bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients
Authors: Bradley John S. , Armstrong Jon , Arrieta Antonio , Bishai Raafat , Das Shampa , Delair Shirley , Edeki Timi , Holmes William C. , Li Jianguo , Moffett Kathryn S. , Mukundan Deepa , Perez Norma , Romero José R. , Speicher David , Sullivan Janice E. , Zhou Diansong 
Published: August 2016

ABSTRACT

This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (
C
max
), and area under the concentration-time curve from time zero to infinity (AUC
0–∞
) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.)
High Prevalence of Carbapenemase-Producing Enterobacteriaceae among Hospitalized Children in Luanda, Angola
Authors: Kieffer Nicolas , Nordmann Patrice , Aires-de-Sousa Marta , Poirel Laurent 
Published: August 2016

ABSTRACT

This study aimed to evaluate the prevalence of carbapenemase-producing
Enterobacteriaceae
in Luanda, Angola. A total of 157 rectal samples were collected from children visiting a pediatric hospital in Luanda in March 2015. Fifty-seven imipenem-nonsusceptible enterobacterial isolates were recovered, most of which were non-clonally related. The
bla
OXA-181
(50/57) and
bla
NDM-1
(7/57) carbapenemase genes were identified. Notably, OXA-181-producing
Escherichia coli
isolates rarely coproduced extended-spectrum β-lactamases and consequently remained susceptible to broad-spectrum cephalosporins. The
bla
OXA-181
gene was always located on an IncX3 plasmid, while the
bla
NDM-1
gene was located on either IncFIA or IncA/C plasmids. The study identified a high prevalence of OXA-181 among hospitalized children in Angola.
Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase
Authors: Palencia Andrés , Li Xianfeng , Bu Wei , Choi Wai , Ding Charles Z. , Easom Eric E. , Feng Lisa , Hernandez Vincent , Houston Paul , Liu Liang , Meewan Maliwan , Mohan Manisha , Rock Fernando L. , Sexton Holly , Zhang Suoming , Zhou Yasheen , Wan Baojie , Wang Yuehong , Franzblau Scott G. , Woolhiser Lisa , Gruppo Veronica , Lenaerts Anne J. , O'Malley Theresa , Parish Tanya , Cooper Christopher B. , Waters M. Gerard , Ma Zhenkun , Ioerger Thomas R. , Sacchettini James C. , Rullas Joaquín , Angulo-Barturen Iñigo , Pérez-Herrán Esther , Mendoza Alfonso , Barros David , Cusack Stephen , Plattner Jacob J. , Alley M. R. K. 
Published: August 2016

ABSTRACT

The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of
Mycobacterium tuberculosis
highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against
M. tuberculosis
in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to
M. tuberculosis
LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against
M. tuberculosis
. Importantly, their good oral bioavailability translates into
in vivo
efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.
AraC-Type Regulator Rbf Controls the Staphylococcus epidermidis Biofilm Phenotype by Negatively Regulating the
icaADBC
Repressor SarR
Authors: Rowe Sarah E. , Campbell Christopher , Lowry Colm , O'Donnell Sinead T. , Olson Michael E. , Lindgren Jill K. , Waters Elaine M. , Fey Paul D. , O'Gara James P. 
Published: August 2016

ABSTRACT

Regulation of
icaADBC
-encoded polysaccharide intercellular adhesin (PIA)/poly-
N
-acetylglucosasmine (PNAG) production in staphylococci plays an important role in biofilm-associated medical-device-related infections. Here, we report that the AraC-type transcriptional regulator Rbf activates
icaADBC
operon transcription and PIA production in
Staphylococcus epidermidis
. Purified recombinant Rbf did not bind to the
ica
operon promoter region in electrophoretic mobility shift assays (EMSAs), indicating that Rbf regulates
ica
transcription indirectly. To identify the putative transcription factor(s) involved in Rbf-mediated
icaADBC
regulation, the ability of recombinant Rbf to interact with the promoter sequences of known
icaADBC
regulators was investigated. Recombinant Rbf bound to the
sarR
promoter and not the
sarX
,
sarA
,
sarZ
,
spx
, and
srrA
promoters. Reverse transcription (RT)-PCR demonstrated that Rbf acts as a repressor of
sarR
transcription. PIA expression and biofilm production were restored to wild-type levels in an
rbf sarR
double mutant grown in brain heart infusion (BHI) medium supplemented with NaCl, which is known to activate the
ica
locus, but not in BHI medium alone. RT-PCR further demonstrated that although Rbf does not bind the
sarX
promoter, it nevertheless exerted a negative effect on
sarX
expression. Apparently, direct downregulation of the SarR repressor by Rbf has a dominant effect over indirect repression of the SarX activator by Rbf in the control of
S. epidermidis
PIA production and biofilm formation.

IMPORTANCE
The importance of
Staphylococcus epidermidis
as an opportunistic pathogen in hospital patients with implanted medical devices derives largely from its capacity to form biofilm. Expression of the
icaADBC
-encoded extracellular polysaccharide is the predominant biofilm mechanism in
S. epidermidis
clinical isolates and is tightly regulated. Here, we report that the transcriptional regulator Rbf promotes
icaADBC
expression by negatively regulating expression of
sarR
, which encodes an
ica
operon repressor. Furthermore, Rbf indirectly represses the
ica
operon activator, SarX. The data reveal complicated interplay between Rbf and two Sar family proteins in fine-tuning regulation of the biofilm phenotype and indicate that in the hierarchy of biofilm regulators, IcaR is dominant over the Rbf-SarR-SarX axis.
Facilitating mental health research for patients, clinicians and researchers: a mixed-method study
Authors: Robotham D , Waterman S , Oduola S , Papoulias C , Craig T , Wykes T 
Published: August 2016

ObjectivesResearch registers using Consent for Contact (C4C) can facilitate recruitment into mental health research studies, allowing investigators to contact patients based on clinical records information. We investigated whether such a register was useful for mental health research, seeking the perspectives of patients and research investigators.Setting and designIn 2012, a C4C register was developed in a large secondary mental health provider within the UK; almost 9000 patients have joined. This mixed-method study audited the effectiveness of the register.ParticipantsA ‘mystery shopper’ exercise was conducted, and patients (n=21) were recruited to ask clinicians about the availability of research opportunities. Structured interviews were conducted with patients (n=52) about their experiences of being on the register. Similar interviews were conducted with 18 investigators from 19 studies, who had attempted to use the register to recruit participants.Outcome measuresThe impact of C4C on study recruitment, and whether it helped patients learn about research.ResultsSo far, the register has provided 928 individuals with 1085 research opportunities (in 60% of cases, the individual agreed to participate in the study). Clinicians were willing to link patients to research opportunities, but often lacked information about studies. For patients, the register provided opportunities which they may not otherwise have; 27 of 52 had participated in studies since joining the register (18 participating for the first time). Most investigators used the register to supplement recruitment to their studies, but described problems in prescreening potential participants from a clinical record for complex studies.ConclusionsAlthough the register helped investigators recruit for studies, and provided patients with research opportunities, clinicians' input is still useful for identifying suitable participants. C4C registers should be adapted to provide clinicians with automatically updated information on local studies allowing them to match patients on their caseload with active studies.
Determinants of out-of-hours service users' potentially inappropriate referral or non-referral to an emergency department: a retrospective cohort study in a local health authority, Veneto Region, Italy
Authors: Buja Alessandra , Toffanin Roberto , Rigon S , Sandonà P , Carrara T , Damiani G , Baldo V 
Published: August 2016

BackgroundA growing presence of inappropriate patients has been recognised as one of the main factors influencing emergency department (ED) overcrowding, which is a very widespread problem all over the world. On the other hand, out-of-hours (OOH) physicians must avoid delaying the diagnostic and therapeutic course of patients with urgent medical conditions. The aim of this study was to analyse the appropriateness of patient management by OOH services, in terms of their potentially inappropriate referral or non-referral of non-emergency cases to the ED.MethodsThis was an observational retrospective cohort study based on data collected in 2011 by the local health authority No. 4 in the Veneto Region (Italy). After distinguishing between patients contacting the OOH service who were or were not referred to the ED, and checking for patients actually presenting to the ED within 24 hours thereafter, these patients’ medical management was judged as potentially appropriate or inappropriate.ResultsThe analysis considered 22 662 OOH service contacts recorded in 2011. The cases of potentially inappropriate non-referral to the ED were 392 (1.7% of all contacts), as opposed to 1207 potentially inappropriate referrals (5.3% of all contacts). Age, nationality, type of disease and type of intervention by the OOH service were the main variables associated with the appropriateness of patient management.ConclusionsThese findings may be useful for pinpointing the factors associated with a potentially inappropriate patient management by OOH services and thus contribute to improving the deployment of healthcare and the quality of care delivered by OOH services.
Incidence and risk factors for gastrointestinal bleeding among patients admitted to medical intensive care units
Authors: Kumar Shria , Ramos Christopher , Garcia-Carrasquillo Reuben J , Green Peter H , Lebwohl Benjamin 
Published: August 2016

ObjectivesTo identify incidence and risk factors for new-onset gastrointestinal bleeding (GIB) in a medical intensive care unit (ICU), a topic for which there is a paucity of recent studies.DesignRetrospective cohort study.SettingMedical ICUs at our tertiary-care hospital, from 2007 to 2013.PatientsPatients who developed clinically significant GIB after entering the ICU.InterventionsUnivariable and multivariable analyses.Main outcome measuresIncidence and risk factors for development of GIB.Results4439 patients entered the medical ICU without a pre-existing GIB and 58 (1.3%) developed GIB while in the ICU. Risk factors included length of ICU stay (OR per additional day 1. 06; 95% CI 1.04 to 1.09) and elevated creatinine on ICU admission (OR 2.35; 95% CI 1.18 to 4.68, p=0.02). Elevated bilirubin on ICU admission (OR 2.08; 95% CI 0.97 to 4.47, p=0.06), and elevated aspartate transaminase (AST) on ICU admission (OR 2.20; 95% CI 0.96 to 5.03, p=0.06) trended towards increased risk of GIB that did not meet statistical significance. Age, gender, admission coagulation studies and mechanical ventilation were not predictive of GIB. Among those patients with new-onset GIB in the ICU, 47% died during that hospitalisation, as compared with those 30% of those without a GIB, p<0.01.ConclusionsOnset of GIB is now an infrequent occurrence in the ICU setting; however those with elevated bilirubin, AST and creatinine upon admission, and with longer length of ICU stay appear at increased risk and may benefit from closer monitoring.
Evidence from randomised controlled trials does not support current dietary fat guidelines: a systematic review and meta-analysis
Authors: Harcombe Zoë , Baker Julien S , DiNicolantonio James J , Grace Fergal , Davies Bruce 
Published: August 2016

ObjectivesNational dietary guidelines were introduced in 1977 and 1983, by the USA and UK governments, respectively, with the ambition of reducing coronary heart disease (CHD) mortality by reducing dietary fat intake. A recent systematic review and meta-analysis by the present authors, examining the randomised controlled trial (RCT) evidence available to the dietary committees during those time periods, found no support for the recommendations to restrict dietary fat. The present investigation extends our work by re-examining the totality of RCT evidence relating to the current dietary fat guidelines.MethodsA systematic review and meta-analysis of RCTs currently available, which examined the relationship between dietary fat, serum cholesterol and the development of CHD, was undertaken.ResultsThe systematic review included 62 421 participants in 10 dietary trials: 7 secondary prevention studies, 1 primary prevention and 2 combined. The death rates for all-cause mortality were 6.45% and 6.06% in the intervention and control groups, respectively. The risk ratio (RR) from meta-analysis was 0.991 (95% CI 0.935 to 1.051). The death rates for CHD mortality were 2.16% and 1.80% in the intervention and control groups, respectively. The RR was 0.976 (95% CI 0.878 to 1.084). Mean serum cholesterol levels decreased in all intervention groups and all but one control group. The reductions in mean serum cholesterol levels were significantly greater in the intervention groups; this did not result in significant differences in CHD or all-cause mortality.ConclusionsThe current available evidence found no significant difference in all-cause mortality or CHD mortality, resulting from the dietary fat interventions. RCT evidence currently available does not support the current dietary fat guidelines. The evidence per se lacks generalisability for population-wide guidelines.
Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells
Authors: Gabai Vladimir L. , Yaglom Julia A. , Wang Yongmei , Meng Le , Shao Hao , Kim Geunwon , Colvin Teresa , Gestwicki Jason , Sherman Michael Y. 
Published: August 2016

Abstract
The stress-induced chaperone protein Hsp70 enables the initiation and progression of many cancers, making it an appealing therapeutic target for development. Here, we show that cancer cells resistant to Hsp70 inhibitors in vitro remain sensitive to them in vivo, revealing the pathogenic significance of Hsp70 in tumor stromal cells rather than tumor cells as widely presumed. Using transgenic mouse models of cancer, we found that expression of Hsp70 in host stromal cells was essential to support tumor growth. Furthermore, genetic ablation or pharmacologic inhibition of Hsp70 suppressed tumor infiltration by macrophages needed to enable tumor growth. Overall, our results illustrate how Hsp70 inhibitors mediate the anticancer effects by targeting both tumor cells and tumor stromal cells, with implications for the broad use of these inhibitors as tools to ablate tumor-associated macrophages that enable malignant progression. Cancer Res; 76(20); 5926–32. ©2016 AACR.
A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia
Authors: Gojo Ivana , Beumer Jan H. , Pratz Keith W. , McDevitt Michael A. , Baer Maria R. , Blackford Amanda L. , Smith B. Douglas , Gore Steven D. , Carraway Hetty E. , Showel Margaret M. , Levis Mark J. , Dezern Amy E. , Gladstone Douglas E. , Ji Jiuping Jay , Wang Lihua , Kinders Robert J. , Pouquet Marie , Ali-Walbi Ismail , Rudek Michelle A. , Poh Weijie , Herman James G. , Karnitz Larry M. , Kaufmann Scott H. , Chen Alice , Karp Judith E. 
Published: August 2016

Abstract
Purpose: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies.
Experimental Design: Patients received veliparib [20–200 mg once a day on day 1 and twice daily on days 4–12 in cycle 1 (days 1–8 in cycle ≥2)] and temozolomide [150–200 mg/m2 daily on days 3–9 in cycle 1 (days 1–5 in cycle ≥2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined.
Results: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting &gt;7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR.
Conclusions: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted. Clin Cancer Res; 23(3); 697–706. ©2016 AACR.
Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure
Authors: Zhang Zhiyuan , Mu Yongxin , Veevers Jennifer , Peter Angela K. , Manso Ana Maria , Bradford William H. , Dalton Nancy D. , Peterson Kirk L. , Knowlton Kirk U. , Ross Robert S. , Zhou Xinmin , Chen Ju 
Published: August 2016

Background—

The striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin β cytoplasmic tail to promote integrin activation. Genetic deficiency of Kindlin-2 results in embryonic lethality, and knockdown of the Kindlin-2 homolog in
Caenorhabditis elegans
and
Danio rerio
suggests that it has an essential role in integrin function and normal muscle structure and function. The precise role of Kindlin-2 in the mammalian cardiac myocyte remains to be determined.

Methods and Results—
The current studies were designed to investigate the role of Kindlin-2 in the mammalian heart. We generated a series of cardiac myocyte–specific Kindlin-2 knockout mice with excision of the Kindlin-2 gene in either developing or adult cardiac myocytes. We found that mice lacking Kindlin-2 in the early developing heart are embryonic lethal. We demonstrate that deletion of Kindlin-2 at late gestation or in adult cardiac myocytes resulted in heart failure and premature death, which were associated with enlargement of the heart and extensive fibrosis. In addition, integrin β1D protein expression was significantly downregulated in the adult heart.

Conclusions—
Kindlin-2 is required to maintain integrin β1D protein stability. Postnatal loss of Kindlin-2 from cardiac myocytes leads to progressive heart failure, showing the importance of costameric proteins like Kindlin-2 for homeostasis of normal heart function.
Moderate Physical Activity in Healthy Adults Is Associated With Cardiac Remodeling
Authors: Dawes Timothy J.W. , Corden Ben , Cotter Sorcha , de Marvao Antonio , Walsh Roddy , Ware James S. , Cook Stuart A. , O’Regan Declan P. 
Published: August 2016

Background—
Cardiac mass and volumes are often elevated in athletes, but it is not known whether moderate physical activity is also associated with cardiac dilatation and hypertrophy in a healthy adult population.

Methods and Results—

In total, 1096 adults (54% female, median age 39 years) without cardiovascular disease or cardiomyopathy-associated genetic variants underwent cardiac magnetic resonance imaging to determine biventricular volumes and function. Physical activity was assessed using a validated activity questionnaire. The relationship between cardiac parameters and activity was assessed using multiple linear regression adjusting for age, sex, race, and systolic blood pressure. Logistic regression was performed to determine the effect of activity on the likelihood of subjects having cardiac dilatation or hypertrophy according to standard cardiac magnetic resonance normal ranges. Increasing physical activity was associated with greater left ventricular (LV) mass (β=0.23;
P
<0.0001) and elevated LV and right ventricular volumes (LV: β=0.26,
P
<0.0001; right ventricular: β=0.26,
P
<0.0001). Physical activity had a larger effect on cardiac parameters than systolic blood pressure (0.06≤β≤0.21) and a similar effect to age (−0.20≤β≤−0.31). Increasing physical activity was a risk factor for meeting imaging criteria for LV hypertrophy (adjusted odds ratio 2.1;
P
<0.0001), LV dilatation (adjusted odds ratio 2.2;
P
<0.0001), and right ventricular dilatation (adjusted odds ratio 2.2;
P
<0.0001).

Conclusions—
Exercise-related cardiac remodeling is not confined to athletes, and there is a risk of overdiagnosing cardiac dilatation or hypertrophy in a proportion of active, healthy adults.