bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flat Intraurothelial Neoplasia Exhibiting Diffuse Immunoreactivity for CD44 and Cytokeratin 5 (Urothelial Stem Cell/Basal Cell Markers): A Variant of Intraurothelial Neoplasia Commonly Associated With Muscle-invasive Urothelial Carcinoma
Authors: Mai Kien T. , Busca Aurelia , Belanger Eric C. 
Published: March 2016

Background:
Immunoreactivity for CD44 and cytokeratin (CK)5 (urothelial stem/basal cell markers) are decreased/negative in the common type of intraurothelial neoplasia including urothelial carcinomas (UC) in situ. Recent studies also reveal that a majority of muscle-invasive UC are basal-like UC with large areas of positive CD44/CK5 immunoreactivity. In addition, approximately 80% of muscle-invasive UC develop de novo as nonpapillary invasive UC. In this study, we investigate the CD44/CK5 immunoreactivity of the flat intraurothelial neoplasia (FIUN) associated with nonpapillary invasive UC.

Materials and Methods:
Consecutive cases of nonpapillary UC were submitted for immunostaining. Immunostaining for CK5/CD44 was scored as high for staining of >25% thickness of urothelium and low for lesser immunoreactivity.

Results:
In total, 109 consecutive cases were grouped into: in situ UC [carcinoma in situ (CIS)] (n=11), pT1 (n=14), and pT2-4 (n=84) with surface urothelium available for study. Forty-four cases including CIS (n=9), pT1 (n=12), and pT2-4 (n=23) showed FIUN with low/negative CD44/CK5 reactivity; 40 cases showed strong CK20 reactivity. Sixty-two cases including CIS (n=2), pT1 (n=2), and pT2-4 (n=58) showed extensive FIUN exhibiting high CD44/CK5 reactivity; 30 cases showed reactive CK20. FIUN lesions with high CD44/CK5 reactivity scores were associated with mild (urothelial dysplasia) to moderate atypia (CIS) and were rarely preceded by papillary UC. Most invasive UC associated with FIUN with high CD44/CK5 reactivity also exhibited extensive CD44/CK5 reactivity. The remaining 3 cases showed only reactive urothelium. Of interest, 4 cases with FIUN showed negative CD44/CK5/CK20 reactivity.

Conclusions:
Existence of CD44/CK5-immunoreactive (or basal-like) FIUN is consistent with the recent distinction of basal and luminal subtypes of UC. This type of FIUN is often associated with UC with progression to high-stage disease not preceded by recurrent papillary UC.
On Shaky Ground
Authors: Whitney Rachel E. , Burke Rita V. , Lehman-Huskamp Kathy , Arora Gitanjli , Park Daniel B. , Cicero Mark X. 
Published: March 2016

Objective
The aim of this study was to evaluate residents' confidence and attitudes related to management of earthquake victims during a tabletop simulation and 6 months after the intervention.

Methods
Pediatric residents from 4 training programs were recruited via e-mail. The tabletop simulation involved 3 pediatric patients (crush injury, head injury, and a nonverbal patient with minor injuries). A facilitated debriefing took place after the simulation. The same simulation was repeated 6 months later. A survey was administered before the simulation, immediately after, and after the 6-month repeat simulation to determine participants' self-rated confidence and willingness to respond in the event of a disaster. A 5-point Likert scale that ranged through novice, advanced beginner, competent, proficient, and expert was used.

Results
Ninety-nine participants completed the survey before the initial simulation session. Fifty-one residents completed the immediate postsurvey, and 75 completed the 6-month postsurvey. There was a statistically significant improvement in self-rated confidence identifying and managing victims of earthquake disasters after participating in the simulation, with 3% rating themselves as competent on the presurvey and 33% rating themselves as competent on the postsurvey (P < 0.05). There was a nonstatistically significant improvement in confidence treating suspected traumatic head injury as well as willingness to deploy to both domestic and international disasters.

Conclusions
Tabletop simulation can improve resident comfort level with rare events, such as caring for children in the aftermath of an earthquake. Tabletop can also be easily integrated into resident curriculum and may be an effective way to provide disaster medical response training for trainees.
The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects
Authors: Song Ivy H. , Zong Jian , Borland Julie , Jerva Fred , Wynne Brian , Zamek-Gliszczynski Maciej J. , Humphreys Joan E. , Bowers Gary D. , Choukour Mike 
Published: March 2016

Background:
Dolutegravir is an integrase strand transfer inhibitor (INSTI) licensed for use in HIV-1 infection and is an inhibitor of organic cation transporter 2 (OCT2). This study assessed the effect of dolutegravir on the pharmacokinetics of metformin, an OCT2 substrate.

Design:
This was an open-label, parallel-group, 3-period crossover study in healthy adult subjects. Subjects were enrolled into 1 of 2 treatment cohorts (15 subjects/cohort) receiving metformin 500 mg q12h for 5 days in period 1; metformin 500 mg q12h plus dolutegravir 50 mg q24h (cohort 1) or 50 mg q12h (cohort 2) for 7 days in period 2; and metformin 500 mg q12h for 10 days in period 3. There were no washout periods between treatments. Effects of dolutegravir on metformin transport and paracellular permeability were evaluated in vitro.

Results:
Co-administration of dolutegravir 50 mg q24h increased metformin area under the curve(0–τ) by 79% and Cmax by 66%, whereas dolutegravir 50 mg q12h increased metformin area under the curve(0–τ) and Cmax by 145% and 111%, respectively. Metformin t(1/2) remained unchanged. Increased metformin exposure during dolutegravir co-administration returned to period 1 levels after dolutegravir discontinuation in period 3. Co-administration of dolutegravir and metformin was well tolerated. In vitro, dolutegravir was not a clinically relevant inhibitor of OCT1, OCT3, multidrug and toxin extrusion protein 1, multidrug and toxin extrusion protein 2-K, or plasma membrane monoamine transporter, and it did not affect metformin paracellular permeability or uptake into an intestinal cell line.

Conclusions:
Dolutegravir significantly increased metformin plasma exposure, which can be partially explained by OCT2 inhibition. It is recommended that dose adjustments of metformin be considered to maintain optimal glycemic control when patients are starting/stopping dolutegravir while taking metformin.
Implementation and Operational Research: A Cost-Effective, Clinically Actionable Strategy for Targeting HIV Preexposure Prophylaxis to High-Risk Men Who Have Sex With Men
Authors: Ross Eric L. , Cinti Sandro K. , Hutton David W. 
Published: March 2016

Background:
Preexposure prophylaxis (PrEP) is effective at preventing HIV infection among men who have sex with men (MSM), but there is uncertainty about how to identify high-risk MSM who should receive PrEP.

Methods:
We used a mathematical model to assess the cost-effectiveness of using the HIV Incidence Risk Index for MSM (HIRI-MSM) questionnaire to target PrEP to high-risk MSM. We simulated strategies of no PrEP, PrEP available to all MSM, and eligibility thresholds set to HIRI-MSM scores between 5 and 45, in increments of 5 (where a higher score predicts greater HIV risk). Based on the iPrEx, IPERGAY, and PROUD trials, we evaluated PrEP efficacies from 44% to 86% and annual costs from $5900 to 8700. We designate strategies with incremental cost-effectiveness ratio (ICER) ≤$100,000/quality-adjusted life-year (QALY) as “cost-effective.”

Results:
Over 20 years, making PrEP available to all MSM is projected to prevent 33.5% of new HIV infections, with an ICER of $1,474,000/QALY. Increasing the HIRI-MSM score threshold reduces the prevented infections, but improves cost-effectiveness. A threshold score of 25 is projected to be optimal (most QALYs gained while still being cost-effective) over a wide range of realistic PrEP efficacies and costs. At low cost and high efficacy (IPERGAY), thresholds of 15 or 20 are optimal across a range of other input assumptions; at high cost and low efficacy (iPrEx), 25 or 30 are generally optimal.

Conclusions:
The HIRI-MSM provides a clinically actionable means of guiding PrEP use. Using a score of 25 to determine PrEP eligibility could facilitate cost-effective use of PrEP among high-risk MSM who will benefit from it most.
The Risk of Cardiovascular Disease Is Not Increasing Over Time Despite Aging and Higher Comorbidity Burden of Kidney Transplant Recipients
Authors: Lam Ngan N. , Kim S. Joseph , Knoll Gregory A. , McArthur Eric , Lentine Krista L. , Naylor Kyla L. , Li Alvin H. , Shariff Salimah Z. , Ribic Christine M. , Garg Amit X. 
Published: March 2016

Background
Cardiovascular death remains the leading cause of mortality in kidney transplant recipients. Cardiovascular events are associated with significant morbidity. However, current trends in cardiovascular events after kidney transplantation are poorly understood.

Methods
We conducted a retrospective study using healthcare databases in Ontario, Canada, to determine whether the incidence of cardiovascular events after kidney transplantation has changed from 1994 to 2009. Our primary endpoint was a 3-year composite outcome of posttransplant death or major cardiovascular event (myocardial infarction, coronary angioplasty, coronary artery bypass graft surgery, stroke).

Results
Recipients (n = 4954) were older and had more baseline comorbidity in recent years. A total of 445 recipients (9.0%) died or experienced a major cardiovascular event within 3 years of transplantation. There was no significant change in the incidence of the composite outcome or death-censored cardiovascular events over time (P = 0.41 and 0.92, respectively). After adjusting for age, sex, and comorbidities, the risk of death or major cardiovascular event steadily declined across the years of transplant (2006-2009 adjusted hazard ratio, 0.70; P = 0.009; referent 1994-1997). When recipients were matched on age, sex, and date of cohort entry to members of the general population and to the chronic kidney disease population, the risk was lowest in the general population and highest in the chronic kidney disease population.

Conclusion
Despite transplant centers accepting recipients who are older with more comorbidities in recent years, the 3-year cumulative incidence of death or major cardiovascular event has remained stable over time.
Probing the causal role of prestimulus interregional synchrony for perceptual integration via tACS
Authors: Stonkus Rolandas , Braun Verena , Kerlin Jess , Volberg Gregor , Hanslmayr Simon 
Published: March 2016

AbstractThe phase of prestimulus oscillations at 7-10 Hz has been shown to modulate perception of briefly presented visual stimuli. Specifically, a recent combined EEG-fMRI study suggested that a prestimulus oscillation at around 7 Hz represents open and closed windows for perceptual integration by modulating connectivity between lower order occipital and higher order parietal brain regions. We here utilized brief event-related transcranial alternating current stimulation (tACS) to specifically modulate this prestimulus 7 Hz oscillation, and the synchrony between parietal and occipital brain regions. To this end we tested for a causal role of this particular prestimulus oscillation for perceptual integration. The EEG was acquired at the same time allowing us to investigate frequency specific after effects phase-locked to stimulation offset. On a behavioural level our results suggest that the tACS did modulate perceptual integration, however, in an unexpected manner. On an electrophysiological level our results suggest that brief tACS does induce oscillatory entrainment, as visible in frequency specific activity phase-locked to stimulation offset. Together, our results do not strongly support a causal role of prestimulus 7 Hz oscillations for perceptual integration. However, our results suggest that brief tACS is capable of modulating oscillatory activity in a temporally sensitive manner.
Epidemiological analysis of psoriatic arthritis patients in Japan
Authors: Yamamoto Toshiyuki , Ohtsuki Mamitaro , Sano Shigetoshi , Igarashi Atsuyuki , Morita Akimichi , Okuyama Ryuhei , Kawada Akira ,   the Working Group of the Epidemiological Survey in the Japanese Society for Psoriasis Research
Published: March 2016

AbstractTo determine the current status of psoriatic arthritis, we conducted a retrospective survey by sending questionnaires. The newly visited psoriatic arthritis patients accounted for 10.5% (95% confidence interval, 7.9–13%) of all newly visited psoriasis patients (n = 2581) between April 2014 and March 2015 in 73 institutes. Additionally, questionnaires on detailed patients’ information were returned by 92 institutes (response rate, 70.8%), where 1282 patients with psoriatic arthritis were identified. There was a male predominance. The mean onset age of psoriatic arthritis was 44.9 years, and mean onset age for cutaneous psoriasis (36.4 years) was lower than that for arthritis (45.1 years). The mean duration in patients who developed psoriasis prior to arthritis was 11.2 years, while that in patients preceded by arthritis was 4.4 years. According to the Moll and Wright criteria, polyarthritis type was most common (36%), followed by distal interphalangeal type (26%) and oligoarthritis type (22%). Peripheral joint pain was 61.5%, back pain such as lumbago and neck pain was 34.3%. Enthesitis and dactylitis were observed in 28.3% and 59.2%, respectively. Biologics were used in 55.5% of psoriatic arthritis patients, and 31% used disease‐modifying antirheumatic drugs. In conclusion, the ratio of psoriatic arthritis in Japan is increasing, and nearly 10% of new psoriasis patients had psoriatic arthritis. This study shows the current status of psoriatic arthritis in Japan, including several unexpected findings such as male predominance, longer duration between the onset of cutaneous psoriasis and arthritis, and dominance of polyarthritis.
Variation and association of fibronectin‐binding protein genes fnbA and fnbB in Staphylococcus aureus Japanese isolates
Authors: Murai Miyo , Moriyama Hideaki , Hata Eiji , Takeuchi Fumihiko , Amemura‐Maekawa Junko 
Published: March 2016

ABSTRACTFibronectin‐binding proteins A and B (FnBPA and FnBPB) mediate adhesion of Staphylococcus aureus to fibrinogen, elastin and fibronectin. FnBPA and FnBPB are encoded by two closely linked genes, fnbA and fnbB, respectively. With the exception of the N‐terminal regions, the amino acid sequences of FnBPA and FnBPB are highly conserved. To investigate the genetics and evolution of fnbA and fnbB, the most variable regions, which code for the 67th amino acids of the A through B regions (A67–B) of fnbA and fnbB, were focused upon. Eighty isolates of S. aureus in Japan were sequenced and 19 and 18 types in fnbA and fnbB, respectively, identified. Although the phylogeny of fnbA and fnbB were found to be quite different, each fnbA type connected with a specific fnbB type, indicating that fnbA and fnbB mutate independently, whereas the combination of both genes after recombination is stable. Hence those fnbA–fnbB combinations were defined as FnBP sequence types (FnSTs). Representative isolates of each FnST were assigned distinct STs by multilocus sequence typing, suggesting correspondence of FnST with genome lineage. Linkage disequilibrium (LD) analysis of the A67–B region revealed that subdomains N2, N3 and FnBR1 form a LD block in fnbA, whereas N2 and N3 form two independent LD blocks in fnbB. N2–N3 three‐dimensional structural models indicated that not only the variable amino acid residues, but also well‐conserved amino acid residues between FnBPA and FnBPB, are located on the surface of the protein. These results highlight a molecular process of the FnBP that has evolved by mingled mutation and recombination with retention of functions.
Food availability and predation risk, rather than intrinsic attributes, are the main factors shaping the reproductive decisions of a long‐lived predator
Authors: Hoy Sarah R. , Millon Alexandre , Petty Steve J. , Whitfield D. Philip , Lambin Xavier 
Published: March 2016

Summary

Deciphering the causes of variation in reproductive success is a fundamental issue in ecology, as the number of offspring produced is an important driver of individual fitness and population dynamics. Little is known, however, about how different factors interact to drive variation in reproduction, such as whether an individual's response to extrinsic conditions (e.g. food availability or predation) varies according to its intrinsic attributes (e.g. age, previous allocation of resources towards reproduction).

We used 29 years of reproductive data from marked female tawny owls and natural variation in food availability (field vole) and predator abundance (northern goshawk) to quantify the extent to which extrinsic and intrinsic factors interact to influence owl reproductive traits (breeding propensity, clutch size and nest abandonment).

Extrinsic and intrinsic factors appeared to interact to affect breeding propensity (which accounted for 83% of the variation in owl reproductive success). Breeding propensity increased with vole density, although increasing goshawk abundance reduced the strength of this relationship. Owls became slightly more likely to breed as they aged, although this was only apparent for individuals who had fledged chicks the year before.

Owls laid larger clutches when food was more abundant. When owls were breeding in territories less exposed to goshawk predation, 99·5% of all breeding attempts reached the fledging stage. In contrast, the probability of breeding attempts reaching the fledging stage in territories more exposed to goshawk predation depended on the amount of resources an owl had already allocated towards reproduction (averaging 87·7% for owls with clutches of 1–2 eggs compared to 97·5% for owls with clutches of 4–6 eggs).

Overall, our results suggested that changes in extrinsic conditions (predominantly food availability, but also predator abundance) had the greatest influence on owl reproduction. In response to deteriorating extrinsic conditions (fewer voles and more goshawks), owls appeared to breed more frequently, but allocated fewer resources per breeding attempt. However, intrinsic attributes also appeared to have a relatively small influence on how an individual responded to variation in extrinsic conditions, which indicates that owl reproductive decisions were shaped by a complex series of extrinsic and intrinsic trade‐offs.
Overwintering strategies of migratory birds: a novel approach for estimating seasonal movement patterns of residents and transients
Authors: Ruiz‐Gutierrez Viviana , Kendall William L. , Saracco James F. , White Gary C. 
Published: March 2016

SummaryOur understanding of movement patterns in wildlife populations has played an important role in current ecological knowledge and can inform landscape conservation decisions. Direct measures of movement can be obtained using marked individuals, but this requires tracking individuals across a landscape or multiple sites.We demonstrate how movements can be estimated indirectly using single‐site, capture–mark–recapture (CMR) data with a multi‐state open robust design with state uncertainty model (MSORD‐SU). We treat residence and transience as two phenotypic states of overwintering migrants and use time‐ and state‐dependent probabilities of site entry and persistence as indirect measures of movement. We applied the MSORD‐SU to data on eight species of overwintering Neotropical birds collected in 14 countries between 2002 and 2011. In addition to entry and persistence probabilities, we estimated the proportions of residents at a study site and mean residence times.We identified overwintering movement patterns and residence times that contrasted with prior categorizations of territoriality. Most species showed an evidence of residents entering sites at multiple time intervals, with transients tending to enter between peak resident movement times. Persistence and the proportion of residents varied by latitude, but were not always positively correlated for a given species.Synthesis and applications. Our results suggest that migratory songbirds commonly move among habitats during the overwintering period. Substantial proportions of populations appear to be comprised of transient individuals, and residents tend to persist at specific sites for relatively short periods of time. This information on persistence and movement patterns should be explored for specific habitats to guide landscape management on the wintering grounds, such as determining which habitats are conserved or restored as part of certification programmes of tropical agroforestry crops. We suggest that research and conservation efforts on Neotropical migrant songbirds focus on identifying landscape configurations and regional habitat networks that support these diverse overwintering strategies to secure full life cycle conservation.
Where, why and how? Explaining the low‐temperature range limits of temperate tree species
Authors: Körner Christian , Basler David , Hoch Günter , Kollas Chris , Lenz Armando , Randin Christophe F. , Vitasse Yann , Zimmermann Niklaus E. 
Published: March 2016

Summary

Attempts at explaining range limits of temperate tree species still rest on correlations with climatic data that lack a physiological justification. Here, we present a synthesis of a multidisciplinary project that offers mechanistic explanations. Employing climatology, biogeography, dendrology, population and reproduction biology, stress physiology and phenology, we combine results from in situ elevational (Swiss Alps) and latitudinal (Alps vs. Scandinavia) comparisons, from reciprocal common garden and phytotron studies for eight European broadleaf tree species.

We show that unlike for low‐stature plants, tree canopy temperatures can be predicted from weather station data, and that low‐temperature extremes in winter do not explain range limits. At the current low‐temperature range limit, all species recruit well. Transplants revealed that the local environment rather than elevation of seed origin dominates growth and phenology. Tree ring width at the range limit is not related to season length, but to growing season temperature, with no evidence of carbon shortage. Bud break and leaf emergence in adults trees are timed in such a way that the probability of freezing damage is almost zero, with a uniform safety margin across elevations and taxa. More freezing‐resistant species flush earlier than less resistant species.

Synthesis: we conclude that the range limits of the examined tree species are set by the interactive influence of freezing resistance in spring, phenology settings, and the time required to mature tissue. Microevolution of spring phenology compromises between demands set by freezing resistance of young, immature tissue and season length requirements related to autumnal tissue maturation.