Curriculum for optical diagnosis training in Europe: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.
This manuscript represents an official Position Statement of the European Society of Gastrointestinal Endoscopy (ESGE) aiming to guide general gastroenterologists to develop and maintain skills in optical diagnosis during endoscopy. In general, this requires additional training beyond the core curriculum currently provided in each country. In this context, ESGE have developed a European core curriculum for optical diagnosis practice across Europe for high quality optical diagnosis training. 1: ESGE suggests that every endoscopist should have achieved general competence in upper and/or lower gastrointestinal (UGI/LGI) endoscopy before commencing training in optical diagnosis of the UGI/LGI tract, meaning personal experience of at least 300 UGI and/or 300 LGI endoscopies and meeting the ESGE quality measures for UGI/LGI endoscopy. ESGE suggests that every endoscopist should be able and competent to perform UGI/LGI endoscopy with high definition white light combined with virtual and/or dye-based chromoendoscopy before commencing training in optical diagnosis. 2: ESGE suggests competency in optical diagnosis can be learned by attending a validated optical diagnosis training course based on a validated classification, and self-learning with a minimum number of lesions. If no validated training course is available, optical diagnosis can only be learned by attending a non-validated onsite training course and self-learning with a minimum number of lesions. 3: ESGE suggests endoscopists are competent in optical diagnosis after meeting the pre-adoption and learning criteria, and meeting competence thresholds by assessing a minimum number of lesions prospectively during real-time endoscopy. ESGE suggests ongoing in vivo practice by endoscopists to maintain competence in optical diagnosis. If a competent endoscopist does not perform in vivo optical diagnosis on a regular basis, ESGE suggests repeating the learning and competence phases to maintain competence.Key areas of interest were optical diagnosis training in Barrett's esophagus, esophageal squamous cell carcinoma, early gastric cancer, diminutive colorectal lesions, early colorectal cancer, and neoplasia in inflammatory bowel disease. Condition-specific recommendations are provided in the main document.


High-sensitivity in vivo THz transmission imaging of early human breast cancer in a subcutaneous xenograft mouse model.
We performed in vivo THz transmission imaging study on a subcutaneous xenograft mouse model for early human breast cancer detection. With a THz-fiber-scanning transmission imaging system, we continuously monitored the growth of human breast cancer in mice. Our in vivo study not only indicates that THz transmission imaging can distinguish cancer from the surrounding fatty tissue, but also with a high sensitivity. Our in vivo study on the subcutaneous xenograft mouse model will encourage broad and further investigations for future early cancer screening by using THz imaging system.


The Global Trachoma Mapping Project: Methodology of a 34-Country Population-Based Study.
To complete the baseline trachoma map worldwide by conducting population-based surveys in an estimated 1238 suspected endemic districts of 34 countries. A series of national and sub-national projects owned, managed and staffed by ministries of health, conduct house-to-house cluster random sample surveys in evaluation units, which generally correspond to "health district" size: populations of 100,000-250,000 people. In each evaluation unit, we invite all residents aged 1 year and older from h households in each of c clusters to be examined for clinical signs of trachoma, where h is the number of households that can be seen by 1 team in 1 day, and the product h × c is calculated to facilitate recruitment of 1019 children aged 1-9 years. In addition to individual-level demographic and clinical data, household-level water, sanitation and hygiene data are entered into the purpose-built LINKS application on Android smartphones, transmitted to the Cloud, and cleaned, analyzed and ministry-of-health-approved via a secure web-based portal. The main outcome measures are the evaluation unit-level prevalence of follicular trachoma in children aged 1-9 years, prevalence of trachomatous trichiasis in adults aged 15 + years, percentage of households using safe methods for disposal of human feces, and percentage of households with proximate access to water for personal hygiene purposes. In the first year of fieldwork, 347 field teams commenced work in 21 projects in 7 countries. With an approach that is innovative in design and scale, we aim to complete baseline mapping of trachoma throughout the world in 2015.


Experimental chronic Lyme borreliosis in Lewis rats.
The course of Lyme borreliosis in LEW/N rats inoculated intraperitoneally as infants with 10(6) Borrelia burgdorferi was followed for 360 days. Spirochetes were detected in the blood through 30 days, in the brain through 60 days, and persisted in the spleen, liver, kidneys and articular tissue through 360 days. Acute exudative arthritis, tendonitis, and bursitis were evident in multiple joints by day 30. Arthritis regressed thereafter but capsular fibrosis and lymphoplasmacytic infiltrates persisted throughout the study. Several rats developed exacerbations of acute arthritis within days 180-360, a pattern similar to that encountered in human Lyme disease. Rats had a high prevalence of nonsuppurative myocarditis and vasculitis during days 90-360. Spirochetes were visualized by microscopy in joints and other tissues during the first month of infection, but were seen only sporadically thereafter. All rats seroconverted to B. burgdorferi by day 30. IgM titers persisted and IgG titers rose progressively through day 360. Immunoblots revealed IgM reactivity to a single 41 kDa protein until 360 days, when reactivity to a 60 kDa protein emerged. IgG reactivity occurred against progressively more proteins with time, indicating continued antigenic stimulation. Chronic and recurrent arthritic lesions and myocardial involvement suggest that the rat is a reliable model for further investigation.


A comparison of antecedents to cardiac arrests, deaths and emergency intensive care admissions in Australia and New Zealand, and the United Kingdom--the ACADEMIA study.
Many patients have physiological deterioration prior to cardiac arrest, death and intensive care unit (ICU) admission, that are detected and documented by medical and nursing staff. Appropriate early response to detected deterioration is likely to benefit patients. In a multi-centre, prospective, observational study over three consecutive days, we studied the incidence of antecedents (serious physiological abnormalities) preceding primary events (defined as in-hospital deaths, cardiac arrests, and unanticipated ICU admissions) in 90 hospitals (69 United Kingdom [UK]; 19 Australia and 2 New Zealand [ANZ]). 68 hospitals reported primary events during the three-day study period (50 United Kingdom, 16 Australia and 2 New Zealand). Data on the availability of ICU/HDU beds and cardiac arrest teams and Medical Emergency Teams were also collected. Of 638 primary events, there were 308 (48.3%) deaths, 141 (22.1%) cardiac arrests, and 189 (29.6%) unplanned ICU admissions. There were differences in the pattern of primary events between the UK and ANZ (P < 0.001). There were proportionally more deaths in the UK (52.3% versus 35.3%) and a higher number of unplanned ICU admissions in ANZ (47.3% versus 24.2%). Sixty percent (383) of primary events had a total of 1032 documented antecedents. The most common antecedents were hypotension and a fall in Glasgow Coma Scale. The proportion of ICU/HDU to general hospital beds was greater in ANZ (0.034 versus 0.016, P < 0.001) and medical emergency teams were more common in ANZ (70.0% versus 27.5%, P = 0.001). The data confirm antecedents are common before death, cardiac arrest, and unanticipated ICU admission. The study also shows differences in patterns of primary events, the provision of ICU/HDU beds and resuscitation teams, between the UK and ANZ. Future research, focusing upon the relationship between service provision and the pattern of primary events, is suggested.


Reduction of Salmonella enterica on alfalfa seeds with acidic electrolyzed oxidizing water and enhanced uptake of acidic electrolyzed oxidizing water into seeds by gas exchange.
Alfalfa sprouts have been implicated in several salmonellosis outbreaks in recent years. The disinfectant effects of acidic electrolyzed oxidizing (EO) water against Salmonella enterica both in an aqueous system and on artificially contaminated alfalfa seeds were determined. The optimum ratio of seeds to EO water was determined in order to maximize the antimicrobial effect of EO water. Seeds were combined with EO water at ratios (wt/vol) of 1:4, 1:10, 1:20, 1:40, and 1:100, and the characteristics of EO water (pH, oxidation reduction potential [ORP], and free chlorine concentration) were determined. When the ratio of seeds to EO water was increased from 1:4 to 1:100, the pH decreased from 3.82 to 2.63, while the ORP increased from +455 to +1,073 mV. EO water (with a pH of 2.54 to 2.38 and an ORP of +1,083 to +1,092 mV) exhibited strong potential for the inactivation of S. enterica in an aqueous system (producing a reduction of at least 6.6 log CFU/ml). Treatment of artificially contaminated alfalfa seeds with EO water at a seed-to-EO water ratio of 1:100 for 15 and 60 min significantly reduced Salmonella populations by 2.04 and 1.96 log CFU/g, respectively (P < 0.05), while a Butterfield's buffer wash decreased Salmonella populations by 0.18 and 0.23 log CFU/g, respectively. After treatment, EO water was Salmonella negative by enrichment with or without neutralization. Germination of seeds was not significantly affected (P > 0.05) by treatment for up to 60 min in electrolyzed water. The uptake of liquid into the seeds was influenced by the internal gas composition (air, N2, or O2) of seeds before the liquid was added.


DAFS: a data-adaptive flag method for RNA-sequencing data to differentiate genes with low and high expression.
Next-generation sequencing (NGS) has advanced the application of high-throughput sequencing technologies in genetic and genomic variation analysis. Due to the large dynamic range of expression levels, RNA-seq is more prone to detect transcripts with low expression. It is clear that genes with no mapped reads are not expressed; however, there is ongoing debate about the level of abundance that constitutes biologically meaningful expression. To date, there is no consensus on the definition of low expression. Since random variation is high in regions with low expression and distributions of transcript expression are affected by numerous experimental factors, methods to differentiate low and high expressed data in a sample are critical to interpreting classes of abundance levels in RNA-seq data. A data-adaptive approach was developed to estimate the lower bound of high expression for RNA-seq data. The Kolmgorov-Smirnov statistic and multivariate adaptive regression splines were used to determine the optimal cutoff value for separating transcripts with high and low expression. Results from the proposed method were compared to results obtained by estimating the theoretical cutoff of a fitted two-component mixture distribution. The robustness of the proposed method was demonstrated by analyzing different RNA-seq datasets that varied by sequencing depth, species, scale of measurement, and empirical density shape. The analysis of real and simulated data presented here illustrates the need to employ data-adaptive methodology in lieu of arbitrary cutoffs to distinguish low expressed RNA-seq data from high expression. Our results also present the drawbacks of characterizing the data by a two-component mixture distribution when classes of gene expression are not well separated. The ability to ascertain stably expressed RNA-seq data is essential in the filtering process of data analysis, and methodologies that consider the underlying data structure demonstrate superior performance in preserving most of the interpretable and meaningful data. The proposed algorithm for classifying low and high regions of transcript abundance promises wide-range application in the continuing development of RNA-seq analysis.


The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration.
Indinavir (IDV) is a protease inhibitor that successfully suppresses HIV-1 replication as part of anti-retroviral therapy. There is evidence to suggest that IDV may also act non-specifically upon host proteases. In this study we investigated whether IDV could modulate protease-dependent molecules involved in dendritic cell (DC) migration - a pivotal process in immunoregulation. Human monocyte-derived DC were exposed to IDV (IDV-DC) and transendothelial migration (TEM) to inflammatory chemokines was determined. TEM of IDV-DC was significantly impaired compared to non-treated DC (p<0.01). Phenotypic analysis revealed that IDV-DC had reduced DC-SIGN expression, correlating with reduced adhesion to immobilized ICAM-2. Nevertheless, the reduction in migration following exposure to IDV could not be fully attributable to DC-SIGN interactions alone. Investigation of IDV-DC interactions with the underlying matrix protein, fibronectin, demonstrated that IDV significantly impaired DC binding to immobilized fibronectin (p<0.01). IDV appeared to act upon VLA-4 and VLA-5 since addition of antagonist monoclonal antibodies (mAb) similarly reduced adhesion of non-treated DC to fibronectin. Combined blockade of DC using anti-VLA-4, VLA-5 and anti-DC-SIGN mAb inhibited TEM to a similar extent as IDV. Our results strongly suggest that IDV inhibits host proteases necessary for DC migration and may, therefore, affect DC immunoregulation in HIV-1-infected patients.


Identification of progenitor cells that contribute to heterotopic skeletogenesis.
Individuals who have fibrodysplasia ossificans progressiva develop an ectopic skeleton because of genetic dysregulation of bone morphogenetic protein (BMP) signaling in the presence of inflammatory triggers. The identity of progenitor cells that contribute to various stages of BMP-induced heterotopic ossification relevant to fibrodysplasia ossificans progressiva and related disorders is unknown. An understanding of the cellular basis of heterotopic ossification will aid in the development of targeted, cell-specific therapies for the treatment and prevention of heterotopic ossification. We used Cre/loxP lineage tracing methods in the mouse to identify cell lineages that contribute to all stages of heterotopic ossification. Specific cell populations were permanently labeled by crossing lineage-specific Cre mice with the Cre-dependent reporter mice R26R and R26R-EYFP. Two mouse models were used to induce heterotopic ossification: (1) intramuscular injection of BMP2/Matrigel and (2) cardiotoxin-induced skeletal muscle injury in transgenic mice that misexpress BMP4 at the neuromuscular junction. The contribution of labeled cells to fibroproliferative lesions, cartilage, and bone was evaluated histologically by light and fluorescence microscopy. The cell types evaluated as possible progenitors included skeletal muscle stem cells (MyoD-Cre), endothelium and endothelial precursors (Tie2-Cre), and vascular smooth muscle (Smooth Muscle Myosin Heavy Chain-Cre [SMMHC-Cre]). Vascular smooth muscle cells did not contribute to any stage of heterotopic ossification in either mouse model. Despite the osteogenic response of cultured skeletal myoblasts to BMPs, skeletal muscle precursors in vivo contributed minimally to heterotopic ossification (<5%), and this contribution was not increased by cardiotoxin injection, which induces muscle regeneration and mobilizes muscle stem cells. In contrast, cells that expressed the vascular endothelial marker Tie2/Tek at some time in their developmental history contributed robustly to the fibroproliferative, chondrogenic, and osteogenic stages of the evolving heterotopic endochondral anlagen. Importantly, endothelial markers were expressed by cells at all stages of heterotopic ossification. Finally, muscle injury and associated inflammation were sufficient to trigger fibrodysplasia ossificans progressiva-like heterotopic ossification in a setting of chronically stimulated BMP activity. Tie2-expressing progenitor cells, which are endothelial precursors, respond to an inflammatory trigger, differentiate through an endochondral pathway, contribute to every stage of the heterotopic endochondral anlagen, and form heterotopic bone in response to overactive BMP signaling in animal models of fibrodysplasia ossificans progressiva. Thus, the ectopic skeleton is not only supplied by a rich vasculature, but appears to be constructed in part by cells of vascular origin. Further, these data strongly suggest that dysregulation of the BMP signaling pathway and an inflammatory microenvironment are both required for the formation of fibrodysplasia ossificans progressiva-like lesions.


Optical investigation of osteoarthritic human cartilage (ICRS grade) by confocal Raman spectroscopy: a pilot study.
Biomolecular changes in the cartilage matrix during the early stage of osteoarthritis may be detected by Raman spectroscopy. The objective of this investigation was to determine vibrational spectral differences among different grades (grades I, II, and III) of osteoarthritis in human osteoarthritic cartilage, which was classified according to the International Cartilage Repair Society (ICRS) grading system. Degenerative articular cartilage samples were collected during total joint replacement surgery and were classified according to the ICRS grading system for osteoarthritis. Twelve cartilage sections (4 sections of each ICRS grades I, II, and III) were selected for Raman spectroscopic analysis. Safranin-O/Fast green was used for histological staining and assignment of the Osteoarthritis Research Society International (OARSI) grade. Multivariate principal component analysis (PCA) was used for data analysis. Spectral analysis indicates that the content of disordered coil collagen increases significantly during the early progression of osteoarthritis. However, the increase was not statistically significant during later stages of the disease. A decrease in the content of proteoglycan was observed only during advanced stages of osteoarthritis. Our investigation shows that Raman spectroscopy can classify the different stage of osteoarthritic cartilage and can provide details on biochemical changes. This proof-of-concept study encourages further investigation of fresh cartilage on a larger population using fiber-based miniaturized Raman probe for the development of in vivo Raman arthroscopy as a potential diagnostic tool for osteoarthritis.


Effects of trophy hunting leftovers on the ranging behaviour of large carnivores: a case study on spotted hyenas.
Human-related food resources such as garbage dumps and feeding sites have been shown to significantly influence space use, breeding success and population dynamics in a variety of animal species. In contrast, relatively little is known on the effects of unpredictable sources of food, such as carcasses discarded by hunters, on carnivore species. We evaluated the effect of elephant carcasses, mainly deriving from trophy hunting, on the ranging and feeding behavior of spotted hyenas (Crocuta crocuta) in the Okavango Delta, Botswana. Using data from hyenas monitored before and during carcass availability via GPS radio-collars and camera traps, we investigated changes in ranging and feeding behavior over time. Carcass availability influenced hyenas' ranging behavior for an average of 10-12 days, after which their movements returned to patterns observed before carcass availability. In particular, we observed an increased spatial clustering of locations and reduced speeds (up to 15% less) between successive locations with carcass availability. Consistent feeding at carcasses during the first two weeks was typical, and some individuals fed from elephant carcasses for as long as 50 days. The impact and conservation value of hunting are often assessed based solely on the effects on the hunted species. Our results show that hunting remains can influence other species and suggest that such extra food could have important effects on critical life history processes and ultimately population dynamics. We recommend conservationists and wildlife managers evaluate management strategies and hunting practices regarding carcass disposal in order to incorporate the potential collateral impacts of hunting on non-hunted species in the same community.


BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial.
For human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings. To determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy. Open, randomised, non-inferiority trial. Europe, Thailand, Uganda, Argentina and the USA. Young people (aged 8-24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of < 50 copies/ml for > 12 months. Young people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART). Follow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VL > 50 copies/ml (confirmed) by 48 weeks, estimated using the Kaplan-Meier method (12% non-inferiority margin) adjusted for region and age. In total, 199 young people (11 countries) were randomised (n = 99 SCT group, n = 100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥ 18 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm(3), respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap(™) Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group, n = 5; CT group, n = 7). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL > 50 copies/ml [difference -1.2%, 90% confidence interval (CI) -7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL > 400 copies/ml (difference -2.1%, 90% CI -6.2% to 1.9%). All six participants in the SCT group with a VL > 50 copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (p = 0.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group, n = 2; CT group, n = 5) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (n = 1 SCT group, n = 1 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group, n = 1; CT group, n = 1). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14; p = 0.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial. Non-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of < 50 copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned. Current Controlled Trials ISRCTN97755073; EUDRACT 2009-012947-40; and CTA 27505/0005/001-0001. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 08/53/25 and 11/136/108), the European Commission through EuroCoord (FP7/2007/2015), the Economic and Social Research Council, the PENTA Foundation, the Medical Research Council and INSERM SC10-US19, France, and will be published in full in Health Technology Assessment; Vol. 20, No. 49. See the NIHR Journals Library website for further project information.


Sentinel lymph node biopsy for cutaneous melanoma: the Stanford experience, 1997-2004.
To review sentinel lymph node (SLN) data from Stanford University Medical Center from January 1, 1997, to January 1, 2004, including rates of SLN positivity according to 2002 American Joint Committee on Cancer (AJCC) tumor classification, relation to other clinical and pathologic prognostic factors, and rates and sites of melanoma recurrence. Retrospective case series. Stanford University Medical Center and Stanford melanoma clinics. A total of 274 consecutive patients with primary melanoma who underwent SLN biopsy (SLNB) between January 1, 1997, and January 1, 2004, or who were referred to the Stanford melanoma clinics after SLNB and were followed up through March 2005. All patients underwent standard wide local excision of their primary tumors and SLNB with intradermal injection of isosulfan blue dye and/or technetium sulfur colloid. Rates of SLN positivity per 2002 AJCC tumor classification, relation to other clinical and pathologic prognostic factors, and rates and sites of melanoma recurrence in node-negative and node-positive patients. Positive SLNs were detected in 39 (15%) of 260 cases, including 0 (0%) of 45 for cutaneous melanomas 1.0 mm thick or less (T1), 21 (18%) of 115 for melanomas 1.01 to 2.0 mm thick (T2), 12 (19%) of 64 for melanomas 2.01 to 4.0 mm thick (T3), and 5 (16%) of 32 for melanomas thicker than 4.0 mm (T4). Median Breslow depths were 1.89 mm for SLN-positive biopsy specimens and 1.50 mm for SLN-negative biopsy specimens (P = .07). The recurrence rate was 46% among SLN-positive patients, with a median time to recurrence of 8 months. Bivariate analysis revealed SLN positivity to be associated with AJCC tumor classification (P = .02), location on the trunk (P = .03), and presence of ulceration (P = .03). By multivariate logistic regression, ulceration (P = .01) was predictive of SLN positivity, whereas SLN status (P< .001), ulceration (P = .02), and location (P = .03) were predictive of recurrent disease. Data from the past 8 years confirm the accuracy and prognostic value of SLNB in cutaneous melanoma and the low rate of regional nodal recurrence for SLN-negative patients.


Sowing Across a State: Development and Delivery of a Grassroots Pediatric Palliative Care Nursing Curriculum.
Rural pediatricians and adult-trained hospice teams report feeling ill-prepared to care for children at end of life, resulting in geographies in which children are not able to access home-based services. To develop a pediatric palliative care curriculum for inpatient nurses and adult-trained hospice teams caring for children in a rural region. Curriculum design and delivery was informed by local culture through an interdisciplinary, iterative development approach with confidence, intention, and support measured pre-, post-, and 4 months after delivery. A needs assessment was completed by pediatric nurses caring for children receiving palliative or end-of-life care to inform curricular content (phase 1). A curriculum was designed by an interdisciplinary pediatric palliative care team and piloted with nursing cohorts annually through educational conferences with monthly discussion series for 3 consecutive years (phase 2). Curricular content was then provided for 31 rural hospice team members (phase 3). Self-reported confidence in caring for children increased by 1.1/10 points for adult-trained hospice team members. Mean score for intention to care for children increased by 5.2 points (sustained 5.1 points above baseline at 4 months). Perception of support in caring for children increased by 5 points (mean sustained 5.4 points above baseline at 4 months). Family needs, care goals, and symptom management were prioritized learning topics. Rural hospices previously unwilling to accept children enrolled pediatric patients in the 4 months following the conference. Grassroots curricular initiatives and ongoing educational mentorship can grow pediatric palliative and hospice services in rural regions.


Pressure changes after balloon distension of the colon wall in diverticular disease.
Balloon distension of the distal colon in diverticular disease does not produce the pressure change in response to increasing volumes that occurs in normal subjects. This phenomenon, though modified at first by resection, is not abolished by resection nor by myotomy or bran. This adaptive quality of the wall of the colon to balloon distension possibly reflects a structural change in its wall, as the phenomenon was present in the colon in diverticular disease in vitro as well as in vivo.


Do medically unexplained symptoms matter? A prospective cohort study of 300 new referrals to neurology outpatient clinics.
To determine (a) the proportion of patients referred to general neurology outpatient clinics whose symptoms are medically unexplained; (b) why they were referred; (c) health status and emotional disorder in this group compared with patients whose symptoms are explained by "organic" neurological disease. The prospective cohort study with case note follow up at 6 months was carried out in the regional neurology service in Lothian, Scotland with 300 newly referred outpatients. Neurologists rated the degree to which patients' symptoms were explained by organic disease (organicity), GPs' reasons for referral, health status (SF-36), anxiety, and depressive disorders (PRIME-MD), RESULTS: Of 300 new patients 11% (95% confidence interval (95% CI) 7%-14%) had symptoms that were rated as "not at all explained" by organic disease, 19% (15% to 23%) "somewhat explained", 27% (22% to 32%) "largely explained", and 43% (37% to 49%) "completely explained" by organic disease. Reason for referral was not associated with "organicity". Comparison of these groups showed that although physical function was similar, the median number of physical symptoms and pain were greater in patients with lower organicity ratings (p<0.0005, p<0. 0005). Depressive and anxiety disorders were more common in patients with symptoms of lower organicity (70% of patients in the not at all group had an anxiety or depressive disorder compared with 32% in the completely explained group (p<0.0005). One third of new referrals to general neurology clinics have symptoms that are poorly explained by identifiable organic disease. These patients were disabled and distressed. They deserve more attention.


Antioxydation And Cell Migration Genes Are Identified as Potential Therapeutic Targets in Basal-Like and BRCA1 Mutated Breast Cancer Cell Lines.
Basal-like breast cancers are among the most aggressive cancers and effective targeted therapies are still missing. In order to identify new therapeutic targets, we performed Methyl-Seq and RNA-Seq of 10 breast cancer cell lines with different phenotypes. We confirmed that breast cancer subtypes cluster the RNA-Seq data but not the Methyl-Seq data. Basal-like tumor hypermethylated phenotype was not confirmed in our study but RNA-Seq analysis allowed to identify 77 genes significantly overexpressed in basal-like breast cancer cell lines. Among them, 48 were overexpressed in triple negative breast cancers of TCGA data. Some molecular functions were overrepresented in this candidate gene list. Genes involved in antioxydation, such as SOD1, MGST3 and PRDX or cadherin-binding genes, such as PFN1, ITGB1 and ANXA1, could thus be considered as basal like breast cancer biomarkers. We then sought if these genes were linked to BRCA1, since this gene is often inactivated in basal-like breast cancers. Nine genes were identified overexpressed in both basal-like breast cancer cells and BRCA1 mutated cells. Amongst them, at least 3 genes code for proteins implicated in epithelial cell migration and epithelial to mesenchymal transition (VIM, ITGB1 and RhoA). Our study provided several potential therapeutic targets for triple negative and BRCA1 mutated breast cancers. It seems that migration and mesenchymal properties acquisition of basal-like breast cancer cells is a key functional pathway in these tumors with a high metastatic potential.


Effects of prism orientation on tensile strength of enamel.
This study tested the hypothesis that the tensile strength of enamel varies according to prismatic orientation. Eight extracted, caries-free human third molars were thoroughly cleaned with pumice and water. The entire enamel surface was conditioned with 37% phosphoric acid for 30 s, air dried, and bonded with Single Bond adhesive system. Several layers of composite (Z-100) were incrementally applied to the crown to build up a "cube-like" resin structure approximately 5 mm thick covering the entire crown of the teeth. The teeth were stored for 24 h in water at 37 degrees C, and then the crown was serially, vertically sectioned in a mesio-distal direction to obtain several slices approximately 0.7 mm thick. The slices were sectioned into halves, and each half was gently trimmed from both sides with a diamond bur to reduce the cross-sectional area to a "neck" located in enamel, either on the external slope or functional slope of the cusps. The specimens were trimmed to permit testing of enamel with its prisms either oriented parallel (PL) or perpendicular (PD) to the applied load. The trimmed specimens were glued to the fixtures of a Vitrodyne tester and stressed in tension at 0.5 mm/min. SEM images were taken from the fractured surfaces to examine the site of failure and confirm the prism orientation. Mean tensile strength of enamel was 24.7 +/- 9.6 MPa (n = 22) for PL and 11.4 +/- 6.3 MPa (n = 22) for PD oriented enamel prisms (t value = -5.45, p < 0.05). There was no significant difference between specimens originating from different slopes of the cusps (p > 0.05). The results showed that tensile strength of enamel is dependent on the prismatic orientation.


Mapping cell populations in flow cytometry data for cross-sample comparison using the Friedman-Rafsky test statistic as a distance measure.
Flow cytometry (FCM) is a fluorescence-based single-cell experimental technology that is routinely applied in biomedical research for identifying cellular biomarkers of normal physiological responses and abnormal disease states. While many computational methods have been developed that focus on identifying cell populations in individual FCM samples, very few have addressed how the identified cell populations can be matched across samples for comparative analysis. This article presents FlowMap-FR, a novel method for cell population mapping across FCM samples. FlowMap-FR is based on the Friedman-Rafsky nonparametric test statistic (FR statistic), which quantifies the equivalence of multivariate distributions. As applied to FCM data by FlowMap-FR, the FR statistic objectively quantifies the similarity between cell populations based on the shapes, sizes, and positions of fluorescence data distributions in the multidimensional feature space. To test and evaluate the performance of FlowMap-FR, we simulated the kinds of biological and technical sample variations that are commonly observed in FCM data. The results show that FlowMap-FR is able to effectively identify equivalent cell populations between samples under scenarios of proportion differences and modest position shifts. As a statistical test, FlowMap-FR can be used to determine whether the expression of a cellular marker is statistically different between two cell populations, suggesting candidates for new cellular phenotypes by providing an objective statistical measure. In addition, FlowMap-FR can indicate situations in which inappropriate splitting or merging of cell populations has occurred during gating procedures. We compared the FR statistic with the symmetric version of Kullback-Leibler divergence measure used in a previous population matching method with both simulated and real data. The FR statistic outperforms the symmetric version of KL-distance in distinguishing equivalent from nonequivalent cell populations. FlowMap-FR was also employed as a distance metric to match cell populations delineated by manual gating across 30 FCM samples from a benchmark FlowCAP data set. An F-measure of 0.88 was obtained, indicating high precision and recall of the FR-based population matching results. FlowMap-FR has been implemented as a standalone R/Bioconductor package so that it can be easily incorporated into current FCM data analytical workflows.


Acute graft-versus-host disease after liver transplantation: role of withdrawal of immunosuppression in therapeutic management.
Graft-versus-host disease (GVHD) after liver transplantation is rare but associated with a very high mortality (over 85%). Most treatments focus on increasing immunosuppression, addition of antibody preparations such as OKT3 and antithymocyte globulin to eliminate the donor lymphocytes, and supporting myelopoiesis by use of cytokines. However, the results are very poor. We reasoned that a better therapeutic approach would be to reduce the immunosuppression and allow the patient's immune system an opportunity to reject the allograft donor T cells. We tested this novel therapeutic approach in 3 patients diagnosed with GVHD. Two patients had rapid loss of donor T cell chimerism and resolution of their symptoms. The other patient continued to progress to severe GVHD and died. The patients who responded to withdrawal of immunosuppression had a later onset of symptoms and a lower level of donor CD3+ T cells at the start of treatment. We conclude that larger studies are needed to further evaluate these results and to determine what factors may affect the likelihood that a patient may respond to this approach.


Pulse compression to 14 fs by third-order dispersion control in a hybrid grating-prism compressor.
A pulse compressor consisting of a fiber and a compact hybrid grating-prism dispersive delay line (DDL) is used to compress readily-available 140-fs pulses from a Ti:sapphire laser. We generate broadband pulses of up to 75 THz FWHM bandwidth in normally-dispersive single-mode conventional and photonic crystal fibers, with a potential of compression to 6 fs. Pulse dechirping in our hybrid DDL through second- and third-order dispersion (TOD) compensation results in 10× compression to 14 fs, limited by the bandwidth of the DDL transfer function and higher-order dispersion. The large tunability of the TOD of the hybrid DDL is shown.


Exploring differences in pain beliefs within and between a large nonclinical (workplace) population and a clinical (chronic low back pain) population using the pain beliefs questionnaire.
Beliefs, cognitions, and behaviors relating to pain can be associated with a range of negative outcomes. In patients, certain beliefs are associated with increased levels of pain and related disability. There are few data, however, showing the extent to which beliefs of patients differ from those of the general population. This study explored pain beliefs in a large nonclinical population and a chronic low back pain (CLBP) sample using the Pain Beliefs Questionnaire (PBQ) to identify differences in scores and factor structures between and within the samples. This was a cross-sectional study. The samples comprised patients attending a rehabilitation program and respondents to a workplace survey. Pain beliefs were assessed using the PBQ, which incorporates 2 scales: organic and psychological. Exploratory factor analysis was used to explore variations in factor structure within and between samples. The relationship between the 2 scales also was examined. Patients reported higher organic scores and lower psychological scores than the nonclinical sample. Within the nonclinical sample, those who reported frequent pain scored higher on the organic scale than those who did not. Factor analysis showed variations in relation to the presence of pain. The relationship between scales was stronger in those not reporting frequent pain. This was a cross-sectional study; therefore, no causal inferences can be made. Patients experiencing CLBP adopt a more biomedical perspective on pain than nonpatients. The presence of pain is also associated with increased biomedical thinking in a nonclinical sample. However, the impact is not only on the strength of beliefs, but also on the relationship between elements of belief and the underlying belief structure.


DuoResp® Spiromax® adherence, satisfaction and ease of use: findings from a multi-country observational study in patients with asthma and COPD in Europe (SPRINT).
Objective: Adherence and inhaler technique are often suboptimal in asthma and chronic obstructive pulmonary disease (COPD). New inhalers have been developed to improve these determinants of treatment effectiveness. We assessed treatment adherence, satisfaction, and ease of use of DuoResp® Spiromax® among SPRINT study participants.Methods: The Phase IV SPRINT study was conducted in 10 European countries. Asthma and COPD patients were receiving a fixed-dose combination of inhaled corticosteroid (ICS) and long-acting β2-agonist (LABA), delivered via various inhalers including DuoResp Spiromax. DuoResp Spiromax users self-assessed adherence using the 8-item Morisky Medication Adherence Scale (MMAS-8®), and ease of use and satisfaction using 10-point scales, during a single physician's office visit.Results: Of 1661 (asthma: n = 1101; COPD: n = 560) SPRINT study participants, 342 (asthma: n = 235; COPD: n = 107) received DuoResp Spiromax prior to inclusion. Overall, 72.5% of DuoResp Spiromax users reported medium or high adherence (MMAS-8 score ≥6). Mean (standard deviation [SD]) satisfaction score for DuoResp Spiromax was 8.9 (1.6). Almost all (98.8%) DuoResp Spiromax users were at least satisfied with their inhaler; 85.4% were very satisfied. Mean (SD) ease of use score for DuoResp Spiromax was 9.1 (1.3).Conclusions: Asthma and COPD patients using DuoResp Spiromax reported moderate-to-high medication adherence, were very satisfied with their inhaler and found it easy to use.


Shape of Training Review: an impact assessment for UK gastroenterology trainees.
Physician training in the UK is undergoing considerable change due to the implementation of recommendations made in the Shape of Training Review. In particular, higher specialty training (HST), including gastroenterology, will be shortened from 5 to 4 years. This will also incorporate general internal medicine (GIM) training. There is concern among gastroenterologists regarding how high-quality gastroenterology training will be delivered in 4 years. The 2018 British Society of Gastroenterology (BSG) trainees' survey results were used to examine the potential impact of a 4-year HST period on achieving key competencies in gastroenterology. 291 (49.4%) gastroenterology trainees responded. Satisfaction with gastroenterology training was high (79.6% respondents), and self-reported confidence in hepatology training was also high (84% senior respondents). However, only half (51.1%) of the respondents achieved complete colonoscopy certification by their final year of training. Comparison with the 2014 BSG trainees' survey demonstrated that the number of endoscopy procedures achieved by trainees has reduced in sigmoidoscopy (p=0.006) and colonoscopy (p<0.001). The proportion of time spent in GIM training has increased since the last survey, with 81.8% of the respondents spending more than 25% of their time in GIM. GIM training was reported to be a key barrier to adequate gastroenterology and endoscopy training. These data indicate significant barriers to delivering gastroenterology and endoscopy training within the current 5-year programme. Novel strategies will be required to improve the rate of progression in endoscopy training, in particular if high-quality gastroenterology HST training is to be delivered in 4 years.


Prediction of toxigenic fungal growth in buildings by using a novel modelling system.
There is growing concern about the adverse effects of fungal bioaerosols on the occupants of damp dwellings. Based on an extensive analysis of previously published data and on experiments carried out within this study, critical limits for the growth of the indoor fungi Eurotium herbariorum, Aspergillus versicolor, and Stachybotrys chartarum were mathematically described in terms of growth limit curves (isopleths) which define the minimum combination of temperature (T) and relative humidity (RH) at which growth will occur. Each growth limit curve was generated from a series of data points on a T-RH plot and mathematically fitted by using a third-order polynomial equation of the form RH = a(3)T(3) + a(2)T(2) + a(1)T + a(0). This fungal growth prediction model was incorporated within the ESP-r (Environmental Systems Performance [r stands for "research"]) computer-based program for transient simulation of the energy and environmental performance of buildings. For any specified location, the ESP-r system is able to predict the time series evolution of local surface temperature and relative humidity, taking explicit account of constructional moisture flow, moisture generation sources, and air movement. This allows the predicted local conditions to be superimposed directly onto fungal growth curves. The concentration of plotted points relative to the curves allows an assessment of the risk of fungal growth. The system's predictive capability was tested via laboratory experiments and by comparison with monitored data from a fungus-contaminated house.


Biomarkers for infection: enzymes, microbes, and metabolites.
Wound infection is a severe complication causing delayed healing and risks for patients. Conventional methods of diagnosis for infection involve error-prone clinical description of the wound and time-consuming microbiological tests. More reliable alternatives are still rare, except for invasive and unaffordable gold standard methods. This review discusses the diversity of new approaches for wound infection determination. There has been progress in the detection methods of microorganisms, including the assessment of the diversity of the bacterial community present in a wound, as well as in the elaboration of specific markers. Another interesting strategy involves the quantification of enzyme activities in the wound fluid secreted by the immune system as response to infection. Color-changing substrates for these enzymes consequently have been shown to allow detection of an infection in wounds in a fast and easy way. Promising results were also delivered in measuring pH changes or detecting enhanced amounts of volatile molecules in case of infection. A simple and effective infection detection tool is not yet on the market, but innovative ideas pave the way for the investigation of fast and easy point-of-care devices.


Undersea air supply.
The interior air of a simulated underwater habitation was continuously washed or scrubbed with sea water by means of a gas exchanger of the venturi type. The sole method for supplying oxygen and removing carbon dioxide was the scrubbing process. A microburner placed inside the experimental habitation chamber continued to burn until it was intentionally extinguished. Two rats maintained in the chamber for 8 hours suffered no discernible ill effects.


Characterising private and shared signatures of positive selection in 37 Asian populations.
The Asian Diversity Project (ADP) assembled 37 cosmopolitan and ethnic minority populations in Asia that have been densely genotyped across over half a million markers to study patterns of genetic diversity and positive natural selection. We performed population structure analyses of the ADP populations and divided these populations into four major groups based on their genographic information. By applying a highly sensitive algorithm haploPS to locate genomic signatures of positive selection, 140 distinct genomic regions exhibiting evidence of positive selection in at least one population were identified. We examined the extent of signal sharing for regions that were selected in multiple populations and observed that populations clustered in a similar fashion to that of how the ancestry clades were phylogenetically defined. In particular, populations predominantly located in South Asia underwent considerably different adaptation as compared with populations from the other geographical regions. Signatures of positive selection present in multiple geographical regions were predicted to be older and have emerged prior to the separation of the populations in the different regions. In contrast, selection signals present in a single population group tended to be of lower frequencies and thus can be attributed to recent evolutionary events.


Subthalamic nucleus deep brain stimulation improves somatosensory function in Parkinson's disease.
An established treatment for the motor symptoms of Parkinson's disease (PD) is deep brain stimulation (DBS) of the subthalamic nucleus (STN). Mounting evidence suggests that PD is also associated with somatosensory deficits, yet the effect of STN-DBS on somatosensory processing is largely unknown. This study investigated whether STN-DBS affects somatosensory processing, specifically the processing of tactile and proprioceptive cues, by systematically examining the accuracy of haptic perception of object size. (Haptic perception refers to one's ability to extract object features such as shape and size by active touch.) Without vision, 13 PD patients with implanted STN-DBS and 13 healthy controls haptically explored the heights of 2 successively presented 3-dimensional (3D) blocks using a precision grip. Participants verbally indicated which block was taller and then used their nonprobing hand to motorically match the perceived size of the comparison block. Patients were tested during ON and OFF stimulation, following a 12-hour medication washout period. First, when compared to controls, the PD group's haptic discrimination threshold during OFF stimulation was elevated by 192% and mean hand aperture error was increased by 105%. Second, DBS lowered the haptic discrimination threshold by 26% and aperture error decreased by 20%. Third, during DBS ON, probing with the motorically more affected hand decreased haptic precision compared to probing with the less affected hand. This study offers the first evidence that STN-DBS improves haptic precision, further indicating that somatosensory function is improved by STN-DBS. We conclude that DBS-related improvements are not explained by improvements in motor function alone, but rather by enhanced somatosensory processing.


The beneficial effects of cognitive training with simple calculation and reading aloud in an elderly postsurgical population: study protocol for a randomized controlled trial.
This project proposes a pilot study to investigate the positive healing effects of cognitive training with simple arithmetic and reading aloud on elderly postsurgical patients. Elderly patients undergoing surgery have an increased risk of Postoperative Cognitive Decline (POCD), a condition in which learning, memory, and processing speed is greatly reduced after surgery. Since elderly patients are more likely to exhibit symptoms of POCD, the incidence is increasing as the population receiving surgery has aged. Little effort has been expended, however, to find treatments for POCD. Learning therapy, which consists of a combination of reading aloud and solving simple arithmetic problems, was developed in Japan as a treatment for Alzheimer's Disease to improve cognitive functions. Because patients with Alzheimer's Disease experience similar issues as those with POCD in learning, memory, and processing speed, a cognitive intervention based on the learning-therapy treatments used for Alzheimer's Disease could show advantageous outcomes for those at risk of POCD. Cognitive function will be measured before and after surgery using three different tests (Mini-Mental Status Exam, Frontal Assessment Battery, and Cogstate computerized tests). Subjects will be randomly divided into two groups-one that receives a Simple Calculation and Reading Aloud intervention (SCRA) and a waitlisted control group that does not receive SCRA. To measure cognition before and after the intervention, the previously mentioned three tests will be used. The obtained data will be analyzed using statistical tests such as ANCOVA to indicate whether the cognitive intervention group has made improvements in their cognitive functions. In addition, questionnaires will also be administered to collect data on mental and emotional statuses. This report will be the first pilot study to investigate the beneficial effects of SCRA on elderly surgical patients. Previous studies have shown sufficient evidence on the effectiveness of learning therapy in healthy elderly people and in those with Dementia. Therefore, this study will clarify whether SCRA can improve cognitive function in the more specialized group of elderly surgical patients. University Hospital Medical Information Network Clinical Trial Registry, UMIN000019832 . Registered on 18 November 2015.


Mouse Models for the Dissection of CHD7 Functions in Eye Development and the Molecular Basis for Ocular Defects in CHARGE Syndrome.
CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary tract abnormalities, and Ear abnormalities and deafness) is the second-leading cause of deaf-blindness after Usher syndrome. Heterozygous mutations in CHD7 cause CHARGE syndrome in 70% to 90% of patients. We tested the hypothesis that tissue-specific mutant mice provide models for molecularly dissecting CHD7 functions during eye development. The conditional Chd7flox allele was mated together with tissue-specific Cre transgenes. Immunohistochemistry was used to determine the normal CHD7 pattern in the early eye primordia and to assess Chd7 mutants for expression of region-specific protein markers. CHD7 is present in the neural ectoderm and surface ectoderm of the eye. Deletion from neural and surface ectoderm results in severely dysmorphic eyes generally lacking recognizable optic cup structures and small lenses. Deletion from the neural ectoderm results in similar defects. Deletion from the surface ectoderm results in eyes with smaller lenses. Lens tissue and the major subdivisions of the neural ectoderm are present following conditional deletion of Chd7 from the neural ectoderm. Closure of the optic fissure depends on the Chd7 gene dose within the neural ectoderm. Eye development requires CHD7 in multiple embryonic tissues. Lens development requires CHD7 in the surface ectoderm, whereas optic cup and stalk morphogenesis require CHD7 in the neural ectoderm. CHD7 is not absolutely required for specification of the major subdivisions within the neural ectoderm. As in humans, normal eye development in mice is sensitive to Chd7 haploinsufficiency. These data indicate the Chd7 mutant mice are models for determining the molecular etiology of ocular defects in CHARGE syndrome.


Neuraxial vs general anaesthesia for total hip and total knee arthroplasty: a systematic review of comparative-effectiveness research.
This systematic review evaluated the evidence comparing patient-important outcomes in spinal or epidural vs general anaesthesia for total hip and total knee arthroplasty. MEDLINE, Ovid EMBASE, EBSCO CINAHL, Thomson Reuters Web of Science, and the Cochrane Central Register of Controlled Trials from inception until March 2015 were searched. Eligible randomized controlled trials or prospective comparative studies investigating mortality, major morbidity, and patient-experience outcomes directly comparing neuraxial (spinal or epidural) with general anaesthesia for total hip arthroplasty, total knee arthroplasty, or both were included. Independent reviewers working in duplicate extracted study characteristics, validity, and outcomes data. Meta-analysis was conducted using the random-effects model. We included 29 studies involving 10 488 patients. Compared with general anaesthesia, neuraxial anaesthesia significantly reduced length of stay (weighted mean difference -0.40 days; 95% confidence interval -0.76 to -0.03; P=0.03; I2 73%; 12 studies). No statistically significant differences were found between neuraxial and general anaesthesia for mortality, surgical duration, surgical site or chest infections, nerve palsies, postoperative nausea and vomiting, or thromboembolic disease when antithrombotic prophylaxis was used. Subgroup analyses failed to find statistically significant interactions (P>0.05) based on risk of bias, type of surgery, or type of neuraxial anaesthesia. Neuraxial anaesthesia for total hip or total knee arthroplasty, or both appears equally effective without increased morbidity when compared with general anaesthesia. There is limited quantitative evidence to suggest that neuraxial anaesthesia is associated with improved perioperative outcomes. Future investigations should compare intermediate and long-term outcome differences to better inform anaesthesiologists, surgeons, and patients on importance of anaesthetic selection.


International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.
Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.


Social disorganization and history of child sexual abuse against girls in sub-Saharan Africa: a multilevel analysis.
Child sexual abuse (CSA) is a considerable public health problem. Less focus has been paid to the role of community level factors associated with CSA. The aim of this study was to examine the association between neighbourhood-level measures of social disorganization and CSA. We applied multiple multilevel logistic regression analysis on Demographic and Health Survey data for 6,351 adolescents from six countries in sub-Saharan Africa between 2006 and 2008. The percentage of adolescents that had experienced CSA ranged from 1.04% to 5.84%. There was a significant variation in the odds of reporting CSA across the communities, suggesting 18% of the variation in CSA could be attributed to community level factors. Respondents currently employed were more likely to have reported CSA than those who were unemployed (odds ratio [OR]=2.05, 95% confidence interval [CI] 1.48 to 2.83). Respondents from communities with a high family disruption rate were 57% more likely to have reported CSA (OR=1.57, 95% CI 1.14 to 2.16). We found that exposure to CSA was associated with high community level of family disruption, thus suggesting that neighbourhoods may indeed have significant important effects on exposure to CSA. Further studies are needed to explore pathways that connect the individual and neighbourhood levels, that is, means through which deleterious neighbourhood effects are transmitted to individuals.


Phylogenetic and genome-wide deep-sequencing analyses of canine parvovirus reveal co-infection with field variants and emergence of a recent recombinant strain.
Canine parvovirus (CPV), a fast-evolving single-stranded DNA virus, comprises three antigenic variants (2a, 2b, and 2c) with different frequencies and genetic variability among countries. The contribution of co-infection and recombination to the genetic variability of CPV is far from being fully elucidated. Here we took advantage of a natural CPV population, recently formed by the convergence of divergent CPV-2c and CPV-2a strains, to study co-infection and recombination. Complete sequences of the viral coding region of CPV-2a and CPV-2c strains from 40 samples were generated and analyzed using phylogenetic tools. Two samples showed co-infection and were further analyzed by deep sequencing. The sequence profile of one of the samples revealed the presence of CPV-2c and CPV-2a strains that differed at 29 nucleotides. The other sample included a minor CPV-2a strain (13.3% of the viral population) and a major recombinant strain (86.7%). The recombinant strain arose from inter-genotypic recombination between CPV-2c and CPV-2a strains within the VP1/VP2 gene boundary. Our findings highlight the importance of deep-sequencing analysis to provide a better understanding of CPV molecular diversity.


Specific immunotherapy in atopic dermatitis.
Allergen specific immunotherapy (SIT) using house dust mite (HDM) extracts has been performed mainly with patients of asthma and allergic rhinitis. In the meanwhile, there has been a long debate on the efficacy of SIT in atopic dermatitis (AD) with only a few double-blind placebo-controlled trials. However, several randomized controlled trials of SIT in AD revealed significant improvement of clinical symptoms and also, positive result was shown by a following meta-analysis study of these trials. In order to predict and evaluate the treatment outcome, finding a biomarker that can predict treatment responses and treatment end-points is critical but it is very challenging at the same time due to the complexity of causes and mechanisms of AD. Other considerations including standardization of the easiest and safest treatment protocol and optimizing the treatment preparations should be studied as well. This review summarizes the basics of SIT in AD including the brief mechanisms, treatment methods and schedules, and also highlights the clinical efficacy of SIT in AD along with mild, controllable adverse reactions. Immunologic effects and studies of various biomarkers are also introduced and finally, future considerations with upcoming studies on SIT were discussed.


An integrative computational model for intestinal tissue renewal.
The luminal surface of the gut is lined with a monolayer of epithelial cells that acts as a nutrient absorptive engine and protective barrier. To maintain its integrity and functionality, the epithelium is renewed every few days. Theoretical models are powerful tools that can be used to test hypotheses concerning the regulation of this renewal process, to investigate how its dysfunction can lead to loss of homeostasis and neoplasia, and to identify potential therapeutic interventions. Here we propose a new multiscale model for crypt dynamics that links phenomena occurring at the subcellular, cellular and tissue levels of organisation. At the subcellular level, deterministic models characterise molecular networks, such as cell-cycle control and Wnt signalling. The output of these models determines the behaviour of each epithelial cell in response to intra-, inter- and extracellular cues. The modular nature of the model enables us to easily modify individual assumptions and analyse their effects on the system as a whole. We perform virtual microdissection and labelling-index experiments, evaluate the impact of various model extensions, obtain new insight into clonal expansion in the crypt, and compare our predictions with recent mitochondrial DNA mutation data. We demonstrate that relaxing the assumption that stem-cell positions are fixed enables clonal expansion and niche succession to occur. We also predict that the presence of extracellular factors near the base of the crypt alone suffices to explain the observed spatial variation in nuclear beta-catenin levels along the crypt axis.


Rheology of red blood cells under flow in highly confined microchannels: I. effect of elasticity.
We analyze the rheology of dilute red blood cell suspensions in pressure driven flows at low Reynolds number, in terms of the morphologies and elasticity of the cells. We focus on narrow channels of width similar to the cell diameter, when the interactions with the walls dominate the cell dynamics. The suspension presents a shear-thinning behaviour, with a Newtonian-behaviour at low shear rates, an intermediate region of strong decay of the suspension viscosity, and an asymptotic regime at high shear rates in which the effective viscosity converges to that of the solvent. We identify the relevant aspects of cell elasticity that contribute to the rheological response of blood at high confinement. In a second paper, we will explore the focusing of red blood cells while flowing at high shear rates and how this effect is controlled by the geometry of the channel.


Autoantibodies stabilize neutrophil extracellular traps in COVID-19.
The release of neutrophil extracellular traps ( NETs ) by hyperactive neutrophils is recognized to play an important role in the thromboinflammatory milieu inherent to severe presentations of COVID-19. At the same time, a variety of functional autoantibodies have been observed in individuals with severe COVID-19 where they likely contribute to immunopathology. Here, we aimed to determine the extent to which autoantibodies might target NETs in COVID-19 and, if detected, to elucidate their potential functions and clinical associations. We measured anti-NET antibodies in 328 individuals hospitalized with COVID-19 alongside 48 healthy controls. We found high anti-NET activity in the IgG and IgM fractions of 27% and 60% of patients, respectively. There was a strong correlation between anti-NET IgG and anti-NET IgM (r=0.4, p<0.0001). Both anti-NET IgG and IgM tracked with high levels of circulating NETs, impaired oxygenation efficiency, and high circulating D-dimer. Furthermore, patients who required mechanical ventilation had a greater burden of anti-NET antibodies than did those not requiring oxygen supplementation. Levels of anti-NET IgG (and to a lesser extent anti-NET IgM) demonstrated an inverse correlation with the efficiency of NET degradation by COVID sera. Furthermore, purified IgG from COVID sera with high levels of anti-NET antibodies impaired the ability of healthy control serum to degrade NETs. In summary, many individuals hospitalized with COVID-19 have anti-NET antibodies, which likely impair NET clearance and may potentiate SARS-CoV-2-mediated thromboinflammation.


Takayasu's arteritis presenting as pulmonary hypertension.
Takayasu's arteritis (pulseless disease) is a vasculitis that affects the large arteries, including the aorta, its branches, and the pulmonary arteries. A 15-year-old girl with Takayasu's arteritis was referred to our institution for marked pulmonary hypertension in the absence of symptoms referable to systemic vasculitis. She was shown to have a thickened, narrowed thoracic aorta, a stenosed right axillary artery, and severely affected pulmonary arteries. Despite corticosteroid therapy she died one month after diagnosis. This patient's illness indicates that pulmonary vessels might be the principal vessels involved in Takayasu's arteritis.


Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis.
Free radicals produced during cancer radiotherapy often leads to dermatitis, with the insult ranging from mild erythema to moist desquamation and ulceration. This toxicity can be dose limiting and promote chronic complications, such as fibrosis and wound recurrence. The purpose of this study was to evaluate if RTA 408, a synthetic triterpenoid that potently activates the antioxidative transcription factor Nrf2 and inhibits the proinflammatory transcription factor nuclear factor-kappa b (NF-κB), could protect skin from radiation-induced dermatitis. Mice were irradiated (10 Gy/day) on days 0-2 and 5-7, and RTA 408 (0.01%, 0.1% and 1.0%) was topically applied once daily starting on day 5 or up to day 40. Dermatitis severity was evaluated using a scale ranging from 0 (normal) to 5 (frank ulceration), as well as histologically. The mRNA expression of Nrf2 and NF-κB target genes in skin was also evaluated. RTA 408 (0.01%, 0.1% and 1.0%) reduced the percentage of animal-days with scores ≥2 by 11%, 31% and 55% and scores ≥3 by 16%, 60% and 80%, respectively. Dose-dependent improvements in the appearance of skin were also manifestly visible, with RTA 408 at 1.0% eliciting a normal macroscopic appearance by the end of the treatment period on day 40, including substantial hair regrowth. Moreover, 1.0% RTA 408 markedly reduced epidermal and collagen thickening, prevented dermal necrosis and completely alleviated skin ulcers. These improvements were associated with significant increases in Nrf2 target genes and significant decreases in NF-κB target genes. Together, these data indicate that RTA 408 represents a potentially promising new therapy for the treatment of radiation-induced dermatitis.


The experience of HIV diagnosis among Aboriginal people living with HIV/AIDS and depression.
In this article, we consider how the broad context of Aboriginal people's lives can shape their experience and understanding of their HIV diagnosis. We conducted interviews across Canada with 72 Aboriginal people living with HIV who also reported feelings of depression. Consistent with what has been found in previous studies, participants responded to their HIV diagnosis with shock, disbelief, and often anger. Prior depression, drug and alcohol use, multiple losses, stigma, and social isolation also shaped how participants experienced their diagnosis. We consider how the history of colonization of Aboriginal communities in Canada relates to the experience of HIV diagnosis, and end with a discussion of the service implications of our findings.


Clostridium difficile infection in dialysis patients.
Clostridium difficile infection (CDI) is the most common cause of nosocomial diarrhea. Patients with end-stage renal disease (ESRD) may be at increased risk for CDI. Patients with ESRD with CDI have increased mortality, longer length of stay, and higher costs. The present studies extend these observations and address associated comorbidities, incidence of recurrence, and risk factors for mortality. We queried the United States Renal Data System (USRDS) for patients with ESRD diagnosed with CDI, and assessed for the incidence of infection, comorbidities, and mortality. The records of 419,875 incident dialysis patients from 2005 to 2008 were reviewed. 4.25% had a diagnosis of a first CDI. In the majority of patients with CDI positive, a hospitalization or ICU stay was documented within 90 days prior to the diagnosis of CDI. The greatest adjusted relative risk (aRR) of CDI was present in patients with HIV (aRR 2.68), age ≥65 years (aRR 1.76), and bacteremia (aRR 1.74). The adjusted HR (aHR) for death was 1.80 in patients with CDI. The comorbidities demonstrating the greatest risk for death in dialysis patients with CDI included age ≥65 years and cirrhosis (aHR 2.28 and 1.76, respectively). Recurrent CDI occurred in 23.6%, was more common in Caucasians, and in those who were older. CDI is a common occurrence in patients with ESRD, with elderly patients, patients with HIV positive, and bacteremic patients at highest risk for infection. Patients with CDI had nearly a twofold increased risk of death.


Structural alterations in a component of cytochrome c oxidase and molecular evolution of pathogenic Neisseria in humans.
Three closely related bacterial species within the genus Neisseria are of importance to human disease and health. Neisseria meningitidis is a major cause of meningitis, while Neisseria gonorrhoeae is the agent of the sexually transmitted disease gonorrhea and Neisseria lactamica is a common, harmless commensal of children. Comparative genomics have yet to yield clear insights into which factors dictate the unique host-parasite relationships exhibited by each since, as a group, they display remarkable conservation at the levels of nucleotide sequence, gene content and synteny. Here, we discovered two rare alterations in the gene encoding the CcoP protein component of cytochrome cbb(3) oxidase that are phylogenetically informative. One is a single nucleotide polymorphism resulting in CcoP truncation that acts as a molecular signature for the species N. meningitidis. We go on to show that the ancestral ccoP gene arose by a unique gene duplication and fusion event and is specifically and completely distributed within species of the genus Neisseria. Surprisingly, we found that strains engineered to express either of the two CcoP forms conditionally differed in their capacity to support nitrite-dependent, microaerobic growth mediated by NirK, a nitrite reductase. Thus, we propose that changes in CcoP domain architecture and ensuing alterations in function are key traits in successive, adaptive radiations within these metapopulations. These findings provide a dramatic example of how rare changes in core metabolic proteins can be connected to significant macroevolutionary shifts. They also show how evolutionary change at the molecular level can be linked to metabolic innovation and its reversal as well as demonstrating how genotype can be used to infer alterations of the fitness landscape within a single host.


Short-Term Effects of Steroid Injection, Kinesio Taping, or Both on Pain, Grip Strength, and Functionality of Patients With Lateral Epicondylitis: A Single-Blinded Randomized Controlled Trial.
The aim of the study was to compare the efficacy of steroid injection and kinesio taping (KT) in the treatment of lateral epicondylitis. A total number of 84 patients were randomized into three groups. Group 1 was given steroid injection, group 2 received KT, and group 3 received both. Pain was measured using a visual analog scale, functional status was measured using a quick form of the Disabilities of Arm, Shoulder and Hand questionnaire, pain-free grip strength was measured using a dynamometer, and the pressure pain threshold was measured using an algometer. All evaluations were performed before treatment and at the third and twelfth weeks after the treatment. Twenty-eight patients were included in each group. A statistically significant difference was found between the pretreatment and posttreatment evaluations of all groups in the third and twelfth weeks after treatment. When group 1 and group 2 were compared, there was a significant difference only in pain-free grip strength measured in the twelfth week. The results of treatment in group 3 patients were significantly better in almost all evaluation parameters compared with the other groups. In the treatment of lateral epicondylitis, KT alone was found to be as effective as steroid injection alone. However, co-administration of steroid injection and KT is more effective compared with each treatment alone.


NKT cells inhibit the development of experimental crescentic glomerulonephritis.
CD1d is an MHC class I-like, beta2-microglobulin-associated protein, constitutively expressed by antigen-presenting cells and some epithelial cells, which is recognized by NKT cells, a subpopulation of T cells. CD1d-dependent NKT cells confer protection in immune-mediated disorders, but whether these cells modulate the development of glomerulonephritis is unknown. Experimental crescentic glomerulonephritis was induced by administering anti-glomerular basement membrane antibodies to NKT cell-deficient (CD1d(-/-)) and wild-type mice. Compared with wild-type mice, NKT cell-deficient mice had an accelerated course of glomerulonephritis measured by renal function and crescent formation, and this was abrogated by adoptive transfer of NKT cells. Reconstitution with NKT cells also attenuated intraglomerular expression of TGF-beta1 and decreased phosphorylation of the transcription factors NF-kappaB and IkappaB. Adopted transfer of fluorescence-labeled NKT cells demonstrated their distribution to glomeruli damaged by anti-glomerular basement membrane antibodies but not to the tubulointerstitium. The chemokine CXCL16, which is the ligand for CXCR6 on NKT cells, was upregulated in glomeruli after induction of glomerulonephritis, and NKT cells were present in the same glomeruli. In vitro, NKT cells inhibited LPS-stimulated proliferation of mesangial cells, an affect that was reduced by co-current treatment with an anti-CXCL16 monoclonal antibody. In summary, these findings highlight the regulatory capacity of CD1d-dependent NKT cells in experimental glomerulonephritis and suggest that CXCL16 is involved in the recruitment of these cells to the site of injury.


Structural basis for membrane anchoring of HIV-1 envelope spike.
HIV-1 envelope spike (Env) is a type I membrane protein that mediates viral entry. We used nuclear magnetic resonance to determine an atomic structure of the transmembrane (TM) domain of HIV-1 Env reconstituted in bicelles that mimic a lipid bilayer. The TM forms a well-ordered trimer that protects a conserved membrane-embedded arginine. An amino-terminal coiled-coil and a carboxyl-terminal hydrophilic core stabilize the trimer. Individual mutations of conserved residues did not disrupt the TM trimer and minimally affected membrane fusion and infectivity. Major changes in the hydrophilic core, however, altered the antibody sensitivity of Env. These results show how a TM domain anchors, stabilizes, and modulates a viral envelope spike and suggest that its influence on Env conformation is an important consideration for HIV-1 immunogen design.


Nano boron nitride flatland.
Recent years have witnessed many breakthroughs in research on two-dimensional (2D) nanomaterials, among which is hexagonal boron nitride (h-BN), a layered material with a regular network of BN hexagons. This review provides an insight into the marvellous nano BN flatland, beginning with a concise introduction to BN and its low-dimensional nanostructures, followed by an overview of the past and current state of research on 2D BN nanostructures. A comprehensive review of the structural characteristics and synthetic routes of BN monolayers, multilayers, nanomeshes, nanowaves, nanoflakes, nanosheets and nanoribbons is presented. In addition, electronic, optical, thermal, mechanical, magnetic, piezoelectric, catalytic, ecological, biological and wetting properties, applications and research perspectives for these novel 2D nanomaterials are discussed.


Anthracene photolysis in aqueous solution and ice: photon flux dependence and comparison of kinetics in bulk ice and at the air-ice interface.
We report an investigation of the photolysis kinetics of polycyclic aromatic hydrocarbons (PAHs) in aqueous solution, frozen in ice, and at air-ice interfaces. Measurements of PAH photolysis rates in aqueous solution and at air-ice interfaces as a function of lamp power show that the kinetics depend nonlinearly on photon flux. In both media, the rates do not increase when lamp powers are above 0.1 W, which corresponds to total photon fluxes lower than 10(13) photon cm(-2) s(-1) in the actinic region. This suggests that extrapolating laboratory-measured rates to expected atmospheric photon fluxes may not yield accurate lifetimes for some species. In the plateau region of the photon flux dependence, anthracene located within the ice matrix (or in liquid pockets or veins in the ice) undergoes photolysis at a similar rate to that in room temperature aqueous solution, but the rate of anthracene photolysis at air-ice interfaces is five times greater. This indicates that in order to accurately predict the lifetimes of aromatic pollutants in snow and ice, the quasi-liquid layer (QLL) must be treated separately from bulk ice.


In vitro release of adenosine triphosphate from the urothelium of human bladders with detrusor overactivity, both neurogenic and idiopathic.
There is increased evidence to suggest a role for nonadrenergic-noncholinergic neurotransmission in the pathogenesis of bladder dysfunction. In this set of experiments, we have assessed the contribution of the urothelium to purinergic activity by quantifying the amount of adenosine triphosphate (ATP) released from the urothelium of patients with idiopathic detrusor overactivity (IDO) and with neurogenic detrusor overactivity (NDO) and comparing these releases to those of controls. Bladder tissue with urodynamically and clinically proven NDO (n=8) and IDO (n=8) were included in this study. The carefully dissected urothelium was stimulated by mechanically stretching as well as electrically stimulating and the ATP; thus, release was quantified. We used a Lucy Anthos 1 luminometre (Anthos Labtec Instruments GmBH, Wals, Austria) to perform the assay. The results were analysed using Stingray software (Dazdaq Ltd, Brighton, UK). Both mechanical stretch and electric field stimulation (EFS) led to increased ATP release in both sets of tissues with overactivity compared to the controls; this rise was even more significant for the IDO urothelium (2416.7±479.8 pmol/g [p<0.005]) than for the NDO urothelium (133.1±22.4 pmol/g [p<0.01]); values for the controls were 77.6±16.2 pmol/g. ATP release following mechanical stretch was more sensitive to tetrodotoxin in bladders with NDO compared to those with IDO as well as to the controls, with ATP levels falling from 233.5±20.7 pmol/g to 107.2±11.6 pmol/g, expressed as percentage of basal levels (p<0.002). The experiments were performed in vitro, and the female patients were a mix of peri- and postmenopausal states. These experiments suggested a significant rise in ATP release from the urothelium of bladders with NDO as well as those with IDO in comparison to controls. Most of the ATP released from bladders with NDO is primarily from neuronal sources.


Effects of a structured exercise programme in sedentary dogs with chronic diarrhoea.
The aim of this investigation was to evaluate the effects of a structured exercise programme in sedentary dogs with chronic diarrhoea. Twenty-two dogs were enrolled in the study. All dogs received oral prednisolone (1 mg/kg/day for 14 days, followed by a tapering dosage) for 10 weeks. After four weeks of prednisolone treatment, dogs were assigned to either the exercise or control group (n=11 each). Owners of dogs in the exercise group were instructed to guide their dogs in structured exercise training (low-intensity to moderate-intensity aerobic and resistance exercise three to five days per week). After 10 weeks of prednisolone treatment with concomitant 6 weeks of complementary exercise, the Canine Inflammatory Bowel Disease Activity Index (CIBDAI) score had decreased significantly in the exercise group (from 8.8±1.5 at the start of the exercise programme to 2.4±1.5; P<0.001); no such change was observed in the control group (from 9.2±0.9 to 9.2±1.1). CIBDAI scores differed significantly between the groups at the end of the 10-week study period (P<0.001). The exercise programme affected all six CIBDAI parameters significantly; bodyweight (P<0.001, adjusted r2=0.722) was most affected. A structured exercise programme may have positive effects on clinical symptoms in sedentary dogs with chronic diarrhoea.


Influence of Water Activity on Thermal Resistance of Microorganisms in Low-Moisture Foods: A Review.
A number of recent outbreaks related to pathogens in low-moisture foods have created urgency for studies to understand the possible causes and identify potential treatments to improve low-moisture food safety. Thermal processing holds the potential to eliminate pathogens such as Salmonella in low-moisture foods. Water activity (aw ) has been recognized as one of the primary factors influencing the thermal resistance of pathogens in low-moisture foods. But most of the reported studies relate thermal resistance of pathogens to aw of low-moisture foods at room temperature. Water activity is a thermodynamic property that varies significantly with temperature and the direction of variation is dependent on the product component. Accurate methods to determine aw at elevated temperatures are needed in related research activities and industrial operations. Adequate design of commercial thermal treatments to control target pathogens in low-moisture products requires knowledge on how aw values change in different foods at elevated temperatures. This paper presents an overview of the factors influencing the thermal resistance of pathogens in low-moisture foods. This review focuses on understanding the influence of water activity and its variation at thermal processing temperature on thermal resistance of pathogens in different low-moisture matrices. It also discusses the research needs to relate thermal resistance of foodborne pathogens to aw value in those foods at elevated temperatures.


Neuronal Avalanches in Input and Associative Layers of Auditory Cortex.
The primary auditory cortex processes acoustic sequences for the perception of behaviorally meaningful sounds such as speech. Sound information arrives at its input layer four from where activity propagates to associative layer 2/3. It is currently not known whether there is a characteristic organization of neuronal population activity across layers and sound levels during sound processing. Here, we identify neuronal avalanches, which in theory and experiments have been shown to maximize dynamic range and optimize information transfer within and across networks, in primary auditory cortex. We used in vivo 2-photon imaging of pyramidal neurons in cortical layers L4 and L2/3 of mouse A1 to characterize the populations of neurons that were active spontaneously, i.e., in the absence of a sound stimulus, and those recruited by single-frequency tonal stimuli at different sound levels. Single-frequency sounds recruited neurons of widely ranging frequency selectivity in both layers. We defined neuronal ensembles as neurons being active within or during successive temporal windows at the temporal resolution of our imaging. For both layers, neuronal ensembles were highly variable in size during spontaneous activity as well as during sound presentation. Ensemble sizes distributed according to power laws, the hallmark of neuronal avalanches, and were similar across sound levels. Avalanches activated by sound were composed of neurons with diverse tuning preference, yet with selectivity independent of avalanche size. Our results suggest that optimization principles identified for avalanches guide population activity in L4 and L2/3 of auditory cortex during and in-between stimulus processing.


Explaining inequity in the use of institutional delivery services in selected countries.
Wealth-related disparities in the use of reproductive health services remain a substantial problem in many low- and middle-income countries. Very few studies have attempted to explain such inequalities through decomposition of the contributions made by various individual- and household-level factors. This study aims to: (1) assess the degree of wealth-related inequality and inequity in the use of institutional delivery services in selected low- and middle-income countries, and (2) to explain wealth-related inequity through decomposition by the contributions made by various components, including health insurance coverage. Data come from Demographic and Health Surveys in three countries: Ghana, Rwanda, and the Philippines. Concentration indices are used to calculate inequality and horizontal inequity in service utilization. Multivariate methods are used to decompose inequity. Findings indicate a moderate to high degree of inequity in institutional delivery service use in all study countries. The study provides some evidence of the contribution of health insurance to increased wealth-related inequity in the use of institutional delivery services, although having health insurance was also associated with increased utilization of services. Results suggest that increased health insurance coverage does not automatically translate to lower wealth-related inequity in service utilization. Inequities in service utilization exist if there are still inequities in the health insurance status. The study advocates for expanding health insurance coverage, particularly among the poor to reduce inequity in insurance coverage and increase service utilization.


Thermally activated delayed fluorescence emitters with dual conformations for white organic light-emitting diodes: mechanism and molecular design.
Thermally activated delayed fluorescence (TADF) molecules with dual emission have great potential for use as single emitters in white organic light-emitting diodes (WOLEDs). In this paper, the light-emitting mechanisms of PTZ-TTR and PTZ-Ph-TTR with blue-orange dual emission are studied systematically. The near-planar and near-orthogonal conformations are responsible for the blue and orange emission, respectively. For PTZ-TTR, the near-orthogonal conformation is only generated by the transformation from the near-planar conformation, while the near-orthogonal conformation of PTZ-Ph-TTR can be generated by both excitation and transformation. This results in relatively strong orange emission in PTZ-Ph-TTR. In addition, the TADF mechanism is investigated, and two up-conversion pathways are revealed for both molecules. Based on the comparison of the photophysical properties of PTZ-TTR in toluene and the aggregation state, we find that aggregation could induce a smaller energy gap between the first singlet excited state and the first triplet excited state. Besides, the substitution effect of donors on light-emitting properties is studied, and the design rules for emitters with dual conformations and compensatory emission are proposed. Our theoretical results would favor the understanding of the light-emitting mechanism as well as the design of new-type TADF emitters for WOLEDs.


Keeping care connected: e-Consultation program improves access to nephrology care.
Health systems are seeking innovative solutions to improve specialty care access. Electronic consultations (eConsults) allow specialists to provide formal clinical recommendations to primary care providers (PCPs) based on patient chart review, without a face-to-face visit. We implemented a nephrology eConsult pilot program within a large, academic primary care practice to facilitate timely communication between nephrologists and PCPs. We used primary care referral data to compare wait times and completion rates between traditional referrals and eConsults. We surveyed PCPs to assess satisfaction with the program. For traditional nephrology referrals placed during the study period (July 2016-March 2017), there was a 51-day median appointment wait time and a 40.9% referral completion rate. For eConsults, there was a median nephrologist response time of one day and a 100% completion rate; 67.5% of eConsults did not require a subsequent face-to-face specialty appointment. For eConsults that were converted to an in-person visit, the median wait time and completion rate were 40 days and 73.1%, respectively. Compared to traditional referrals placed during the study period, eConsults converted to in-person visits were more likely to be completed ( p = 0.001). Survey responses revealed that PCPs were highly satisfied with the program and consider the quick turnaround time as the greatest benefit. Our eConsult pilot program reduced nephrology wait times and significantly increased referral completion rates. In large integrated health systems, eConsults have considerable potential to improve access to specialty care, reduce unnecessary appointments, and optimize the patient population being seen by specialists.


The impact of age on vascular smooth muscle function in humans.
Advanced age is associated with vascular endothelial dysfunction, characterized by reductions in the endothelium-dependent vasodilation of the conduit and resistance arteries, in part, from decreased nitric oxide bioavailability. Although vascular smooth muscle function (SMF), assessed by responsiveness to an exogenous nitric oxide donor, is typically reported to be intact, many of these studies are limited by a small sample size. Therefore, the purpose of this meta-analysis is to systematically review and determine whether vascular SMF is different between older versus young healthy individuals. We conducted a systematic search of MEDLINE, Cochrane and Scopus, since their inceptions until January 2014, for articles evaluating SMF in the brachial artery and/or resistance arteries (BASMF and RASMF, respectively), as assessed by the endothelium-independent vasodilator response to exogenous nitric oxide donors in older (≥60 years) and young (<30 years) groups of healthy individuals. Meta-analyses were performed to compare the mean difference in BASMF and the standardized mean difference in RASMF between older and young groups. Subgroup analyses were performed to identify sources of heterogeneity. Fifteen studies assessing BASMF and 20 studies assessing RASMF were included, comprising 550 older and 516 young healthy individuals. After data pooling, BASMF and RASMF were lower in older compared with the young groups (mean difference = -1.89%, P = 0.04; standardized mean difference = -0.46, P = 0.0008, respectively). Significant heterogeneity was observed in the BASMF (I2 = 74%, P < 0.00001) and the RASMF (I2 = 57%, P = 0.0008) meta-analyses. Subgroup analyses revealed that studies with (predominantly) men showed similar SMF responses between the older and the young groups. On the basis of the current published studies, vascular SMF is reduced in conduit and resistance arteries of otherwise healthy older individuals, particularly in women.


Magnetic metamaterials in the blue range using aluminum nanostructures.
We report an experimental and theoretical study of the optical properties of two-dimensional arrays of aluminum nanoparticle in-tandem pairs. Plasmon resonances and effective optical constants of these structures are investigated, and strong magnetic response as well as negative permeability is observed down to 400 nm wavelength. Theoretical calculations based on the finite-difference time-domain method are performed for various particle dimensions and lattice parameters, and are found to be in good agreement with the experimental findings. The results show that metamaterials operating across the whole visible wavelength range are feasible.


Treatment options for refractory angina pectoris: enhanced external counterpulsation therapy.
Refractory angina pectoris, defined as angina refractory to maximal medical therapy and standard coronary revascularization procedures, remains a significant health problem in the United States and the world. Despite a panoply of recent therapeutic advances, patients with refractory angina pectoris are not adequately treated; therefore, scientists have been investigating new technologies to help these patients. The technique of counterpulsation, studied for almost half a century, is considered a safe, highly beneficial, low-cost, noninvasive treatment for these angina patients and now also for those with heart failure. Recent evidence suggests that enhanced external counterpulsation (EECP) therapy may improve symptoms and decrease long-term morbidity via several mechanisms, including improvement in endothelial function, promotion of collateralization, enhancement of ventricular function, improvement in oxygen consumption (Vo(2)), regression of atherosclerosis, and peripheral "training effects" similar to exercise. Numerous clinical trials in the past two decades have shown EECP therapy to be safe and effective for patients with refractory angina, with a clinical response rate averaging 70% to 80%, which is sustained up to 5 years. This review summarizes the current evidence to support EECP's use in treating refractory angina pectoris.