct developmental trajectories. Claustrum-ACA connectivity matures rapidly and reaches adult-like innervation density by P10, whereas claustrum-RSP innervation emerges later over a protracted time window. This work establishes the timeline of claustrum development and provides a framework for understanding how the claustrum is built and develops its unique connectivity.


Purcell effect in nonlinear photonic structures: a coupled mode theory analysis.
We develop a coupled mode theory (CMT) model of the behavior of a polarization source in a general photonic structure, and obtain an analytical expression for the resulting generated electric field; loss, gain and/or nonlinearities can also be modeled. Based on this treatment, we investigate the criteria needed to achieve an enhancement in various nonlinear effects, and to produce efficient sources of terahertz radiation, in particular. Our results agree well with exact finite-difference time-domain (FDTD) results. Therefore, this approach can also in certain circumstances be used as a potential substitute for the more numerically intensive FDTD method.


Exercise training enhanced SIRT1 longevity signaling replaces the IGF1 survival pathway to attenuate aging-induced rat heart apoptosis.
Cardiovascular disease is the second leading cause of death (9.1 %) in Taiwan. Heart function deteriorates with age at a rate of 1 % per year. As society ages, we must study the serious problem of cardiovascular disease. SIRT1 regulates important cellular processes, including anti-apoptosis, neuronal protection, cellular senescence, aging, and longevity. In our previous studies, rats with obesity, high blood pressure, and diabetes exhibiting slowed myocardial performance and induced cell apoptosis were reversed via sports training through IGF1 survival signaling compensation. This study designed a set of experiments with rats, in aging and exercise groups, to identify changes in myocardial cell signaling transduction pathways. Three groups of three different aged rats, 3, 12, and 18 months old, were randomly divided into aging groups (C3, A12, and A18) and exercise groups (E3, AE12, and AE18). The exercise training consisted of swimming five times a week with gradual increases from the first week from 20 to 60 min for 12 weeks. After the sports training process was completed, tissue sections were taken to observe cell organization (hematoxylin and eosin (H&E) stain) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays) and to observe any changes in the myocardial tissues and proteins (Western blotting). The experimental results show that cardiomyocyte apoptotic pathway protein expression increased with age in the aging groups (C3, A12, and A18), with improvement in the exercise group (E3, AE12, and AE18). However, the expression of the pro-survival p-Akt protein decreased significantly with age and reduced performance. The IGF1R/PI3K/Akt survival pathway in the heart of young rats can indeed be increased through exercise training. As rats age, this pathway loses its original function, even with increasing upstream IGF1. However, levels of SIRT1 and its downstream target PGC-1α were found to increase with age and compensatory performance. Moreover, exercise training enhanced the SIRT longevity pathway compensation instead of IGF1 survival signaling to improve cardiomyocyte survival.


Recent progress on exploring exceptionally high and anisotropic H+/OH- ion conduction in two-dimensional materials.
Ion conducting membranes/electrolytes have been employed extensively in some important industrial and biological systems, especially in fuel cells, water electrolyzers, gas separation, sensors and biological selective ion transport, acting as one of the core components and sometimes directly determining the device performance. However, the traditional polymeric proton exchange membranes (PEMs)/anion exchange membranes (AEMs) suffer from highly toxic preparation procedures, poor thermal and chemical stabilities, and unsatisfactory ion conductivities. This has triggered researchers worldwide to explore alternative inorganic building blocks with high ion conductivities and stabilities from the new materials library, hoping to solve the above long-lasting problems. The recent burgeoning research on two-dimensional (2D) materials has unveiled exceptionally high ionic conductivities, which raises the feasibility of fabricating high-performance nanosheet-based ion conductors/membranes. In this perspective, the recent advances in measuring and understanding the exceptionally high and anisotropic H+/OH- ion conductivities of representative 2D materials, e.g. graphene oxide (GO), vermiculite and layered double hydroxide (LDH) nanosheets, are reviewed. In particular, regarding the anisotropic ionic conduction in 2D nanosheets, possible design strategies and technological innovations for fabricating macroscopic nanosheet-based ionic conductors/membranes are proposed for maximizing the high in-plane conduction, which may serve to guide future development of high-performance industrial and biological systems relying on H+/OH- conducting membranes.


Congruent Deep Relationships in the Grape Family (Vitaceae) Based on Sequences of Chloroplast Genomes and Mitochondrial Genes via Genome Skimming.
Vitaceae is well-known for having one of the most economically important fruits, i.e., the grape (Vitis vinifera). The deep phylogeny of the grape family was not resolved until a recent phylogenomic analysis of 417 nuclear genes from transcriptome data. However, it has been reported extensively that topologies based on nuclear and organellar genes may be incongruent due to differences in their evolutionary histories. Therefore, it is important to reconstruct a backbone phylogeny of the grape family using plastomes and mitochondrial genes. In this study,next-generation sequencing data sets of 27 species were obtained using genome skimming with total DNAs from silica-gel preserved tissue samples on an Illumina NextSeq 500 instrument [corrected]. Plastomes were assembled using the combination of de novo and reference genome (of V. vinifera) methods. Sixteen mitochondrial genes were also obtained via genome skimming using the reference genome of V. vinifera. Extensive phylogenetic analyses were performed using maximum likelihood and Bayesian methods. The topology based on either plastome data or mitochondrial genes is congruent with the one using hundreds of nuclear genes, indicating that the grape family did not exhibit significant reticulation at the deep level. The results showcase the power of genome skimming in capturing extensive phylogenetic data: especially from chloroplast and mitochondrial DNAs.


Influence of continuous combined estradiol-norethisterone acetate preparations on insulin sensitivity in postmenopausal nondiabetic women.
Estrogen-progestogen replacement therapy (HRT) may be associated with deterioration of insulin sensitivity in comparison to estrogens alone, which tend to improve insulin sensitivity in postmenopausal women. Insulin sensitivity with the use of continuous combined 17-beta estradiol/norethisterone acetate (E2/NETA) preparations has not been examined before in postmenopausal women. In a double-blind randomized parallel study, we evaluated the effect of 2 mg E2/1 mg NETA (high dose E2/NETA), 1 mg E2/0.5 mg NETA (low dose E2/NETA), or placebo (P) on the insulin sensitivity index (SI) in three groups (18 women/group) of postmenopausal nondiabetic women (follicle stimulating hormone [FSH] > 40 mIU/mL, mean +/- SD) aged 56 +/- 3 years, BMI 25 +/- 4 kg/m2, cholesterol 233 +/- 42 mg/dL, and triglycerides 87 +/- 36 mg/dL. Insulin sensitivity was measured by means of a two-step hyperinsulinemic euglycemic glucose clamp (insulin infusion rate, 0.25 and 1.0 mU/kg/min for 120 min each) at baseline and after 3 months of daily administration of high dose E2/NETA, low dose E2/NETA, or P. Analysis was performed assuming equivalence of start-end changes of insulin sensitivity among treatment groups (Anderson-Hauck test). SI was 7.7 +/- 2.9, 7.5 +/- 3.4, 6.8 +/- 2.2 at baseline and 6.3 +/- 3.0, 7.9 +/- 2.5, 7.1 +/- 3.1 mL/min/m2 per mu U/mL 3 months after the administration of high dose E2/NETA, low dose E2/NETA, and P, respectively. The low dose E2/NETA group had start-to-end changes of SI which were equivalent to the P group (0.4 [95% confidence interval [CI] -0.8; 1.7] vs. 0.4 [-0.3; 1.0]) (p = 0.02). For the high dose E2/NETA group, equivalence could not be shown with either the P (p = 0.89) or with the low dose E2/NETA group (p = 0.90). SI within the high dose E2/NETA group decreased by -1.5 (95% CI -2.7; -0.2) mL/min/m2 per mu U/mL. HbAlc decreased from 5.3 +/- 0.3 to 5.1 +/- 0.3% within the high dose E2/NETA group (p < 0.03) and remained unchanged within the low dose E2/NETA and P group. Fasting plasma glucose, fasting serum insulin, and C-peptide, as well as triglycerides and BMI were comparable among the groups at baseline and after 3 months. Total cholesterol decreased by 12% and 8% in women treated with high dose and low dose E2/NETA (p < 0.02), respectively, and remained unchanged within the P group. These results indicate that 3 months use of a low dose continuous E2/NETA preparation does not change insulin sensitivity in postmenopausal women. At high dose of E2/NETA, a modest decrease seems possible. The effects of E2/NETA on other parameters of carbohydrate and lipid metabolism are neutral or favorable.


Dietary intakes assessed by 24-h recalls in peri-urban African adolescents: validity of energy intake compared with estimated energy expenditure.
The objective of this study is to determine the relative validity of reported energy intake (EI) derived from multiple 24-h recalls against estimated energy expenditure (EE(est)). Basal metabolic rate (BMR) equations and physical activity factors were incorporated to calculate EE(est). This analysis was nested in the multidisciplinary PhysicaL Activity in the Young study with a prospective study design. Peri-urban black South African adolescents were investigated in a subsample of 131 learners (87 girls and 44 boys) from the parent study sample of 369 (211 girls and 158 boys) who had all measurements taken. Pearson correlation coefficients and Bland-Altman plots were calculated to identify the most accurate published equations to estimate BMR (P<0.05 statistically significant). EE(est) was estimated using BMR equations and estimated physical activity factors derived from Previous Day Physical Activity Recall questionnaires. After calculation of EE(est), the relative validity of reported energy intake (EI(rep)) derived from multiple 24-h recalls was tested for three data subsets using Pearson correlation coefficients. Goldberg's formula identified cut points (CPs) for under and over reporting of EI. Pearson correlation coefficients between calculated BMRs ranged from 0.97 to 0.99. Bland-Altman analyses showed acceptable agreement (two equations for each gender). One equation for each gender was used to calculate EE(est). Pearson correlation coefficients between EI(rep) and EE(est) for three data sets were weak, indicating poor agreement. CPs for physical activity groups showed under reporting in 87% boys and 95% girls. The 24-h recalls measured at five measurements over 2 years offered poor validity between EI(rep) and EE(est).


Anti-cholelithogenic potential of dietary spices and their bioactives.
Dietary hypocholesterolemic spices-curcumin (active compound of turmeric (Curcuma longa)) and capsaicin (active compound of red pepper (Capsicum annuum)), the active principles of spices-turmeric (Curcuma longa) and red pepper (Capsicum annuum), fenugreek (Trigonella foenum-graecum) seeds, garlic (Allium sativum), and onion (Allium cepa) are documented to have anti-cholelithogenic property in animal model. These spices prevent the induction of cholesterol gallstones by lithogenic high cholesterol diet and also regress the pre-established cholesterol gallstones, by virtue of their hypolipidemic potential. The antilithogenic influence of these spices is primarily attributable to their hypocholesterolemic effect. Increased cholesterol saturation index, cholesterol:phospholipid ratio and cholesterol:bile acid ratio in the bile caused by the lithogenic diet was countered by these spices. The antilithogenicity of these hypocholesterolemic spices was considered to be due also to their influence on biliary proteins that have pro-nucleating activity and anti-nucleating activity. Investigations on the involvement of biliary proteins in cholesterol crystal nucleation revealed that in an in vitro bile model, low molecular weight biliary proteins of the lithogenic diet fed animals have a pro-nucleating activity. On the contrary, low molecular weight biliary proteins of the animals fed hypocholesterolemic spices along with lithogenic diet showed a potent anti-nucleating activity.


Resting autonomic modulations and the heart rate response to exercise.
Identify the underlying role of resting heart rate variability (HRV) in the hearts response to graded exercise testing (GXT). Resting 5-min HRV and heart rate (HR) measurements were made in 33 volunteers (19 males, median age 34, range 25-63 years and 14 females median age 48, range 21-63 years). Measures of VO2 peak and HR obtained during a maximal GXT and heart rate recovery (HRR) post-GXT were assessed for associations with resting HRV. Differences and effect size (d) for measures of HRV were assessed between groups based on established risk cut-points for resting, exercise and recovery HR responses. Small associations were observed for the majority of resting HRV and GXT HR responses (best r value = -0.27, P > 0.05). Measures of HRV demonstrated moderate associations with HRR (best r value = 0.46, P < 0.05) and were able to predict a negative risk HRR. In contrast to other dependent variables, measures of HRV were consistently able to demonstrate significant and moderate to large (d = 0.9-2.0) differences between groups based on literature defined prognostic HR cut-points. Small associations with HR responses to exercise prevent their accurate prediction from resting HRV. Data support the use of vagally mediated resting HRV in predicting better HRR. Lower resting autonomic modulations underlined high risk resting and exercise HR responses. Resting short-term HRV measurements should be considered when assessing cardiac autonomic health from the HR response before, during and/or after exercise.


Synoptic assessment of coastal total alkalinity through community science.
Comprehensive sampling of the carbonate system in estuaries and coastal waters can be difficult and expensive because of the complex and heterogeneous nature of near-shore environments. We show that sample collection by community science programs is a viable strategy for expanding estuarine carbonate system monitoring and prioritizing regions for more targeted assessment. 'Shell Day' was a single-day regional water monitoring event coordinating coastal carbonate chemistry observations by 59 community science programs and seven research institutions in the northeastern United States, in which 410 total alkalinity (TA) samples from 86 stations were collected. Field replicates collected at both low and high tides had a mean standard deviation between replicates of 3.6 ± 0.3 μmol kg-1 (σ mean ± SE, n = 145) or 0.20 ± 0.02%. This level of precision demonstrates that with adequate protocols for sample collection, handling, storage, and analysis, community science programs are able to collect TA samples leading to high-quality analyses and data. Despite correlations between salinity, temperature, and TA observed at multiple spatial scales, empirical predictions of TA had relatively high root mean square error >48 μmol kg-1. Additionally, ten stations displayed tidal variability in TA that was not likely driven by low TA freshwater inputs. As such, TA cannot be predicted accurately from salinity using a single relationship across the northeastern US region, though predictions may be viable at more localized scales where consistent freshwater and seawater endmembers can be defined. There was a high degree of geographic heterogeneity in both mean and tidal variability in TA, and this single-day snapshot sampling identified three patterns driving variation in TA, with certain locations exhibiting increased risk of acidification. The success of Shell Day implies that similar community science based events could be conducted in other regions to not only expand understanding of the coastal carbonate system, but also provide a way to inventory monitoring assets, build partnerships with stakeholders, and expand education and outreach to a broader constituency.


Silica nanoparticles pre-spotted onto target plate for laser desorption/ionization mass spectrometry analyses of peptides.
We report on the simple deposition of Stöber silica nanoparticles (SiO(2) NPs) on conventional MALDI target plate for high throughput laser desorption/ionization mass spectrometry (LDI-MS) analyses of peptide mixtures with sensitivity in the femtomolar range. This low-cost easily prepared material allowed straightforward LDI experiments by deposition of the studied samples directly onto a pre-spotted MALDI plate. This analytical strategy can be performed in any laboratory equipped with a MALDI-TOF instrument. All key benefits of organic matrix-free technologies were satisfied while maintaining a high level of detection performances (sensitivity and reproducibility/repeatability). In particular, sample preparation was simple and detection in the low mass range was not hampered by matrix ions. Imaging studies were undertaken to query sample dispersion into the inert SiO(2) NPs and to help into the search of the best experimental conditions producing homogeneous analyte distribution within the deposit. In contrast to commercial disposable LDI targets designed for single use and requiring an adaptor such as NALDI™, the proposed SiO(2) NPs pre-spotting on a MALDI target plate allowed very easily switching between MALDI and LDI experiments. They can be conducted either simultaneously (positions with an organic matrix or SiO(2) NPs) or in the row (support prepared in advance, stored and washed after use). The overall cost and versatility of the methodology made it very attractive to MALDI users in many domains (peptidomics, proteomics, metabolomics).


The effect of a sports chiropractic manual therapy intervention on the prevention of back pain, hamstring and lower limb injuries in semi-elite Australian Rules footballers: a randomized controlled trial.
Hamstring injuries are the most common injury in Australian Rules football. It was the aims to investigate whether a sports chiropractic manual therapy intervention protocol provided in addition to the current best practice management could prevent the occurrence of and weeks missed due to hamstring and other lower-limb injuries at the semi-elite level of Australian football. Sixty male subjects were assessed for eligibility with 59 meeting entry requirements and randomly allocated to an intervention (n = 29) or control group (n = 30), being matched for age and hamstring injury history. Twenty-eight intervention and 29 control group participants completed the trial. Both groups received the current best practice medical and sports science management, which acted as the control. Additionally, the intervention group received a sports chiropractic intervention. Treatment for the intervention group was individually determined and could involve manipulation/mobilization and/or soft tissue therapies to the spine and extremity. Minimum scheduling was: 1 treatment per week for 6 weeks, 1 treatment per fortnight for 3 months, 1 treatment per month for the remainder of the season (3 months). The main outcome measure was an injury surveillance with a missed match injury definition. After 24 matches there was no statistical significant difference between the groups for the incidence of hamstring injury (OR:0.116, 95% CI:0.013-1.019, p = 0.051) and primary non-contact knee injury (OR:0.116, 95% CI:0.013-1.019, p = 0.051). The difference for primary lower-limb muscle strains was significant (OR:0.097, 95%CI:0.011-0.839, p = 0.025). There was no significant difference for weeks missed due to hamstring injury (4 v 14, chi2:1.12, p = 0.29) and lower-limb muscle strains (4 v 21, chi2:2.66, p = 0.10). A significant difference in weeks missed due to non-contact knee injury was noted (1 v 24, chi2:6.70, p = 0.01). This study demonstrated a trend towards lower limb injury prevention with a significant reduction in primary lower limb muscle strains and weeks missed due to non-contact knee injuries through the addition of a sports chiropractic intervention to the current best practice management.


Inequalities in the provision of sexual health information for young people.
Sexual health has been emphasised in national and regional strategies as a target for health and social well-being. In Northern Ireland (NI), the Sexual Health Promotion Strategy concentrates on reducing the incidence of sexually transmitted infections (STIs), reducing the number of unplanned births to teenage mothers, providing appropriate, effective and equitable sexual health information, and facilitating access to sexual health services. This article reports on a study carried out within NI and explores young people's knowledge and sources of sexual health information. School pupils aged 14-18 years (n = 414) participated in the study and a self-administered questionnaire was used to collect the data. Whilst approximately half of the respondents reported being sexually active, only 68.2% always used some form of contraception. In fact, 40.8% of sexually active females had used the 'morning-after pill', with 37.5% of these respondents using this method more than once. The results also indicated that students receive varying amounts of sexual health information from schools resulting in inequalities with regard to sources of information. Students from a Roman Catholic religious background were more likely to receive information on sexual health from informal sources such as friends, books/magazines or television/radio than from within the school environment compared with their Protestant counterparts. The provision of standard and accurate information appropriate to the target population is necessary in order to reduce the increasing rates of STIs and help the Government reach their target of halving the teenage pregnancy rate by the year 2010.


Distinctive phosphoinositide- and Ca2+-binding properties of normal and cognitive performance-linked variant forms of KIBRA C2 domain.
Kidney- and brain-expressed protein (KIBRA), a multifunctional scaffold protein with around 20 known binding partners, is involved in memory and cognition, organ size control via the Hippo pathway, cell polarity, and membrane trafficking. KIBRA includes tandem N-terminal WW domains, a C2 domain, and motifs for binding atypical PKC and PDZ domains. A naturally occurring human KIBRA variant involving residue changes at positions 734 (Met-to-Ile) and 735 (Ser-to-Ala) within the C2 domain affects cognitive performance. We have elucidated 3D structures and calcium- and phosphoinositide-binding properties of human KIBRA C2 domain. Both WT and variant C2 adopt a canonical type I topology C2 domain fold. Neither Ca2+ nor any other metal ion was bound to WT or variant KIBRA C2 in crystal structures, and Ca2+ titration produced no significant reproducible changes in NMR spectra. NMR and X-ray diffraction data indicate that KIBRA C2 binds phosphoinositides via an atypical site involving β-strands 5, 2, 1, and 8. Molecular dynamics simulations indicate that KIBRA C2 interacts with membranes via primary and secondary sites on the same domain face as the experimentally identified phosphoinositide-binding site. Our results indicate that KIBRA C2 domain association with membranes is calcium-independent and involves distinctive C2 domain-membrane relative orientations.


Optogenetic control of cardiac function.
The cardiac pacemaker controls the rhythmicity of heart contractions and can be substituted by a battery-operated device as a last resort. We created a genetically encoded, optically controlled pacemaker by expressing halorhodopsin and channelrhodopsin in zebrafish cardiomyocytes. Using patterned illumination in a selective plane illumination microscope, we located the pacemaker and simulated tachycardia, bradycardia, atrioventricular blocks, and cardiac arrest. The pacemaker converges to the sinoatrial region during development and comprises fewer than a dozen cells by the time the heart loops. Perturbation of the activity of these cells was entirely reversible, demonstrating the resilience of the endogenous pacemaker. Our studies combine optogenetics and light-sheet microscopy to reveal the emergence of organ function during development.


Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma in Col4a1 Mutant Mice.
Mutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma. Col4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves. We found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head. Ocular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations.


Peeling back the layers of learning: a classroom model for problem-based learning.
This paper aims to provide an informative discussion with underpinning rationales about the use of a problem-based learning (PBL) classroom model, supported by a structured process for undertaking PBL. PBL was implemented as a main teaching and learning strategy for a diploma in nursing programme as advised by the Department of Health [Department of Health., 1999. Making a difference: Strengthening the Nursing, Midwifery and Health Visiting Contribution to Health and Health Care. Department of Health, London.] and the United Kingdom Central Council for nurses, midwifes and health visitors [United Kingdom Central Council for Nursing, Midwifery and Health Visiting, 1999. Fitness for Practice. UKCC, London.]. The implementation and change to the PBL approach is not without challenges, and so it was considered important to facilitate this change effectively. Through ongoing reflection, peer discussions and continuous review of the literature following studies at Masters Level, it was identified that the design of a model may guide students and facilitators who were new to the PBL process to help students identify relevant learning needs and thus enable them to achieve the learning outcomes of a dynamic curriculum [Darvill, A., 2000. Developing Problem-based Learning in the Nursing Education Curriculum: A Case Study. Unpublished MSc Dissertation, University of Huddersfield, Huddersfield; McLoughlin, M., 2002. An Exploration of the Role of the Problem-based Learning Facilitator: An Ethnographic Study of Role Transition in a Higher Education Institution 'Paradigm Shift or New Ways of Working'. Unpublished MSc Dissertation. University of Huddersfield, Huddersfield.]. In this paper the key components of the model will be described.


Early Doppler echocardiographic dysfunction is associated with an increased mortality after orthotopic cardiac transplantation.
Doppler echocardiographic (DE) diastolic dysfunction has been correlated with rejection after orthotopic cardiac transplantation (Tx). However, the relationship of early diastolic dysfunction to late outcome is unknown. The purpose of this study was to assess the correlation between early DE diastolic dysfunction and outcome after heart Tx. Of 133 patients undergoing heart Tx between October 1990 and April 1994, 83 were identified with > or = 4 routine DE performed during the first 6 months. Assessment of diastolic function included measurement of isovolumic relaxation time (IVRT), pressure half-time (PHT), and peak early mitral inflow velocity (M1). Diastolic dysfunction was defined as a decrease of 15% from baseline (IVRT and PHT) or an increase of 20% (M1). A mean dysfunction score (MDS) was calculated for each patient (number of episodes of dysfunction by Doppler total number of echocardiograms performed). The population diastole MDS was determined and two groups established (group 1, MDS < mean; group 2, MDS > mean). Actuarial survival, rejection, and transplant coronary artery disease (TxCAD) were compared between groups. Actuarial survival was significantly reduced in patients with greater early diastolic dysfunction (P < .05). There were 17 deaths overall: 5 in group 1 (mean, 786 days) and 12 in group 2 (mean, 384 days). There were no significant differences in treated rejection episodes, actuarial freedom from rejection or TxCAD, immunosuppression, sex, donor age, donor ischemic time, or cytomegalovirus between the two groups. Diastolic dysfunction within 6 months of transplant was associated with an increased late mortality.


Musculoskeletal response to exercise is greatest in women with low initial values.
The "initial values" principle of exercise training states those with the lowest initial values of a physiologic system have the greatest capacity for improvement in response to training. We sought to determine whether initial values predicted the musculoskeletal response to training in premenopausal women (N = 31) who participated in a 1-yr program of resistance and jump training designed to improve physical indices of fracture risk. Significant improvements in trochanteric bone mineral density (BMD), hip abductor strength, power, and postural stability occurred in response to training. To determine the predictive power of initial values, we performed separate stepwise regression analyses for each variable including the following dependent variables: age, initial value, highest weight lifted during training, and total number of exercise sessions attended. In each case, the initial value was the most significant predictor of percent change in response to training. Initial values explained 15-29% of the variance in the magnitude of the training response. For each unit lower BMD of the greater trochanter (0.01 g.cm-2), the training response was 12% greater. For each unit decrease in initial strength (1 N.m), power (1 W), and stability (1 SI unit), the training response was 1.0%, 0.2%, and 8.0% greater, respectively. When categorized by quartile of initial values, women in the lowest quartile had two- to fivefold greater improvements in musculoskeletal measures than those in the upper quartile. Women who began training with the lowest initial values had the greatest improvements in hip BMD, hip abductor strength, leg power, and postural stability. These results support the training principle of initial values and suggest that this training program may be most successful in premenopausal women with lower values of musculoskeletal indices of fracture risk.


A new model for raf kinase inhibitory protein induced chemotherapeutic resistance.
Therapeutic resistance remains the most challenging aspect of treating cancer. Raf kinase inhibitory protein (RKIP) emerged as a molecule capable of sensitizing cancerous cells to radio- and chemotherapy. Moreover, this small evolutionary conserved molecule, endows significant resistance to cancer therapy when its expression is reduced or lost. RKIP has been shown to inhibit the Raf-MEK-ERK, NFκB, GRK and activate the GSK3β signaling pathways. Inhibition of Raf-MEK-ERK and NFκB remains the most prominent pathways implicated in the sensitization of cells to therapeutic drugs. Our purpose was to identify a possible link between RKIP-KEAP 1-NRF2 and drug resistance. To that end, RKIP-KEAP 1 association was tested in human colorectal cancer tissues using immunohistochemistry. RKIP miRNA silencing and its inducible overexpression were employed in HEK-293 immortalized cells, HT29 and HCT116 colon cancer cell lines to further investigate our aim. We show that RKIP enhanced Kelch-like ECH-associated protein1 (KEAP 1) stability in colorectal cancer tissues and HT29 CRC cell line. RKIP silencing in immortalized HEK-293 cells (termed HEK-499) correlated significantly with KEAP 1 protein degradation and subsequent NRF2 addiction in these cells. Moreover, RKIP depletion in HEK-499, compared to control cells, bestowed resistance to supra physiological levels of H(2)O(2) and Cisplatin possibly by upregulating NF-E2-related nuclear factor 2 (NRF2) responsive genes. Similarly, we observed a direct correlation between the extent of apoptosis, after treatment with Adriamycin, and the expression levels of RKIP/KEAP 1 in HT29 but not in HCT116 CRC cells. Our data illuminate, for the first time, the NRF2-KEAP 1 pathway as a possible target for personalized therapeutic intervention in RKIP depleted cancers.


Improving quality of care through improved audit and feedback.
The Department of Veterans Affairs (VA) has led the industry in measuring facility performance as a critical element in improving quality of care, investing substantial resources to develop and maintain valid and cost-effective measures. The External Peer Review Program (EPRP) of the VA is the official data source for monitoring facility performance, used to prioritize the quality areas needing most attention. Facility performance measurement has significantly improved preventive and chronic care, as well as overall quality; however, much variability still exists in levels of performance across measures and facilities. Audit and feedback (A&F), an important component of effective performance measurement, can help reduce this variability and improve overall performance. Previous research suggests that VA Medical Centers (VAMCs) with high EPRP performance scores tend to use EPRP data as a feedback source. However, the manner in which EPRP data are used as a feedback source by individual providers as well as service line, facility, and network leadership is not well understood. An in-depth understanding of mental models, strategies, and specific feedback process characteristics adopted by high-performing facilities is thus urgently needed.This research compares how leaders of high, low, and moderately performing VAMCs use clinical performance data from the EPRP as a feedback tool to maintain and improve quality of care. We will conduct a qualitative, grounded theory analysis of up to 64 interviews using a novel method of sampling primary care, facility, and Veterans Integrated Service Network (VISN) leadership at high-, moderate-, and low-performing facilities. We will analyze interviews for evidence of cross-facility differences in perceptions of performance data usefulness and strategies for disseminating performance data evaluating performance, with particular attention to timeliness, individualization, and punitiveness of feedback delivery. Most research examining feedback to improve provider and facility performance lacks a detailed understanding of the elements of effective feedback. This research will highlight the elements most commonly used at high-performing facilities and identify additional features of their successful feedback strategies not previously identified. Armed with this information, practices can implement more effective A&F interventions to improve quality of care.


Apical and Basal Matrix Remodeling Control Epithelial Morphogenesis.
Epithelial tissues can elongate in two dimensions by polarized cell intercalation, oriented cell division, or cell shape change, owing to local or global actomyosin contractile forces acting in the plane of the tissue. In addition, epithelia can undergo morphogenetic change in three dimensions. We show that elongation of the wings and legs of Drosophila involves a columnar-to-cuboidal cell shape change that reduces cell height and expands cell width. Remodeling of the apical extracellular matrix by the Stubble protease and basal matrix by MMP1/2 proteases induces wing and leg elongation. Matrix remodeling does not occur in the haltere, a limb that fails to elongate. Limb elongation is made anisotropic by planar polarized Myosin-II, which drives convergent extension along the proximal-distal axis. Subsequently, Myosin-II relocalizes to lateral membranes to accelerate columnar-to-cuboidal transition and isotropic tissue expansion. Thus, matrix remodeling induces dynamic changes in actomyosin contractility to drive epithelial morphogenesis in three dimensions.


Lessons for preparedness and reasons for concern from the early COVID-19 epidemic in Iran.
Many countries with an early outbreak of SARS-CoV-2 struggled to gauge the size and start date of the epidemic mainly due to limited testing capacities and a large proportion of undetected asymptomatic and mild infections. Iran was among the first countries with a major outbreak outside China. We constructed a globally representative sample of 802 genomes, including 46 samples from patients inside or with a travel history to Iran. We then performed a phylogenetic analysis to identify clades related to samples from Iran and estimated the start of the epidemic and early doubling times in cases. We leveraged air travel data from 36 exported cases of COVID-19 to estimate the point-prevalence and the basic reproductive number across the country. We also analysed the province-level all-cause mortality data during winter and spring 2020 to estimate under-reporting of COVID-19-related deaths. Finally, we use this information in an SEIR model to reconstruct the early outbreak dynamics and assess the effectiveness of intervention measures in Iran. By identifying the most basal clade that contained genomes from Iran, our phylogenetic analysis showed that the age of the root is placed on 2019-12-21 (95 % HPD: 2019-09-07 - 2020-02-14). This date coincides with our estimated epidemic start date on 2019-12-25 (95 %CI: 2019-12-11 - 2020-02-24) based air travel data from exported cases with an early doubling time of 4.0 (95 %CI: 1.4-6.7) days in cases. Our analysis of all-cause mortality showed 21.9 (95 % CI: 16.7-27.2) thousand excess deaths by the end of summer. Our model forecasted the second epidemic peak and suggested that by 2020-08-31 a total of 15.0 (95 %CI: 4.9-25.0) million individuals recovered from the disease across the country. These findings have profound implications for assessing the stage of the epidemic in Iran despite significant levels of under-reporting. Moreover, the results shed light on the dynamics of SARS-CoV-2 transmissions in Iran and central Asia. They also suggest that in the absence of border screening, there is a high risk of introduction from travellers from areas with active outbreaks. Finally, they show both that well-informed epidemic models are able to forecast episodes of resurgence following a relaxation of interventions, and that NPIs are key to controlling ongoing epidemics.


A Predictive Analysis of Wall Stress in Abdominal Aortic Aneurysms Using a Neural Network Model.
Rupture risk assessment of abdominal aortic aneurysms (AAAs) by means of quantifying wall stress is a common biomechanical strategy. However, the clinical translation of this approach has been greatly limited due to the complexity associated with the computational tools required for its implementation. Thus, being able to estimate wall stress using nonbiomechanical markers that can be quantified as a direct outcome of clinical image segmentation would be advantageous in improving the potential implementation of said strategy. In the present work, we investigated the use of geometric indices to predict patient-specific AAA wall stress by means of a novel neural network (NN) modeling approach. We conducted a retrospective review of existing clinical images of two patient groups: 98 asymptomatic and 50 symptomatic AAAs. The images were subject to a protocol consisting of image segmentation, processing, volume meshing, finite element modeling, and geometry quantification, from which 53 geometric indices and the spatially averaged wall stress (SAWS) were calculated. SAWS estimated from finite element analysis was considered the gold standard for the predictions. We developed feed-forward NN models composed of an input layer, two dense layers, and an output layer using Keras, a deep learning library in python. The NN models were trained, tested, and validated independently for both AAA groups using all geometric indices, as well as a reduced set of indices resulting from a variable reduction procedure. We compared the performance of the NN models with two standard machine learning algorithms (MARS: multivariate adaptive regression splines and GAM: generalized additive model) and a linear regression model (GLM: generalized linear model). With the reduced sets of indices, the NN-based approach exhibited the highest mean goodness-of-fit (for the symptomatic group 0.71 and for the asymptomatic group 0.79) and lowest mean relative error (17% for both groups). In contrast, MARS yielded a mean goodness-of-fit of 0.59 for the symptomatic group and 0.77 for the asymptomatic group, with relative errors of 17% for the symptomatic group and 22% for the asymptomatic group. GAM had a mean goodness-of-fit of 0.70 for the symptomatic group and 0.80 for the asymptomatic group, with relative errors of 16% for the symptomatic group and 20% for the asymptomatic group. GLM did not perform as well as the other algorithms, with a mean goodness-of-fit of 0.53 for the symptomatic group and 0.70 for the asymptomatic group, with relative errors of 19% for the symptomatic group and 23% for the asymptomatic group. Nevertheless, the NN models required a reduced set of 15 and 13 geometric indices to predict SAWS for the symptomatic and asymptomatic AAA groups, respectively. This was in contrast to the reduced set of nine and eight geometric indices required to predict SAWS with the MARS and GAM algorithms for each AAA group, respectively. The use of NN modeling represents a promising alternative methodology for the estimation of AAA wall stress using geometric indices as surrogates, in lieu of finite element modeling. The performance metrics of NN models are expected to improve with significantly larger group sizes, given the suitability of NN modeling for "big data" applications.


Strong discomfort during vaginal examination: why consider a history of abuse?
To study factors associated with strong discomfort during vaginal examinations (SD/VE) by means of four hypotheses. A cross sectional postal questionnaire study, conducted at three Swedish departments of obstetrics and gynaecology and with a random population sample (n=4453). The associations between a self-reported history of emotional, physical and sexual abuse and abuse in health care, flashbacks during the previous year, emotional contact with the examiner, and SD/VE during the index visit (discomfort estimated on a ten-point scale; six-ten=SD). Statistical analyses used were Chi-square, Binary logistic regression, and Pearson Correlation. Eighteen percent of the women reported SD/VE. There was an association between SD/VE and a lifetime history of abuse. Having experienced combinations of abuse, especially combinations including emotional abuse and abuse in health care, was strongly associated with SD/VE. SD/VE was furthermore associated with flashbacks during the previous year, and negative emotional contact with the examiner during the index visit. We conclude that women who unexpectedly react with SD/VE are more likely to have a background of abuse, and may even run a risk of feeling re-traumatised during the VE. A clinical implication is to consider a history of abuse in patients who react with SD/VE or experience negative emotional contact during the consultation.


A NONSENSE GATA6 MUTATION EXPLAINS HISTORY OF CONGENITAL HEART DEFECTS AND 10 YEARS OF POORLY-CONTROLLED DIABETES LACKING DKA IN A NON-OBESE 30 YEAR-OLD INCIDENTALLY FOUND TO HAVE PANCREATIC HYPOPLASIA.
To report a case of diabetes mellitus (DM) associated with partial pancreatic agenesis and congenital heart disease (CHD) in a patient found to have a nonsense mutation of the GATA6 gene. We present the imaging, laboratory, and genetic findings, and describe the clinical course of a patient with an atypical presentation of DM as well as CHD, who was found to have partial pancreatic agenesis on computed tomography (CT) imaging. Genetic testing was performed to identify monogenic DM. A 30-year-old nonobese female with a waxing and waning pattern of insulin-dependent DM diagnosed at the age of 20 was found to have partial pancreatic agenesis on CT scan. It was unclear whether the patient was experiencing undetected hyperglycemia prior to initial diagnosis of DM. She had no history of diabetic ketoacidosis (DKA) despite poorly-controlled diabetes and years without insulin treatment. The patient also had congenital tricuspid atresia, ventricular septal defect, and transposition of the great vessels with surgical correction in childhood. Partial pancreatic agenesis and CHD with atypical DM prompted genetic testing for monogenic DM, and a nonsense mutation of the GATA6 (c.1242C>A, p.C414*) gene was found. GATA6 mutations are associated with a broad spectrum of diabetic phenotypes, pancreatic agenesis, and a variety of CHDs. This case highlights the importance of considering monogenic diabetes in young, nonobese patients with diabetes, particularly with negative pancreatic antibodies and no history of DKA. Further, this case demonstrates the importance of testing for GATA6 mutations in any young patient with diabetes and CHD.


Effects of concurrent physical and cognitive demands on muscle activity and heart rate variability in a repetitive upper-extremity precision task.
Most previous studies of concurrent physical and cognitive demands have addressed tasks of limited relevance to occupational work, and with dissociated physical and cognitive task components. This study investigated effects on muscle activity and heart rate variability of executing a repetitive occupational task with an added cognitive demand integral to correct task performance. Thirty-five healthy females performed 7.5 min of standardized repetitive pipetting work in a baseline condition and a concurrent cognitive condition involving a complex instruction for correct performance. Average levels and variabilities of electromyographic activities in the upper trapezius and extensor carpi radialis (ECR) muscles were compared between these two conditions. Heart rate and heart rate variability were also assessed to measure autonomic nervous system activation. Subjects also rated perceived fatigue in the neck-shoulder region, as well as exertion. Concurrent cognitive demands increased trapezius muscle activity from 8.2% of maximum voluntary exertion (MVE) in baseline to 9.0% MVE (p = 0.0005), but did not significantly affect ECR muscle activity, heart rate, heart rate variability, perceived fatigue or exertion. Trapezius muscle activity increased by about 10%, without any accompanying cardiovascular response to indicate increased sympathetic activation. We suggest this slight increase in trapezius muscle activity to be due to changed muscle activation patterns within or among shoulder muscles. The results suggest that it may be possible to introduce modest cognitive demands necessary for correct performance in repetitive precision work without any major physiological effects, at least in the short term.


Variation in intensive care unit outcomes: a search for the evidence on organizational factors.
This study was undertaken to determine the extent of empirical evidence on the role of organizational factors in the critical care literature and to categorize these factors. Studies evaluating organizational factors were identified through electronic and hand searching of the critical care literature. Sixty-three publications relating to 54 different studies were identified. The studies were grouped into eight main categories: staffing, teamwork, volume and pressure of work, protocols, admission to intensive care, technology, structure, and error. Studies evaluating organizational factors exist in the critical care literature, and there is evidence that the number is increasing each year. Results indicate that organizational factors may have an impact on mortality after case mix adjustment. Some areas have been investigated more thoroughly than others and are ripe for systematic review. Variation in case mix adjusted hospital mortality after intensive care is an old theme. This study has shown that emerging data will help us understand mortality differences and deliver better outcomes for patients.


Patient-based estimation of organ dose for a population of 58 adult patients across 13 protocol categories.
This study aimed to provide a comprehensive patient-specific organ dose estimation across a multiplicity of computed tomography (CT) examination protocols. A validated Monte Carlo program was employed to model a common CT system (LightSpeed VCT, GE Healthcare). The organ and effective doses were estimated from 13 commonly used body and neurological CT examination. The dose estimation was performed on 58 adult computational extended cardiac-torso phantoms (35 male, 23 female, mean age 51.5 years, mean weight 80.2 kg). The organ dose normalized by CTDIvol (h factor) and effective dose normalized by the dose length product (DLP) (k factor) were calculated from the results. A mathematical model was derived for the correlation between the h and k factors with the patient size across the protocols. Based on this mathematical model, a dose estimation iPhone operating system application was designed and developed to be used as a tool to estimate dose to the patients for a variety of routinely used CT examinations. The organ dose results across all the protocols showed an exponential decrease with patient body size. The correlation was generally strong for the organs which were fully or partially located inside the scan coverage (Pearson sample correlation coefficient (r) of 0.49). The correlation was weaker for organs outside the scan coverage for which distance between the organ and the irradiation area was a stronger predictor of dose to the organ. For body protocols, the effective dose before and after normalization by DLP decreased exponentially with increasing patient's body diameter (r > 0.85). The exponential relationship between effective dose and patient's body diameter was significantly weaker for neurological protocols (r < 0.41), where the trunk length was a slightly stronger predictor of effective dose (0.15 < r < 0.46). While the most accurate estimation of a patient dose requires specific modeling of the patient anatomy, a first order approximation of organ and effective doses from routine CT scan protocols can be reasonably estimated using size specific factors. Estimation accuracy is generally poor for organ outside the scan range and for neurological protocols. The dose calculator designed in this study can be used to conveniently estimate and report the dose values for a patient across a multiplicity of CT scan protocols.


New steps for tobacco control in and outside of China.
In China during the last decade, citizens have rarely agitated against the ubiquity of cigarettes, at the same time that tobacco products have been responsible for killing more than a million people a year and tobacco-control programs have been enjoying a marked growth in logistical support, discursive attention, and funding. In this article, the author argues that China's ongoing popular quiescence regarding tobacco stems in part from strategic miscalculations that public health advocates are making. Favoring conceptual logics of expertise, population management, health economics, disease etiology, and rational choice, tobacco control in China is leaving unproblematized the political economic sources of cigarettes, the social suffering tobacco generates, and the ethics, everyday practices, and desires binding citizens and cigarettes together into webs of sociality. Bringing anthropological research to bear, the article describes ways that these strategic miscalculations have unfolded and makes suggestions for alternative ways that public health advocates can help Chinese citizens achieve the collective purpose to repudiate tobacco.


Striatum processes reward differently in adolescents versus adults.
Adolescents often respond differently than adults to the same salient motivating contexts, such as peer interactions and pleasurable stimuli. Delineating the neural processing differences of adolescents is critical to understanding this phenomenon, as well as the bases of serious behavioral and psychiatric vulnerabilities, such as drug abuse, mood disorders, and schizophrenia. We believe that age-related changes in the ways salient stimuli are processed in key brain regions could underlie the unique predilections and vulnerabilities of adolescence. Because motivated behavior is the central issue, it is critical that age-related comparisons of brain activity be undertaken during motivational contexts. We compared single-unit activity and local field potentials in the nucleus accumbens (NAc) and dorsal striatum (DS) of adolescent and adult rats during a reward-motivated instrumental task. These regions are involved in motivated learning, reward processing, and action selection. We report adolescent neural processing differences in the DS, a region generally associated more with learning than reward processing in adults. Specifically, adolescents, but not adults, had a large proportion of neurons in the DS that activated in anticipation of reward. More similar response patterns were observed in NAc of the two age groups. DS single-unit activity differences were found despite similar local field potential oscillations. This study demonstrates that in adolescents, a region critically involved in learning and habit formation is highly responsive to reward. It thus suggests a mechanism for how rewards might shape adolescent behavior differently, and for their increased vulnerabilities to affective disorders.


Comparing the effect of modeled climatic variables on the distribution of African horse sickness in South Africa and Namibia.
Africa horse sickness (AHS) is a lethal disease of horses with a seasonal occurrence that is influenced by environmental conditions that favor the development of Culicoides midges (Diptera: Ceratopogonidae). This study compared and evaluated the relationship of various modeled climatic variables with the distribution and abundance of AHS in South Africa and Namibia. A comprehensive literature review of the historical AHS reported data collected from the Windhoek archives as well as annual reports from the Directorate of Veterinary services in Namibia were conducted. South African AHS reported data were collected from the South African Department of Agriculture, Forestry, and Fisheries. Daily climatic data were extracted for the time period 1993-2011 from the ERA-interim re-analysis dataset. The principal component analysis of the complete dataset indicated a significant statistical difference between Namibia and South Africa for the various climate variables and the outbreaks of AHS. The most influential parameters in the distribution of AHS included humidity, precipitation, evaporation, and minimum temperature. In South Africa, temperature had the most significant effect on the outbreaks of AHS, whereas in Namibia, humidity and precipitation were the main drivers. The maximum AHS cases in South Africa occurred at temperatures of 20-22° C and relative humidity between 50-70%. Furthermore, anthropogenic effects must be taken into account when trying to understand the distribution of AHS.


Treatment algorithms in stage IV melanoma.
The molecular classification of melanoma and the advent of new drugs are changing the paradigm of therapy for advanced melanoma. A review of the recent key studies was performed, followed by a discussion in an expert forum. The aim of this review was to generate a therapeutic algorithm for stage IV melanoma. Tumor genotyping for BRAF and/or KIT should be performed before selection of therapy. For most BRAF-mutated melanoma patients and particularly those with a high tumor load, vemurafenib or other BRAF inhibitors such as dabrafenib are the treatment of choice. KIT inhibitors can be effective in KIT-mutant tumors, especially in those patients with mutations at exons 11 and 13. Ipilimumab is a good option for patients with nontargetable or nondetected mutations and those who progress under therapy with vemurafenib or a KIT inhibitor. There is still a role for conventional chemotherapy either as first-line treatment in BRAF wild-type patients or as salvage therapy in second or third line, or after other treatment modalities. Participation in clinical trials is strongly encouraged, either in first or in subsequent lines. New therapeutic options for advanced melanoma are guided by tumor genotyping. The current therapeutic algorithm includes kinase inhibitors, anti-CTLA4 therapy, immunotherapy, and chemotherapy, depending on the tumor genotype and response to previous treatments. Participation in clinical trials should always be encouraged because the treatment goal is long-term survival and potential cure in a subset of patients.


Dynamic species distribution models from categorical survey data.
1. Species distribution models are static models for the distribution of a species, based on Hutchinson's niche concept. They make probabilistic predictions about the distribution of a species, but do not have a temporal interpretation. In contrast, density-structured models based on categorical abundance data make it possible to incorporate population dynamics into species distribution modelling. 2. Using dynamic species distribution models, temporal aspects of a species' distribution can be investigated, including the predictability of future abundance categories and the expected persistence times of local populations, and how these may respond to environmental or anthropogenic drivers. 3. We built density-structured models for two intertidal marine invertebrates, the Lusitanian trochid gastropods Phorcus lineatus and Gibbula umbilicalis, based on 9 years of field data from around the United Kingdom. Abundances were recorded on a categorical scale, and stochastic models for year-to-year changes in abundance category were constructed with winter mean sea surface temperature (SST) and wave fetch (a measure of the exposure of a shore) as explanatory variables. 4. Both species were more likely to be present at sites with high SST, but differed in their responses to wave fetch. Phorcus lineatus had more predictable future abundance and longer expected persistence times than G. umbilicalis. This is consistent with the longer lifespan of P. lineatus. 5. Where data from multiple time points are available, dynamic species distribution models of the kind described here have many applications in population and conservation biology. These include allowing for changes over time when combining historical and contemporary data, and predicting how climate change might alter future abundance conditional on current distributions.


The implications of propensity score variable selection strategies in pharmacoepidemiology: an empirical illustration.
To examine the effect of variable selection strategies on the performance of propensity score (PS) methods in a study of statin initiation, mortality, and hip fracture assuming a true mortality reduction of < 15% and no effect on hip fracture. We compared seniors initiating statins with seniors initiating glaucoma medications. Out of 202 covariates with a prevalence > 5%, PS variable selection strategies included none, a priori, factors predicting exposure, and factors predicting outcome. We estimated hazard ratios (HRs) for statin initiation on mortality and hip fracture from Cox models controlling for various PSs. During 1 year follow-up, 2693 of 55,610 study subjects died and 496 suffered a hip fracture. The crude HR for statin initiators was 0.64 for mortality and 0.46 for hip fracture. Adjusting for the non-parsimonious PS yielded effect estimates of 0.83 (95%CI:0.75-0.93) and 0.72 (95%CI:0.56-0.93). Including in the PS only covariates associated with a greater than 20% increase or reduction in outcome rates yielded effect estimates of 0.84 (95%CI:0.75-0.94) and 0.76 (95%CI:0.61-0.95), which were closest to the effects predicted from randomized trials. Due to the difficulty of pre-specifying all potential confounders of an exposure-outcome association, data-driven approaches to PS variable selection may be useful. Selecting covariates strongly associated with exposure but unrelated to outcome should be avoided, because this may increase bias. Selecting variables for PS based on their association with the outcome may help to reduce such bias.


Two fractions of high-dose-rate brachytherapy in the management of cervix cancer: clinical experience with and without chemotherapy.
In recent years, high-dose-rate brachytherapy has become popular in the management of carcinoma of the uterine cervix, because it eliminates many of the problems associated with low-dose-rate brachytherapy. However, the optimum time-dose-fractionation remains controversial. Two fractions of high-dose-rate brachytherapy are convenient for patients, but most radiation oncologists in the United States do not use them, because of fear that they could lead to excessive rectal or bladder toxicity. Here we present our experience, which suggests that a two-fraction regimen is indeed safe and effective. We treated 49 patients with Stages I-III biopsy-proven carcinoma of the uterine cervix by external beam radiation therapy (EBRT), plus two fractions of high-dose-rate brachytherapy. The histology was squamous cell carcinoma in 43 patients (88%) and nonsquamous in 6 (12%). The median size of the primary tumor was 6 cm (range: 3-10 cm). Each patient received EBRT to the pelvis to a median dose of 45 Gy (range: 41.4-50.4 Gy), followed by a parametrial boost when indicated. Thirty patients (61%) also received irradiation to the para-aortic lymph nodes to a dose of 45 Gy. After EBRT, each patient underwent two applications of high-dose-rate brachytherapy, 1 week apart. The dose delivered to point A was 9 Gy per application for 49 applications (50%) and 9.4 Gy for 43 applications (44%), and it varied from 7 to 11 Gy for the rest (6%). The total dose to the rectum from both high-dose-rate brachytherapy applications ranged from 4.7 to 11.7 Gy (median: 7.1 Gy), and the total dose to the bladder from 3.8 to 15.5 Gy (median: 10.5 Gy). Twenty-five of the 49 patients (51%) received concomitant chemotherapy (cisplatin 20 mg/m(2)/day for 5 days) during the first and fourth weeks of EBRT and once after the second high-dose-rate brachytherapy application. Chemotherapy was not assigned in a randomized fashion. The use of chemotherapy increased during the time period spanned by this study as increasing evidence supporting the use of chemotherapy began to appear. The observed survival rates after 2, 3, and 5 years were 83%, 78%, and 78%, respectively. The surviving patients have been followed up for a median of 3 years (range: 2-6 years). Eight of the 49 patients suffered local failures. Among patients treated without chemotherapy, the 3-year local control rate was 77%; it was 88% among those receiving chemotherapy. There have been no regional failures. Four patients developed distant metastases. At 3 years, 91% of the patients in each group were free of distant metastases. Ten of the 49 patients (20%) suffered Grade 3 acute toxicity; 11 (22%) had Grade 4. Among the 24 patients treated without chemotherapy, only 1 (4%) suffered Grade 3 toxicity. Among the 25 patients receiving chemotherapy, in contrast, 8 (32%) suffered Grade 3 and 12 (48%) Grade 4 acute toxicity. Only 2 patients suffered late toxicity: One suffered Grade 2 and the other Grade 3 late toxicity. The actuarial risk of Grade 2 or worse late toxicity was 5%, with or without chemotherapy. Our experience suggests that two fractions of high-dose-rate brachytherapy are safe and effective in the management of cervix cancer, even in conjunction with concomitant cisplatin. The fears that the use of two fractions would lead to excessive rectal or bladder toxicity proved unfounded. Guidelines for ensuring a low complication rate are discussed.


Reassociation kinetics-based approach for partial genome sequencing of the cattle tick, Rhipicephalus (Boophilus) microplus.
The size and repetitive nature of the Rhipicephalus microplus genome makes obtaining a full genome sequence fiscally and technically problematic. To selectively obtain gene-enriched regions of this tick's genome, Cot filtration was performed, and Cot-filtered DNA was sequenced via 454 FLX pyrosequencing. The sequenced Cot-filtered genomic DNA was assembled with an EST-based gene index of 14,586 unique entries where each EST served as a potential "seed" for scaffold formation. The new sequence assembly extended the lengths of 3,913 of the 14,586 gene index entries. Over half of the extensions corresponded to extensions of over 30 amino acids. To survey the repetitive elements in the tick genome, the complete sequences of five BAC clones were determined. Both Class I and II transposable elements were found. Comparison of the BAC and Cot filtration data indicates that Cot filtration was highly successful in filtering repetitive DNA out of the genomic DNA used in 454 sequencing. Cot filtration is a very useful strategy to incorporate into genome sequencing projects on organisms with large genome sizes and which contain high percentages of repetitive, difficult to assemble, genomic DNA. Combining the Cot selection approach with 454 sequencing and assembly with a pre-existing EST database as seeds resulted in extensions of 27% of the members of the EST database.


Task-related oxygenation and cerebral blood volume changes estimated from NIRS signals in motor and cognitive tasks.
Although functional near-infrared spectroscopy (fNIRS) has an advantage of simultaneously measuring changes in oxy- and deoxy-hemoglobin concentrations (Δ[HbO] and Δ[HbR]), only few analysis approaches exploit this advantage. As an extension of our recently proposed method (task-related component analysis, TRCA), this study proposes a new analysis method that extracts task-related oxygenation and cerebral blood volume (CBV) changes. In the original formulation of TRCA, task-relatedness of a signal is defined as consistent appearance of a same waveform in every task block, thereby constructing task-related components by maximizing inter-block covariance. The new method proposes that, in addition to maximizing inter-block covariance, the covariance between task-related Δ[HbO] and Δ[HbR] is maximized (TRCA(+)) or minimized (TRCA(-)) so that oxygenation and CBV changes are maximally contrasted. The proposed method (collectively called TRCA(±)) was formulated as a matrix eigenvalue problem, which can be solved efficiently with standard numerical methods, and was tested with a synthetic data generated by a balloon model, successfully recovering oxygenation and CBV components. fNIRS data from sensorimotor areas in a finger-tapping task and from prefrontal lobe in a working-memory (WM) task were then analyzed. For both tasks, the time courses and the spatial maps for oxygenation and CBV changes were found to differ consistently, providing certain constraints in the parameters of balloon models. In summary, TRCA can estimate task-related oxygenation and CBV changes simultaneously, thereby extending the applicability of fNIRS.


The influence of mean climate trends and climate variance on beaver survival and recruitment dynamics.
Ecologists are increasingly aware of the importance of environmental variability in natural systems. Climate change is affecting both the mean and the variability in weather and, in particular, the effect of changes in variability is poorly understood. Organisms are subject to selection imposed by both the mean and the range of environmental variation experienced by their ancestors. Changes in the variability in a critical environmental factor may therefore have consequences for vital rates and population dynamics. Here, we examine ≥90-year trends in different components of climate (precipitation mean and coefficient of variation (CV); temperature mean, seasonal amplitude and residual variance) and consider the effects of these components on survival and recruitment in a population of Eurasian beavers (n = 242) over 13 recent years. Within climatic data, no trends in precipitation were detected, but trends in all components of temperature were observed, with mean and residual variance increasing and seasonal amplitude decreasing over time. A higher survival rate was linked (in order of influence based on Akaike weights) to lower precipitation CV (kits, juveniles and dominant adults), lower residual variance of temperature (dominant adults) and lower mean precipitation (kits and juveniles). No significant effects were found on the survival of nondominant adults, although the sample size for this category was low. Greater recruitment was linked (in order of influence) to higher seasonal amplitude of temperature, lower mean precipitation, lower residual variance in temperature and higher precipitation CV. Both climate means and variance, thus proved significant to population dynamics; although, overall, components describing variance were more influential than those describing mean values. That environmental variation proves significant to a generalist, wide-ranging species, at the slow end of the slow-fast continuum of life histories, has broad implications for population regulation and the evolution of life histories.


N-heterocyclic carbene-catalyzed [3+4] cycloaddition and kinetic resolution of azomethine imines.
The first N-heterocyclic carbene (NHC)-catalyzed [3+4] cycloaddition of azomethine imines and enals is disclosed. Oxidative catalytic remote activation of enals affords 1,4-dipolarophile intermediates that react with 1,3-dipolar azomethine imines to generate dinitrogen-fused seven-membered heterocyclic products with high optical purities. Our approach also provides effective kinetic resolution of azomethine imines, in which the substrate chiral center that is remote from the NHC catalyst can be well resolved.


Preventive measures for cyclophosphamide-related hemorrhagic cystitis in blood and bone marrow transplantation: an Italian multicenter retrospective study.
Hemorrhagic cystitis (HC) is a troublesome and potentially life-threatening complication of bone marrow transplantation (BMT). HC can appear within a few hours after chemotherapy or after weeks or months. Early-onset HC (EOHC) is usually associated with the conditioning regimen. The main aim of this study was to describe the incidence of EOHC in patients undergoing BMT regimens including high-dose cyclophosphamide (CY) and the effects of the main preventive measures adopted in Italian nursing practice. The authors retrospectively analyzed the clinical records of 158 Italian patients who underwent BMT from 2006-2008. Thirty-one patients (19.6%) developed EOHC. One hundred and forty-seven patients (93%) given high-dose CY were treated with hyperhydration combined with 2-mercaptoethane sulphonate (mesna) and diuresis alkalinization, and only 51 (32.3%) patients were preventively catheterized and received continuous bladder irrigation (CBI). By univariate analysis, prophylactic urethral catheterization and CBI did not decrease EOHC incidence questioning if these measures were to be routinely recommended. Previous studies showed increased discomfort and urinary tract infection in catheterized patients; therefore, nurses may fulfill an important role in balancing the benefits and harms of preventive catheterization and CBI in patients who received BMT conditioning including high-dose CY.


High Throughput Micropatterning of Optical Oxygen Sensor for Single Cell Analysis.
In this paper, we present our results from process development and characterization of optical oxygen sensors that are patterned by traditional UV lithography. An oxygen sensitive luminescent probe, platinum octaethylporphyrin (PtOEP), was encapsulated in commercially purchased photoresist (AZ5214) to form uniform thin sensor films on fused silica substrates. Plasticizer ethoxylated trimethylolpropane triacrylate (SR454) was added to the dye-photoresist sensor mixtures to improve the oxygen sensitivity. The optimum sensor mixture composition that can be patterned with maximum sensitivity was identified. The microfabrication process conditions, cell adherence and oxygen sensitivity results from patterned structures were characterized in detail. Down to 3 µm features have been fabricated on fused silica substrates using the developed techniques. The result implies the developed methods can provide a feasible way to miniaturize the optical sensor system for single cell analysis with precise control of sensor volume and response.


Comparison of voice-use profiles between elementary classroom and music teachers.
Among teachers, music teachers are roughly four times more likely than classroom teachers to develop voice-related problems. Although it has been established that music teachers use their voices at high intensities and durations in the course of their workday, voice-use profiles concerning the amount and intensity of vocal use and vocal load have neither been quantified nor has vocal load for music teachers been compared with classroom teachers using these same voice-use parameters. In this study, total phonation time, fundamental frequency (F₀), and vocal intensity (dB SPL [sound pressure level]) were measured or estimated directly using a KayPENTAX Ambulatory Phonation Monitor (KayPENTAX, Lincoln Park, NJ). Vocal load was calculated as cycle and distance dose, as defined by Švec et al (2003), which integrates total phonation time, F₀, and vocal intensity. Twelve participants (n = 7 elementary music teachers and n = 5 elementary classroom teachers) were monitored during five full teaching days of one workweek to determine average vocal load for these two groups of teachers. Statistically significant differences in all measures were found between the two groups (P < 0.05) with large effect sizes for all parameters. These results suggest that typical vocal loads for music teachers are substantially higher than those experienced by classroom teachers (P < 0.01). This study suggests that reducing vocal load may have immediate clinical and educational benefits in vocal health in music teachers.


Adoption of Electronic Health Records and Perceptions of Financial and Clinical Outcomes Among Ophthalmologists in the United States.
Assessing the rate of electronic health record (EHR) adoption and ophthalmologists' perceptions on financial and clinical productivity is important in understanding how to direct future design and health care policy. To assess adoption rate and perceptions of financial and clinical outcomes of EHRs among ophthalmologists in the United States. Population-based, cross-sectional study. A random sample of 2000 ophthalmologists was generated on the basis of mailing address zip codes from the 2015 American Academy of Ophthalmology US active membership database, which included more than 18 000 ophthalmologists. A survey was sent by email to assess adoption rate of EHRs, perceptions of financial and clinical productivity, and engagement with Medicare and Medicaid programs that incentivize the use of EHRs. The survey was conducted between 2015 and 2016. Adoption rate of EHRs and perceptions of financial and clinical productivity. The adoption rate of EHRs among surveyed ophthalmologists (348 respondents) was 72.1%. The responding ophthalmologists perceived that their net revenues and productivity have declined and that practice costs are higher with EHR use. Of those who attested for stage 1 of the EHR incentive program, 83% had already or were planning to attest to stage 2, but 9% had no plans. The adoption of EHRs by ophthalmologists has more than doubled since a 2011 survey and is similar to that of primary care physicians (79%). In comparison with 2 previous surveys of ophthalmologists, respondents had more negative perceptions of EHR productivity outcomes and effect on practice costs, although financial data were not collected in this survey to support these opinions. These negative perceptions suggest that more attention should be placed on improving the efficiency and usability of EHR systems.


Kinetics and differentiation of marrow stromal cells in diffusion chambers in vivo.
Rabbit marrow cells inoculated into diffusion chambers (10(7) cells/chamber) were implanted intraperitoneally into athymic mouse hosts and cultured in vivo for 20 days. A connective tissue consisting of bone, cartilage and fibrous tissues is formed by the stromal fibroblastic cells of marrow within the chambers. Cell kinetics and tissue differentiation have been studied using histomorphometric and biochemical analyses. Haemopoietic cell numbers decrease to less than 0.05% of the initial inoculum during the 20-day period. At 3 days an average of 15 stromal fibroblastic cells only are identifiable within the chambers. After 3 days there is a high rate of stromal cell proliferation with a doubling time of 14.5 h during the period from 3 to 8 days and an increase in the total stromal cell population by more than six orders of magnitude from 3 to 20 days. Thirteen to fourteen population doublings occur before expression of the first observable differentiation parameter, alkaline phosphatase activity. The data demonstrate that the mixture of connective tissues formed within the chamber is generated by a small number of cells with high capacity for proliferation and differentiation. This is consistent with the current hypothesis that stromal stem cells are present in bone marrow.


Anti Bacterial Efficacy of Terminalia Chebula, Terminalia Bellirica, Embilica Officinalis and Triphala on Salivary Streptococcus Mutans Count - A Linear Randomized Cross Over Trial.
From the oral health perspective, it is well established that microorganisms have an important role in caries aetiology. From the dawn of civilization, herbal plants have served an array of roles. Triphala a tradtional herbal Ayurvedic formula consists of three native fruits of india including Terminalia Chebula (T. chebula), Terminalia Bellirica (T. bellirica) and Embilica Officinalis (E. officinalis). As per Ayurvedic Formulary of India (AFI) Triphala is prepared by combining a 1:1:1 mixture of ground dry fruits called myrobalans. Till date, an inadequate number of clinical researches on herb based mouth rinses have been reported in Asia, especially in India and other Southeast Asian countries (where these products are most accepted and widely used). The present study was planned to assess the effectiveness of Triphala with its three constituents. The objective of this study was to determine the effect of Triphala, T. chebula, T. bellirica and E. officinalis aqueous extract rinses separately on Streptococcusmutans count at various time intervals. This is a double-blind, linear cross over, within group experimental trial conducted among subjects visiting the Department of Public Health Dentistry aged 15 to 40 years. In this design, subjects received all of the treatments sequentially in time. The independent variables to be assessed in this study were all the four interventions of herbal preparations used and the dependent variable assessed is anti bacterial efficacy. Each subject receives two or more different treatments. All the subjects were exposed to all four interventions: 1) T. chebula; 2) T. bellirica; 3) E. officinalis; and 4) Triphala and were provided 15 ml of the freshly prepared 10% rinse. The subjects were instructed not to eat or drink between salivary samples collection. Post rinse unstimulated salivary samples were collected at five minutes and 60 minutes intervals. All the salivary samples were transferred immediately to microbiological laboratory in sterile containers within one hour for microbiological analysis. The mean Colony Forming Units (CFUs) of S. mutans with Triphala when compared to other three intervention was significantly reduced at 5 minutes and 60 minutes (p=0.001). E. officinalis showed least reduction of mean CFUs when compared to other three groups. It can be concluded that all four rinses were effective in reducing S. mutans CFUs, but 10% Triphala has greater efficacy than its other constituents.


Investigation of the actin scavenging system in pre-eclampsia.
Cell injury releases actin, the most abundant cell protein. Gelsolin and vitamin D binding protein (VDBP) together depolymerise and clear cell-free actin. Impaired actin clearance is associated with several diseases and correlates with clinical outcome. The actin scavenging system was investigated in pre-eclampsia (PE), a procoagulant and proinflammatory state with placental and vascular damage. Plasma gelsolin and actin free VDBP (AFVDBP) were measured in PE (early onset <33weeks; late onset ≥36weeks), matched normal pregnant (normP) and non-pregnant (nonPr) women, using commercially available ELISAs. Longitudinal samples from normP and women who subsequently developed PE were also analysed. Plasma gelsolin fell during pregnancy (p=0.0002), with a concomitant rise in actin-free VDBP (p<0.001). Gelsolin concentrations were only significantly lower in established PE (p<0.05) when compared to non-pregnant controls. We have shown that the components of the actin clearance system, gelsolin and AFVDBP, are altered in normal pregnancy and further changes occur in established PE, suggesting depleted actin clearance in PE. Whether this is a cause or consequence of PE pathophysiology requires further investigation.


The epidemiology of symptomatic midfoot osteoarthritis in community-dwelling older adults: cross-sectional findings from the Clinical Assessment Study of the Foot.
The foot is largely overlooked in calls for better characterisation of clinical phenotypes in osteoarthritis (OA). Yet the midfoot complex in particular has the potential to provide important insights into OA pathogenesis given its central role in lower limb load transmission and alignment. Its recent inclusion in radiographic atlases has paved the way for international studies. In this UK study, we provide the first comprehensive account of the descriptive epidemiology of symptomatic midfoot OA. Participants aged ≥50 years registered with four general practices were recruited via a mailed health survey (n = 5109 responders) and research clinic (n = 560 responders). Symptomatic midfoot OA was defined as midfoot pain in the last 4 weeks, combined with radiographic OA in one or more joints (1st and 2nd cuneometatarsal, navicular first cuneiform and talonavicular joints) graded from weight-bearing dorso-plantar and lateral radiographs using a validated atlas. Prevalence estimates, overall and stratified by age, gender, and socio-economic class, were derived using multiple imputation and weighted logistic regression. Associations between symptomatic midfoot OA and current body mass index, previous injury, history of high-heeled footwear, nodal interphalangeal joint OA and patterns of comorbidity were estimated using binary logistic regression. Healthcare use was summarised. Symptomatic midfoot OA was present in 12.0% (95 % CI: 10.9, 13.2) of the population aged over 50 years. Higher occurrence was observed in females, adults aged over 75 years, and those in intermediate/routine occupational classes. Obesity, previous foot/ankle injury, and pain in other weight-loaded joints, but not high-heeled footwear or nodal interphalangeal joint OA, were associated with increased risk of symptomatic midfoot OA. Persons with symptomatic midfoot OA were also more likely to report multiple non-musculoskeletal comorbidities, including diabetes. In the previous 12 months, the proportions consulting a general practitioner, physiotherapist or podiatrist/chiropodist about foot pain were 46.2%, 18.5% and 47.9% respectively. A total of 64.7% had used oral analgesia in the past month for foot pain (36.1% paracetamol, 31.9% mild/moderate opioids, 27.7% NSAIDs). Our study confirms that symptomatic OA frequently affects the midfoot. The patterns of associations are interpreted as being largely consistent with the role of mechanical factors in its pathogenesis.


First Report of Tomato chlorotic dwarf viroid in Petunia hybrida from the United States of America.
In November 2005, 13 accessions of Petunia hybrida from the United States of America entered the post-entry quarantine station of the Plant Protection Service in the Netherlands. The plants were inspected and tested for quarantine organisms according to Directives 95/44 and 97/46 of the European Union. No virus and viroid symptoms were observed in the imported plants or in mechanically inoculated plants of Chenopodium quinoa, Nicotiana benthamiana, and N. occidentalis-P1 (3). Testing for pospiviroids by return-polyacrylamide gel electrophoresis (1) and reverse transcriptase-PCR with universal pospiviroid primers Pospi1-RE/FW (2) indicated the presence of pospiviroids in 3 and 11 P. hybrida accessions, respectively. The 196-bp amplicons of six accessions were sequenced. Sequence analysis showed the highest identity for all amplicons to both isolates of Tomato chlorotic dwarf viroid (TCDVd) in NCBI GenBank, Accession Nos. AF162131and AY372399, from Canada and the United States, respectively. Additional RT-PCRs with the Pospi1-RE/FW primers in opposite order and the semi-universal pospiviroid primers Vid-RE/FW (2) for one isolate, followed by sequence analysis, confirmed the identity as TCDVd. The isolate consisted of 359 nucleotides (GenBank Accession No. DQ859013) and showed sequence identities of 98.6 and 96.1% to the Canadian and American tomato isolates of this viroid, respectively. The next highest sequence identity was 90.0% to two accessions of Potato spindle tuber viroid (GenBank Accession Nos. AJ593449 and AY962324). On the basis of these results, the viroid from P. hybrida was identified as TCDVd. To our knowledge, this is the first report of TCDVd in this plant species. Reference: (1) J. W. Roenhorst et al. EPPO Bull. 30:453, 2000. (2) J. Th. J. Verhoeven et al. Eur. J. Plant Pathol. 110:823, 2004. (3) J. Th. J. Verhoeven and J. W. Roenhorst. EPPO Bull. 33:305, 2003.


Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension.
To determine the cause of pulmonary hypertension (PH) in systemic sclerosis (SSc) patients since PH can occur because of pulmonary arteriopathy, pulmonary parenchymal destruction, and left ventricular cardiac dysfunction. Consecutive case series in a university hospital. Nine SSc patients with PH (mean pulmonary artery pressure, 41 mm Hg), with (n = 6) or without (n = 3) concomitant interstitial lung disease (ILD). Acute infusion of epoprostenol was begun at 2 ng/kg/min and was titrated upward at a rate of 2 ng/kg/min every 30 min until symptomatic complications developed or pulmonary artery vascular resistance (PVR) was reduced by 50%. Eight of nine patients demonstrated a reduction of > or = 20% in PVR, suggesting that vasoreactivity is common despite the presence of significant ILD. A single patient had no response to infusion with unchanged hemodynamics and oxygenation. One patient developed hypoxemia as cardiac output increased, suggesting a worsening of ventilation/perfusion matching or the presence of an anatomic shunt. Acute pulmonary edema developed in one patient at an infusion rate of 6 ng/kg/min. The results of cardiac catheterization suggested that pulmonary edema was caused by SSc heart disease. SSc patients with ILD have diverse and sometimes multiple causes of PH that can be determined by short-term epoprostenol infusion. Beneficial effects can be obtained from epoprostenol despite extensive ILD.


From dysphonia to dysphoria: Mokken scaling shows a strong, reliable hierarchy of voice symptoms in the Voice Symptom Scale questionnaire.
Symptoms of hoarseness (dysphonia) are common and often associated with psychological distress. The Voice Symptom Scale (VoiSS) is a 30-item self-completed questionnaire concerning voice and throat symptoms. Psychometric and clinical studies on the VoiSS show that it has good reliability and validity, and a clear factorial structure. The present article presents a further advance in voice measurement from the patient's point of view. To date, there has been no examination of whether voice-related symptoms form a hierarchy; that is, whether people who suffer voice problems progress through a reliable set of problems from mild to severe. To address this question, the technique of Mokken scaling was applied to the VoiSS in 480 patients with dysphonia. A strong and reliable Mokken scale--a symptom hierarchy--was found, which included 17 of the 30 items. This new information on dysphonia shows that voice symptoms progress from voice-oriented difficulties, through practical problems, to disturbances of social relationships and mood (dysphoria). The results add information about the structured phenomenology of voice problems, further establish the relationship between voice impairment and psychosocial impairment, and suggest practical applications in the assessment of dysphonic voices.


Relationship between plantar pressures, physical activity and sedentariness among preschool children.
It has been speculated that high plantar pressures might cause foot pain and discomfort which, in turn, may discourage children from being physically active and result in them spending more time in sedentary activities. The purpose of this study was to determine whether plantar pressure distributions generated by preschool children were correlated with objectively measured time spent in physical activity and sedentary behaviour. Dynamic plantar pressures were measured for 33 preschool children (age=4.3±0.6 years; height=1.06±0.1 m; mass=18.4±2.9 kg; 17 boys) as they walked across an emed AT-4 pressure platform. Physical activity was objectively assessed using MTI ActiGraph accelerometers. Total physical activity (counts per minute), percentage of time spent in moderate-to-vigorous physical activity (MVPA), light activity and sedentary behaviour were then calculated. Peak pressures across the heel were found to significantly correlate with total physical activity (r=-0.53; p=0.03) and time in MVPA (r=-0.47; p=0.05) in boys. Similarly, the correlation data suggested that girls who generated higher peak pressures in the toe region spent more time in sedentary behaviour (r=0.53; p=0.04). As high plantar pressures appear to be a potential negative correlate of physical activity and sedentary behaviour, it is recommended that further research be conducted to design, test and evaluate the potential of interventions to reduce plantar pressures in inactive children so they can enjoy the benefits associated with participating in a more active lifestyle.


Hydrophobic solvation increases thermal conductivity of water.
The interaction of water with small alcohols can be used as a model for understanding hydrophobic solvation of larger and more complex amphiphilic molecules. Despite its apparent simplicity, water/ethanol mixtures show important anomalies in several of their properties, like specific heat or partial molar volume, whose precise origin are still a matter of debate. Here we report high-resolution thermal conductivity, compressibility, and IR-spectroscopy data for water/ethanol solutions showing three distinct regions of solvation, related to changes in the H-bond network. Notably, the thermal conductivity shows a surprising increase of ≈3.1% with respect to pure water at dilute concentrations of ethanol (x = 0.025), which suggests a strengthening of H-bond network of water. Our results prove that the rate of energy transfer in water can be increased by hydrophobic solvation, due to the cooperative nature of the H-bond network.


Availability of antidotes and key emergency drugs in tertiary care hospitals of Punjab and assessment of the knowledge of health care professionals in the management of poisoning cases.
This study was conducted to evaluate the availability of antidotes/key emergency drugs in tertiary care hospitals of the Punjab province, and to assess the knowledge of health care professionals in the stocking and administration of antidotes in the proper management of poisoning cases. Seventeen (n=17) tertiary care hospitals of Punjab Pakistan were selected. Two performas (A and B) were designed for 26 antidotes/key emergency drugs and given to the hospital pharmacists and physicians respectively. It was observed that Activated Charcoal, being the universal antidote was found only in 6 hospitals (41%). Digoxin Immune Fab, Edentate Calcium disodium and Glucagon were not available in emergency department of any hospital and even not included in the formulary of any hospital. About 80% pharmacists were aware of the method of preparation of Activated Charcoal and 85% physicians were familiar with its route of administration. Data showed that tertiary care hospitals of Punjab do not stock antidotes according to national drug policy. Moreover the study strongly suggests the development of health care centers and professional by organizing antidote awareness programs, continuous education and record keeping of poisonous cases and availability of emergency drugs around the clock.