bluuebunny/crossref_metadata_2025_split huggingface dataset:
Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients
Authors: Hashemizadeh Zahra , Badiee Parisa , Malekhoseini Seyed Ali , Raeisi Shahraki Hadi , Geramizadeh Bita , Montaseri Hashem 
Published: September 2017

ABSTRACT

The aim of this study was to investigate the variability of the voriconazole plasma level and its relationships with clinical outcomes and adverse events among liver transplant recipients to optimize the efficacy and safety of their treatment. Liver transplant recipients treated with voriconazole were included, and voriconazole trough levels were quantified by a validated high-performance liquid chromatography method. Cytochrome P450 genotypes for CYP2C19 were evaluated in allograft liver tissues. A total of 832 voriconazole trough levels from 104 patients were measured. Proven, probable, and possible invasive fungal infections were reported for 8/104 (7.7%), 42/104 (40.4%), and 54/104 (51.9%) patients, respectively. Receiver operating characteristic (ROC) curve analysis indicated that trough concentrations of ≥1.3 μg/ml minimized the incidence of treatment failure (95% confidence interval [CI], 0.68 to 0.91 μg/ml) (
P
< 0.001) and that those of <5.3 μg/ml minimized the incidence of any adverse events (95% CI, 0.83 to 0.97 μg/ml) (
P
< 0.001). Voriconazole trough levels were significantly higher for heterozygous extensive metabolizers, poor metabolizers, and individuals receiving coadministration with proton pump inhibitors. For ultrarapid metabolizers, oral administration of voriconazole, and concomitant use of glucocorticoids, voriconazole blood concentrations were significantly reduced. Furthermore, there was no statistically significant association of patient age, weight, or gender or coadministration of tacrolimus and cyclosporine with the voriconazole trough level. In conclusion, the results of our analysis indicate large inter- and intraindividual variabilities of voriconazole concentrations in liver transplant recipients. Voriconazole trough concentrations of ≥1.3 μg/ml and <5.3 μg/ml are optimal for treatment and for minimization of adverse events. Optimization of drug efficacy and safety requires the use of rational doses for voriconazole therapy.
Altered Regulation of the Diguanylate Cyclase YaiC Reduces Production of Type 1 Fimbriae in a Pst Mutant of Uropathogenic Escherichia coli CFT073
Authors: Crépin Sébastien , Porcheron Gaëlle , Houle Sébastien , Harel Josée , Dozois Charles M. 
Published: September 2017

ABSTRACTThepstgene cluster encodes the phosphate-specific transport (Pst) system. Inactivation of the Pst system constitutively activates the two-component regulatory system PhoBR and attenuates the virulence of pathogenic bacteria. In uropathogenicEscherichia colistrain CFT073, attenuation by inactivation ofpstis predominantly attributed to the decreased expression of type 1 fimbriae. However, the molecular mechanisms connecting the Pst system and type 1 fimbriae are unknown. To address this, a transposon library was constructed in thepstmutant, and clones were tested for a regain in type 1 fimbrial production. Among them, the diguanylate cyclase encoded byyaiC(adrAinSalmonella) was identified to connect the Pst system and type 1 fimbrial expression. In thepstmutant, the decreased expression of type 1 fimbriae is connected by the induction ofyaiC. This is predominantly due to altered expression of the FimBE-like recombinase genesipuAandipbA, affecting at the same time the inversion of thefimpromoter switch (fimS). In thepstmutant, inactivation ofyaiCrestoredfim-dependent adhesion to bladder cells and virulence. Interestingly, the expression ofyaiCwas activated by PhoB, since transcription ofyaiCwas linked to the PhoB-dependentphoA-psiFoperon. As YaiC is involved in cyclic di-GMP (c-di-GMP) biosynthesis, an increased accumulation of c-di-GMP was observed in thepstmutant. Hence, the results suggest that one mechanism by which deletion of the Pst system reduces the expression of type 1 fimbriae is through PhoBR-mediated activation ofyaiC, which in turn increases the accumulation of c-di-GMP, represses thefimoperon, and, consequently, attenuates virulence in the mouse urinary tract infection model.IMPORTANCEUrinary tract infections (UTIs) are common bacterial infections in humans. They are mainly caused by uropathogenicEscherichia coli(UPEC). We previously showed that interference with phosphate homeostasis decreases the expression of type 1 fimbriae and attenuates UPEC virulence. Herein, we identified that alteration of the phosphate metabolism increases production of the signaling molecule c-di-GMP, which in turn decreases the expression of type 1 fimbriae. We also determine the regulatory cascade leading to the accumulation of c-di-GMP and identify the Pho regulon as new players in c-di-GMP-mediated cell signaling. By understanding the molecular mechanisms leading to the expression of virulence factors, we will be in a better position to develop new therapeutics.
Concussion in field hockey: a retrospective analysis into the incidence rates, mechanisms, symptoms and recovery of concussive injuries sustained by elite field hockey players
Authors: Rossiter Michael , Challis Michael 
Published: September 2017

ObjectivesTo identify the incidence and mechanisms of concussion in elite Field Hockey in different age groups and also the postconcussion symptoms and recovery times.MethodsData was collected retrospectively, for both training and matches, over a 12-month period from national level Field Hockey players across under-16, under-18, under-21, Development and Senior players.Mechanism of injury (including player role and field position), postconcussive symptoms and recovery times were recorded following a semistructured interview with each player. Additional information on training hours, matches and squad size were also recorded in order to calculate the incidence per 1000 match hours.ResultsOf the 28 recorded cases, only 11 could be included in the study. Women had the highest incidence of concussion, with the majority being in the under-21 age group. Overall incidence varied from 3/1000 match hours in training to 0.02/1000 match hours in matches, with an overall incidence of 0–0.02/1000 match hours across all age groups. The most common mechanism of injury was collision with another player, followed by impact from a stick or ball Midfield and attacking forwards sustained the highest incidence of concussion. None of the concussed athletes wore protective headgear (there were no cases of concussion in goal keepers) and all occurred in open play rather than a penalty corner (when protective headgear is often worn). Postconcussion headaches and difficulty concentrating were the most commonly reported postconcussion symptoms. Average recovery time and return-to-play was 2–4 weeks.ConclusionsDue to the low numbers, only limited conclusions can be made, but it would appear that the risk of concussion in elite Field Hockey is low. As age and skill increases, the risk decreases. Postconcussion symptoms and average return-to-play times are similar to other sports. From this study, no conclusions can be made as to the role of protective headgear to reduce the risk of concussion.
Associations between coronary and carotid artery atherosclerosis in patients with inflammatory joint diseases
Authors: Svanteson Mona , Rollefstad Silvia , Kløw Nils Einar , Hisdal Jonny , Ikdahl Eirik , Semb Anne Grete , Haig Ylva 
Published: September 2017

ObjectiveLow association between cardiac symptoms and coronary artery disease (CAD) in patients with inflammatory joint diseases (IJD) demands for objective markers to improve cardiovascular risk stratification. Our main aim was to evaluate the prevalence and characteristics of CAD in patients with IJD with carotid artery plaques. Furthermore, we aimed to assess associations of carotid ultrasonographic findings and coronary plaques.MethodsEighty-six patients (61% female) with IJD (55 with rheumatoid arthritis, 21 with ankylosing spondylitis and 10 with psoriatic arthritis) and carotid artery plaque were referred to coronary CT angiography (CCTA). CAD was evaluated using the modified 17-segment American Heart Association model. Calcium score, plaque composition, segment involvement score and segment stenosis score were assessed and correlated to the carotid artery plaques and cardiovascular disease risk factors in logistic and linear regression analyses. Risk prediction models were tested with various cut-off values for associating variables.ResultsFifty-five patients (66%) had CAD assessed by CCTA and 36 (43%) of these had coronary plaques defined as either mixed or soft. Eleven patients (13%) had obstructive CAD. The best risk prediction model (area under the curve: 0.832, 95% CI 0.730 to 0.935) included the combination of variables with cut-off values: age ≥55 years (OR: 12.18, 95% CI 2.80 to 53.05), the carotid-intima media thickness ≥0.7 mm (OR: 4.08, 95% CI 1.20 to 13.89) and carotid plaque height ≥1.5 mm (OR: 8.96, 95% CI 1.68 to 47.91), p<0.05.ConclusionPresence of carotid plaque is alone not sufficient to identify patients at risk for CAD, and a combination of ultrasonographic measurements may be useful in risk stratification of patients with IJD.Trial registration numberNCT01389388, Results.
Orbital-climate control of mass-flow sedimentation in a Miocene alluvial-fan succession (Teruel Basin, Spain)
Authors: Ventra Dario , Abels Hemmo A. , Hilgen Frederik J. , de Boer Poppe L. 
Published: September 2017

Abstract

The role of climate change in driving alluvial-fan sedimentation is hard to assess in pre-Quaternary successions, for which detailed chronologies and climate-proxy records cannot be easily established. In the Teruel Basin (Spain), high-resolution (10
4
–10
5
years) chronological and palaeoclimatic information was derived by orbital tuning of Late Miocene mudflat to ephemeral-lake deposits. The semi-arid palaeoclimate made this low-gradient, basinal environment sensitive to thresholds in the local hydrological balance. Basic facies rhythms are attributed to alternating, relatively humid/arid phases controlled by the climatic precession cycle. The lower stratigraphic interval of this reference section interfingers with distal, coarse-clastic beds from a coeval alluvial fan. The consistent interdigitation of debris-flow deposits with distal strata indicative of arid-to-humid climate transitions shows that fan sedimentation was regulated by climate cyclicity. In particular, the largest volumes of terrigenous debris were shed from the fan onto adjacent mudflats during transitions to relatively humid periods with pronounced seasonality, during precession minima. Distal to medial sections within alluvial-fan outcrops also feature prominent, laterally continuous alternations of coarse- and fine-clastic packages. This high degree of architectural organization, uncommon in fan successions, and stratigraphic relationships with the reference section suggest orbitally controlled climate change to have been the forcing mechanism.
Syngeneic Mouse Models of Oral Cancer Are Effectively Targeted by Anti–CD44-Based NIR-PIT
Authors: Nagaya Tadanobu , Nakamura Yuko , Okuyama Shuhei , Ogata Fusa , Maruoka Yasuhiro , Choyke Peter L. , Allen Clint , Kobayashi Hisataka 
Published: September 2017

Abstract
Oral cavity squamous cell carcinoma (OSCC) is considered one of the most aggressive subtypes of cancer. Anti-CD44 monoclonal antibodies (mAb) are a potential therapy against CD44 expressing OSCC; however, to date the therapeutic effects have been disappointing. Here, a new cancer treatment is described, near-infrared photoimmunotherapy (NIR-PIT), that uses anti-CD44 mAbs conjugated to the photoabsorber IR700DX. This conjugate is injected into mice harboring one of three CD44 expressing syngeneic murine oral cancer cell (MOC) lines, MOC1 (immunogenic), MOC2 mKate2 (moderately immunogenic), and MOC2-luc (poorly immunogenic). Binding of the anti-CD44–IR700 conjugate was shown to be specific and cell-specific cytotoxicity was observed after exposure of the cells to NIR light in vitro. The anti-CD44–IR700 conjugate, when assessed in vivo, demonstrated deposition within the tumor with a high tumor-to-background ratio. Tumor-bearing mice were separated into four cohorts: no treatment; 100 μg of anti-CD44–IR700 i.v. only; NIR light exposure only; and 100 μg of anti-CD44–IR700 i.v. with NIR light exposure. NIR-PIT therapy, compared with the other groups, significantly inhibited tumor growth and prolonged survival in all three cell model systems. In conclusion, these data reveal that anti-CD44 antibodies are suitable as mAb–photoabsorber conjugates for NIR-PIT in MOC cells.
Implications: This study using syngeneic mouse models, which better model the disease in humans than conventional xenografts, suggests that NIR-PIT with anti-CD44–IR700 is a potential candidate for the treatment of OSCC. Mol Cancer Res; 15(12); 1667–77. ©2017 AACR.
YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63
Authors: Li Yunguang , Kong Fei , Shao Qirui , Wang Rui , Hu Enze , Liu Jin , Jin Chang , He Dacheng , Xiao Xueyuan 
Published: September 2017

Abstract
In several squamous cell carcinoma (SCC) cells, it has been previously observed that induction of the S100 calcium-binding protein A7 (S100A7) is repressed by YAP via the Hippo pathway. This report now demonstrates that S100A7 also represses YAP expression and activity by ΔNp63 in cancer cells. Stable overexpression of S100A7 activates the NFκB pathway and inhibits the expression of ΔNp63. Caffeic acid phenethyl ester (CAPE), as a specific inhibitor of NFκB, counteracts the inhibitory effect of S100A7 on the expression of ΔNp63 and its target genes. Depletion of S100A7 significantly promotes ΔNp63 expression. These data indicate that S100A7 acts as a suppressor of ΔNp63. Mechanistic examination finds that ΔNp63 not only directly binds to the region of YAP promoter and induces its expression, but also inhibits the Hippo pathway and enhances YAP activity. Importantly, either the positive correlation between S100A7 and YAP phosphorylation at S127 or the negative correlation between S100A7 and ΔNp63 is also observed in skin SCC tissues. Chemosensitivity analysis reveals that S100A7 enhances cancer cells' resistance by inhibition of YAP expression and activity. These results demonstrate that S100A7 is an upstream modulator of the Hippo pathway and extend our understanding of S100A7 functions in cancer.
Implications: S100A7 is a new upstream regulator of the Hippo signaling pathway and reduces chemosensitivity of SCC cells through inhibitions of YAP expression and activity. Mol Cancer Res; 15(12); 1752–63. ©2017 AACR.
Competing Risks of Cardiovascular Versus Noncardiovascular Death During Long‐Term Follow‐Up After Acute Coronary Syndromes
Authors: Fanaroff Alexander C. , Roe Matthew T. , Clare Robert M. , Lokhnygina Yuliya , Navar Ann Marie , Giugliano Robert P. , Wiviott Stephen D. , Tershakovec Andrew M. , Braunwald Eugene , Blazing Michael A. 
Published: September 2017

Background

Understanding the relative risk of cardiovascular versus noncardiovascular death is important for designing clinical trials. These risks may differ depending on patient age, sex, and type of acute coronary syndrome (
ACS
).

Methods and Results

IMPROVE
‐
IT
(Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized controlled trial of simvastatin plus either ezetimibe or placebo following stabilized
ACS
. Cause of death was adjudicated by an independent committee. We compared the cumulative incidence of cardiovascular and noncardiovascular death for patients with unstable angina/non‐
ST
‐segment elevation myocardial infarction (
UA
/
NSTEMI
) and
ST
‐segment elevation myocardial infarction (
STEMI
), in those <65 and ≥65 years old, and males and females, over 7 years of follow‐up. Of 18 131 patients, the presenting event was
STEMI
for 5190 (29%) and
UA
/
NSTEMI
for 12 941 (71%); 10 173 (56%) patients were <65 years old and 7971 (44%) were ≥65 years old at presentation.
UA
/
NSTEMI
patients were older than
STEMI
patients, with more cardiovascular and noncardiovascular risk factors. In
STEMI
patients, the cumulative incidence of cardiovascular death was higher for ∼4 years following the index event, after which noncardiovascular death predominated. In
UA
/
NSTEMI
patients, the cumulative incidence of cardiovascular death remained higher than noncardiovascular death over the full follow‐up period. Patients ≥65 years old and <65 years old had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of follow‐up. Female patients had a higher incidence of cardiovascular death than noncardiovascular death for ∼6 years following the index event; male patients had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of follow‐up.

Conclusions

Among post‐
ACS
patients enrolled in a long‐term clinical trial, the relative incidence of cardiovascular and noncardiovascular death differed based on type of
ACS
presentation and sex, but not age. These findings further delineate long‐term prognosis after
ACS
and should inform the design of future cardiovascular outcomes trials.
Treatment of Chronic Hepatitis C Virus Infection With Crushed Ledipasvir/Sofosbuvir Administered via a Percutaneous Endoscopic Gastrostomy Tube
Authors: Jindracek Lauren , Stark Jennifer 
Published: September 2017

Introduction: Ledipasvir/sofosbuvir (Harvoni®) is a fixed-dose tablet indicated for the treatment of chronic hepatitis C virus (HCV) infection. There are currently no data available on the safety and efficacy of crushed ledipasvir/sofosbuvir tablets. Case Summary: This report describes the first documented case of successful treatment of chronic HCV infection in a patient crushing ledipasvir/sofosbuvir for administration via a percutaneous endoscopic gastrostomy (PEG) tube. The patient was treatment experienced and had evidence of compensated cirrhosis. Treatment duration was 24 weeks, and HCV RNA was undetectable 12 weeks after completion of treatment (SVR12) which is the accepted measure of a clinical cure. Discussion: Issues may arise during or prior to starting HCV treatment that necessitate crushing tablets. Stopping or interrupting HCV treatment could lead to development of resistance or treatment failure. Conclusion: This is the first published case in which crushed ledipasvir/sofosbuvir administered via a PEG tube is documented as a safe and effective option for treatment of chronic HCV infection.
Effects of low-dose lipopolysaccharide and age on spatial learning in different Morris water maze protocols
Authors: Kupferschmid Barbara J , Therrien Barbara , Rowsey Pamela J 
Published: September 2017

Objectives: Animals administered lipopolysaccharide exhibit dose-related sickness behaviors (decreased food intake, weight loss, and cognitive changes). While research has demonstrated that spatial learning is impaired following a lipopolysaccharide immune challenge, the results differ depending on the methodology used to evaluate spatial learning. Additionally, few studies have evaluated the effects of low-dose lipopolysaccharide on spatial learning. Therefore, we assessed spatial learning, food intake, and weight changes in adult and aged rats after a low-dose lipopolysaccharide immune challenge in the Morris water maze using two water temperatures. Methods: Adult (5–6 months) and aged (22 months) male Brown-Norway rats were administered either 50 or 100 μg/kg lipopolysaccharide or saline, and then tested in the Morris water maze for 5 days, rested for 7 days, and later underwent 2 days of retention tests. Probe trials were conducted at the end of initial and retention testing. Results: Low-dose lipopolysaccharide administration did not result in food intake or weight changes. While the aged experimental group took longest to improve directional heading error in both cold and warm water, heading error was greater in cold water. Behavioral testing revealed an apparent age and water temperature effect on swim time. Retention and probe trial results showed that aged experimental animals had the worst performance in cold water. Conclusion: We conclude that while low-dose lipopolysaccharide did not result in typical sickness behaviors (decreased food intake or weight), spatial learning and memory were impaired in the aged experimental group. These results have important implications for the care of elderly individuals experiencing mild to moderate infections.
Periaortic lymphoma in a cat
Authors: Bree Laura , Bergamino Chiara , Mullins Ronan , Kelly Pamela , Shiel Robert 
Published: September 2017

Case summary A 14-year-old neutered male Siamese cat was presented with a 3 month history of lethargy, inappetence, dehydration, hindlimb ataxia and intermittent proprioceptive deficits in the hindlimbs. Physical examination revealed low body condition score (1.75/5), pallor and bilateral basilar grade II/VI systolic heart murmur. Neurological examination revealed hindlimb ataxia, severe atrophy of the hindlimb musculature, intermittent hindlimb proprioceptive deficits and normoreflexia. Clinicopathological investigations revealed non-regenerative anaemia (haematocrit 0.17 l/l; reference interval [RI] 0.24–0.45 l/l) and increased feline pancreatic lipase concentration (Spec fPL test [IDEXX] 8.3 μg/l; RI 0.1–3.5 μg/l). Feline leukaemia virus antigen and feline immunodeficiency virus antibody tests were negative. Thoracic and abdominal imaging revealed a soft tissue structure in the area of the thoracoabdominal aorta. CT confirmed a periaortic contrast-enhancing mass extending from the level of T9–L2, with associated intervertebral infiltration at the level of T11–T12. Post-mortem examination confirmed the presence of a solid, white, multinodular, well-demarcated mass encircling the aorta extending from T9–L2. Based on histopathology and immunohistochemistry, a diagnosis of B-cell lymphoma was made. Lymphoma was also identified histopathologically within the kidneys and spleen. Evidence of mild Wallerian degeneration was present within the spinal cord, indicating compression at the level of the periaortic mass. Relevance and novel information To our knowledge, this is the first report of periaortic lymphoma in the cat. Although periaortic tumours are exceptionally rare in veterinary medicine, lymphoma should be considered as a differential in cats.
Granulomatous colitis: more than a canine disease? A case of Escherichia coli-associated granulomatous colitis in an adult cat
Authors: Leal Rodolfo Oliveira , Simpson Kenny , Fine Mélanie , Husson Jean-Charles , Hernandez Juan 
Published: September 2017

Case summary This report describes a 4-year-old cat with chronic intermittent haematochezia and faecal incontinence of 7 months’ duration. Investigation revealed severe colonic multifocal mucosal ulcerations and infiltration of the mucosal lamina propria by large numbers of periodic acid–Schiff-positive macrophages. Fluorescence in situ hybridisation analysis of colonic biopsies revealed multifocal clusters of intracellular Escherichia coli. Treatment with fluoroquinolones for 6 weeks led to a complete resolution of clinical signs. Relevance and novel information The findings reveal that mucosally invasive E coli can also be associated with granulomatous colitis in cats and indicate the need for diagnostic testing of mucosal samples for E coli and other infectious agents.
Ibrutinib for chronic graft-versus-host disease after failure of prior therapy
Authors: Miklos David , Cutler Corey S. , Arora Mukta , Waller Edmund K. , Jagasia Madan , Pusic Iskra , Flowers Mary E. , Logan Aaron C. , Nakamura Ryotaro , Blazar Bruce R. , Li Yunfeng , Chang Stephen , Lal Indu , Dubovsky Jason , James Danelle F. , Styles Lori , Jaglowski Samantha 
Published: September 2017

Key Points
Ibrutinib induced a high rate of sustained responses for patients with cGVHD and inadequate response to corticosteroid-containing therapy. This trial supported the approval of ibrutinib for treatment of adult patients with cGVHD after failure of ≥1 lines of systemic therapy.