bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin
Authors: Zasowski Evan J. , Murray Kyle P. , Trinh Trang D. , Finch Natalie A. , Pogue Jason M. , Mynatt Ryan P. , Rybak Michael J. 
Published: October 2017

ABSTRACT

Evidence supports vancomycin therapeutic-drug monitoring by area under the concentration-time curve (AUC), but data to establish an AUC upper limit are limited and published nephrotoxicity thresholds range widely. The objective of this analysis was to examine the association between initial vancomycin AUC and nephrotoxicity. This was a multicenter, retrospective cohort study of adult patients receiving intravenous vancomycin from 2014 to 2015. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/liter and 50% from baseline on consecutive measurements. Vancomycin exposure profile during the initial 48 h of therapy was estimated using maximum
a posteriori
probability Bayesian estimation. Vancomycin AUC and minimum-concentration (
C
min
) thresholds most strongly associated with nephrotoxicity were identified via classification and regression tree (CART) analysis. Predictive performances of CART-derived and other candidate AUC thresholds was assessed through positive and negative predictive value and receiver operating characteristic curves. Poisson regression was used to quantify the association between exposure thresholds and nephrotoxicity while adjusting for confounders. Among 323 patients included, nephrotoxicity was significantly higher in patients with AUCs from 0 to 48 h (AUC
0–48
) of ≥1,218 mg · h/liter, AUC
0–24
of ≥677 mg · h/liter, AUC
24–48
of ≥683 mg · h/liter, and day 1
C
min
(
C
min24
) of ≥18.8 mg/liter. Vancomycin exposure in excess of these thresholds was associated with a 3- to 4-fold-increased risk of nephrotoxicity in Poisson regression. The predictive performance of AUC for nephrotoxicity was maximized at daily AUC values between 600 and 800 mg · h/liter. Although these data support an AUC range for vancomycin-associated nephrotoxity rather than a single threshold, available evidence suggests that a daily AUC limit of 700 mg · h/liter is reasonable.
Detection of
Mycobacterium tuberculosis pncA
Mutations by the Nipro Genoscholar PZA-TB II Assay Compared to Conventional Sequencing
Authors: Willby Melisa J. , Wijkander Maria , Havumaki Joshua , Johnson Kartee , Werngren Jim , Hoffner Sven , Denkinger Claudia M. , Posey James E. 
Published: October 2017

ABSTRACT

Pyrazinamide (PZA) is a standard component of first-line treatment regimens for
Mycobacterium tuberculosis
and is included in treatment regimens for drug-resistant
M. tuberculosis
whenever possible. Therefore, it is imperative that susceptibility to PZA be assessed reliably prior to the initiation of therapy. Currently available growth-based PZA susceptibility tests are time-consuming, and results can be inconsistent. Molecular tests have been developed for most first-line antituberculosis drugs; however, a commercial molecular test is not yet available for rapid detection of PZA resistance. Recently, a line probe assay, the Nipro Genoscholar PZA-TB II assay, was developed for the detection of mutations within the
pncA
gene, including the promoter region, that are likely to lead to PZA resistance. The sensitivity and specificity of this assay were evaluated by two independent laboratories, using a combined total of 249 strains with mutations in
pncA
or its promoter and 21 strains with wild-type
pncA
. Overall, the assay showed good sensitivity (93.2% [95% confidence interval, 89.3 to 95.8%]) and moderate specificity (91.2% [95% confidence interval, 77.0 to 97.0%]) for the identification of
M. tuberculosis
strains predicted to be resistant to PZA on the basis of the presence of mutations (excluding known PZA-susceptible mutations) in the
pncA
coding region or promoter. The assay shows promise for the molecular prediction of PZA resistance.
Activation of the Innate Immune System by Treponema denticola Periplasmic Flagella through Toll-Like Receptor 2
Authors: Ruby John , Martin Michael , Passineau Michael J. , Godovikova Valentina , Fenno J. Christopher , Wu Hui 
Published: October 2017

ABSTRACT

Treponema denticola
is an indigenous oral spirochete that inhabits the gingival sulcus or periodontal pocket. Increased numbers of oral treponemes within this environment are associated with localized periodontal inflammation, and they are also part of an anaerobic polymicrobial consortium responsible for endodontic infections. Previous studies have indicated that
T. denticola
stimulates the innate immune system through Toll-like receptor 2 (TLR2); however, the pathogen-associated molecular patterns (PAMPs) responsible for
T. denticola
activation of the innate immune system are currently not well defined. In this study, we investigated the role played by
T. denticola
periplasmic flagella (PF), unique motility organelles of spirochetes, in stimulating an innate immune response. Wild-type
T. denticola
stimulated the production of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-12 by monocytes from human peripheral blood mononuclear cells, while its isogenic nonmotile mutant lacking PF resulted in significantly diminished cytokine stimulation. In addition, highly purified PF were able to dose dependently stimulate cytokine TNF-α, IL-1β, IL-6, IL-10, and IL-12 production in human monocytes. Wild-type
T. denticola
and the purified PF triggered activation of NF-κB through TLR2, as determined using a variety of TLR-transfected human embryonic 293 cell lines, while the PF-deficient mutants lacked the ability to stimulate, and the complemented PF-positive
T. denticola
strain restored the activation. These findings suggest that
T. denticola
stimulates the innate immune system in a TLR2-dependent fashion and that PF are a key bacterial component involved in this process.
Characterization of Mutations That Affect the Nonoxidative Pentose Phosphate Pathway in Sinorhizobium meliloti
Authors: Hawkins Justin P. , Ordonez Patricia A. , Oresnik Ivan J. 
Published: October 2017

ABSTRACT

Sinorhizobium meliloti
is a Gram-negative alphaproteobacterium that can enter into a symbiotic relationship with
Medicago sativa
and
Medicago truncatula
. Previous work determined that a mutation in the
tkt2
gene, which encodes a putative transketolase, could prevent medium acidification associated with a mutant strain unable to metabolize galactose. Since the pentose phosphate pathway in
S. meliloti
is not well studied, strains carrying mutations in either
tkt2
and
tal
, which encodes a putative transaldolase, were characterized. Carbon metabolism phenotypes revealed that both mutants were impaired in growth on erythritol and ribose. This phenotype was more pronounced for the
tkt2
mutant strain, which also displayed auxotrophy for aromatic amino acids. Changes in pentose phosphate pathway metabolite concentrations were also consistent with a mutation in either
tkt2
or
tal
. The concentrations of metabolites in central carbon metabolism were also found to shift dramatically in strains carrying a
tkt2
mutation. While the concentrations of proteins involved in central carbon metabolism did not change significantly under any conditions, the levels of those associated with iron acquisition increased in the wild-type strain with erythritol induction. These proteins were not detected in either mutant, resulting in less observable rhizobactin production in the
tkt2
mutant. While both mutants were impaired in succinoglycan synthesis, only the
tkt2
mutant strain was unable to establish symbiosis with alfalfa. These results suggest that
tkt2
and
tal
play central roles in regulating the carbon flow necessary for carbon metabolism and the establishment of symbiosis.

IMPORTANCE
Sinorhizobium meliloti
is a model organism for the study of plant-microbe interactions and metabolism, especially because it effects nitrogen fixation. The ability to derive the energy necessary for nitrogen fixation is dependent on an organism's ability to metabolize carbon efficiently. The pentose phosphate pathway is central in the interconversion of hexoses and pentoses. This study characterizes the key enzymes of the nonoxidative branch of the pentose phosphate pathway by using defined genetic mutations and shows the effects the mutations have on the metabolite profile and on physiological processes such as the biosynthesis of exopolysaccharide, as well as the ability to regulate iron acquisition.
Increasing admissions to paediatric intensive care units in England and Wales: more than just rising a birth rate
Authors: Davis Peter , Stutchfield Christopher , Evans T Alun , Draper Elizabeth 
Published: October 2017

ObjectiveTo determine the number of individual children admitted to Paediatric Intensive Care Units (PICUs) in England and Wales between 2004 and 2013 and to investigate potential factors for any change over time, including ethnicity.MethodsAnonymised demographic and epidemiological data were extracted from the Paediatric Intensive Care Audit Network (PICANet) database and analysed for all children resident in England and Wales admitted to PICUs of National Health Service (NHS) hospitals in those countries between 2004 and 2013. Population data, including births, were obtained from the Office of National Statistics and analysed. Predicted numbers of children admitted to PICU were compared with actual admissions, averaged over 3-year periods.ResultsIncreasing numbers of individual children were admitted to PICUs in England and Wales between 2004 and 2013. The largest increases were among younger children (0–5 years) and those with primary respiratory or cardiac diagnoses. They were also greatest in regions with the most mothers born overseas. From 2009 onwards, more children were admitted to PICUs than predicted, separate from overall population growth, South Asian ethnicity or requirement for ventilation.ConclusionsAn additional increase in the number of children from England and Wales admitted to PICU from 2009 onwards is not explained by a rising child population or an increased risk of admission among South Asian children. There was no evidence of a reduction in the admission criteria to PICUs. Given healthcare funding in England and Wales, continued increases would present a challenging prospect for both providers and commissioners of these services.
Temporal trends in the cardiorespiratory fitness of children and adolescents representing 19 high-income and upper middle-income countries between 1981 and 2014
Authors: Tomkinson Grant R , Lang Justin J , Tremblay Mark S 
Published: October 2017

ObjectiveTo estimate international and national temporal trends in the cardiorespiratory fitness (CRF) of children and adolescents and to examine relationships between temporal trends in CRF and temporal trends in broad socioeconomic and health-related indicators across countries.MethodsData were obtained from a systematic search of studies that explicitly reported 20 m shuttle run test (a validated measure of CRF) descriptive data on apparently healthy individuals aged 9–17 years. Following the estimation of relative peak oxygen uptake (mL/kg/min) as a measure of CRF, sample-weighted temporal trends were estimated at the country–sex–age level using best-fitting linear or polynomial regression models relating the year of testing to mean CRF. Poststratified population-weighted mean changes in absolute and per cent CRF were estimated. Pearson’s correlations were used to describe the association between linear temporal trends in CRF and linear temporal trends in broad socioeconomic and health-related indicators.ResultsTemporal trends were estimated from 965 264 children and adolescents from 19 high-income and upper middle-income countries between 1981 and 2014, using data from 137 studies. Collectively, there was a moderate decline in CRF of 3.3 mL/kg/min (95% CI −3.5 to −3.1), equivalent to a decline of 7.3% (95% CI −7.8% to −6.7%) over the 33-year time period. This international decline diminished with each decade and stabilised near zero around 2000. The decline was larger for boys than girls and was similar for children and adolescents. Trends also differed in magnitude and direction between countries, with most showing declines. There was a strong negative association between country-specific trends in income inequality (Gini index) and trends in CRF across 18 countries; meaning, countries approaching income equality had more favourable trends in CRF.ConclusionsThere has been a substantial decline in CRF since 1981, which is suggestive of a meaningful decline in population health. However, the international trend in CRF has not followed the anticipated trajectory, diminishing and stabilising with negligible change since 2000. CRF data are needed from children in low-income and middle-income countries to more confidently determine true international trends and determine whether temporal trends are similar to those observed in high-income and upper middle-income countries.
Triage in preventive child healthcare: a prospective cohort study of care use and referral rates for children at risk
Authors: Bezem Janine , Kocken Paul L , Kamphuis Mascha , Theunissen Meinou H C , Buitendijk Simone E , Numans Mattijs E 
Published: October 2017

ObjectivesA novel triage approach to routine assessments was introduced to improve the efficiency of Preventive Child Healthcare (PCH): PCH assistants carried out pre-assessments of all children and sent the children with suspected health problems to follow-up assessments conducted by a physician or nurse. This two-step approach differed from the usual approach, in which physicians or nurses assessed all children. This study was aimed to examine the impact of triage and task shifting on care for children at risk identified by PCH or parents and schools.Design and participantsAn observational prospective cohort design was used, with an analysis of the basic registration data from the preventive health assessments for 1897 children aged 5 to 6, and 10 to 11, years from a sample of 41 schools stratified by socioeconomic status, region of PCH service and urbanisation.SettingA comparison was made between two PCH services in the Netherlands that used the triage approach and two PCH services that provided the usual approach.Main outcome measuresThe primary outcome measures were the referral rates to either additional PCH assessments or external services. The secondary outcome measures were the rates of PCH assessments requested by, for example, parents and schools.ResultsOverall, a higher referral rate to additional PCH assessments was found for the triage approach than for the usual approach (OR 1.3, 95% CI 1.0 to 1.6), mainly in the age group of 5 to 6 years (OR 1.9, 95% CI 1.3 to 2.7). We found a lower rate of referral to external services in the triage approach (OR 0.4, 95% CI 0.3 to 0.7) and a higher referral rate to PCH assessments on request (OR=4.6, 95% CI 3.0 to 7.0).ConclusionsThe triage approach provides extra opportunities to deliver PCH assessments and PCH assessments on request for children at risk. Further research is needed into the cost benefits of the triage approach.
Associations of adiposity measurements with thyroid nodules in Chinese children living in iodine-sufficient areas: an observational study
Authors: Wang Na , Fang Hong , Fu Chaowei , Huang Peixin , Su Meifang , Jiang Feng , Zhao Qi , Chen Yue , Jiang Qingwu 
Published: October 2017

ObjectivesObesity has been found to be associated with an elevated risk of thyroid nodule(s), mainly in adults; however, evidence for this association in children was limited. The objective of this study was to investigate the association of adiposity and thyroid nodule(s) in children living in iodine-sufficiency areas.Setting and participantsWe conducted a cross-sectional study of 1403 Chinese children living in the East Coast of China in 2014.Outcome measuresAnthropometric measures including height, weight and waist and hip circumferences were taken, and body mass index (BMI), body surface area (BSA) and waist–hip ratio (WHR) were then calculated. Thyroid ultrasonography was performed to assess thyroid volume and nodules.ResultsBased on BMI, 255 (18.17%) children were overweight and 174 (12.40%) were obese. Thyroid nodule(s) was detected in 18.46% of all participants and showed little age and sex variations. As compared with normal-weight children, obese children experienced significantly higher risks for solitary (OR 2.07 (95% CI 1.16 to 3.71)) and multiple (OR 1.67 (95% CI 1.03 to 2.70)) thyroid nodules. Similar associations with thyroid nodule(s) were observed with adiposity measured by waist circumference and BSA, but not WHR. There were no notable differences in the associations between children consuming iodised and non-iodised salt.ConclusionsThese findings provide further evidence that childhood obesity is associated with the risk for thyroid nodule(s).
Health-related quality of life in congenital heart disease surgery patients in Pakistan: protocol for a mixed-methods study
Authors: Ladak Laila Akbar , Hasan Babar Sultan , Gullick Janice , Awais Khadija , Abdullah Ahmed , Gallagher Robyn 
Published: October 2017

IntroductionReduced health-related quality of life (HRQOL) has been reported in postoperative patients with congenital heart disease (CHD). However, there is a paucity of data from low-income and middle-income countries (LMIC). Differences in sociodemographics and sociocultural contexts may influence HRQOL. This protocol paper describes a study exploring HRQOL in surgical patients with CHD from a tertiary hospital in Pakistan. The study findings will assist development of strategies to improve HRQOL in a resource-constrained context.Methods and analysisThis prospective, concurrent triangulation, mixed-methods study aims to compare HRQOL of postsurgery patients with CHD with age-matched healthy siblings and to identify HRQOL predictors. A qualitative component aims to further understand HRQOL data by exploring the experiences related to CHD surgery for patients and parents. Participants include patients with CHD (a minimum of n~95) with at least 1-year postsurgery follow-up and no chromosomal abnormality, their parents and age-matched, healthy siblings. PedsQL 4.0 Generic Core Scales, PedsQL Cognitive Functioning Scale and PedsQL 3.0 Cardiac Module will measure HRQOL. Clinical/surgical data will be retrieved from patients’ medical files. Student’s t-test will be used to compare the difference in the means of HRQOL between CHD and siblings. Multiple regression will identify HRQOL predictors. A subsample of enrolled patients (n~20) and parents (n~20) from the quantitative arm will be engaged in semistructured qualitative interviews, which will be analysed using directed content analysis. Anticipated challenges include patient recruitment due to irregular follow-up compliance. Translation of data collection tools to the Urdu language and back-translation of interviews increases the study complexity.Ethics and disseminationEthics approval has been obtained from The Aga Khan University, Pakistan (3737-Ped-ERC-15). Study findings will be published in peer-reviewed journals and presented at national and international conferences.
Comparison of early radiological predictors of outcome in patients with colorectal cancer with unresectable hepatic metastases treated with bevacizumab
Authors: Mazard Thibault , Boonsirikamchai Piyaporn , Overman Michael J , Asran Mohamed A , Choi Haesun , Herron Delise , Eng Cathy , Maru Dipen M , Ychou Marc , Vauthey Jean-Nicolas , Loyer Evelyne M , Kopetz Scott 
Published: October 2017

ObjectiveThe purpose was to validate the prognostic value of an early optimal morphological response on CT in patients treated with bevacizumab-containing chemotherapy for unresectable colorectal cancer liver metastases (CLM). It also evaluated the prognostic value of size-based criteria and the association of optimal morphological response with the receipt of bevacizumab.Design141 patients treated first using bevacizumab and 142 patients from a randomised study evaluating the addition of bevacizumab to oxaliplatin-based chemotherapy were retrospectively analysed. Radiologists evaluated pretreatment and restaging CT scans using morphological response criteria. Responses were also assessed with size-based criteria: Response Evaluation Criteria in Solid Tumors (RECIST), early tumour shrinkage (ETS) and deepness of response (DpR). The ability of each criterion to predict progression-free survival (PFS), overall survival (OS) and postprogression survival (PPS) was determined using a univariate Cox proportional hazards model.ResultsIn both populations, median PFS was significantly longer for patients achieving an optimal morphological response (10.4 vs 6.8 months, p=0.03; and 8.3 vs 4.9 months, p<00001, respectively). Neither RECIST nor ETS responses were associated with a prolonged PFS. Median OS was longer for those with an optimal morphological response but only at second restaging in the first population (n=141, 20.8 vs 12.3 months, p=0.002). DpR but not optimal morphological response was associated with PPS. In the randomised study, an optimal morphological response was 6.2 times more likely among patients receiving bevacizumab (p<0.0001).ConclusionIn patients with unresectable CLM, early morphological response may be a better predictor of PFS than size-based response. The addition of bevacizumab improves morphological response rate.
Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials
Authors: van Eijk Ruben P A , Eijkemans Marinus J C , Ferguson Toby A , Nikolakopoulos Stavros , Veldink Jan H , van den Berg Leonard H 
Published: October 2017

ObjectivesPlasma creatinine is a predictor of survival in amyotrophic lateral sclerosis (ALS). It remains, however, to be established whether it can monitor disease progression and serve as surrogate endpoint in clinical trials.MethodsWe used clinical trial data from three cohorts of clinical trial participants in the LITRA, EMPOWER and PROACT studies. Longitudinal associations between functional decline, muscle strength and survival with plasma creatinine were assessed. Results were translated to trial design in terms of sample size and power.ResultsA total of 13 564 measurements were obtained for 1241 patients. The variability between patients in rate of decline was lower in plasma creatinine than in ALS functional rating scale–Revised (ALSFRS-R; p<0.001). The average rate of decline was faster in the ALSFRS-R, with less between-patient variability at baseline (p<0.001). Plasma creatinine had strong longitudinal correlations with the ALSFRS-R (0.43 (0.39–0.46), p<0.001), muscle strength (0.55 (0.51–0.58), p<0.001) and overall mortality (HR 0.88 (0.86–0.91, p<0.001)). Using plasma creatinine as outcome could reduce the sample size in trials by 21.5% at 18 months. For trials up to 10 months, the ALSFRS-R required a lower sample size.ConclusionsPlasma creatinine is an inexpensive and easily accessible biomarker that exhibits less variability between patients with ALS over time and is predictive for the patient’s functional status, muscle strength and mortality risk. Plasma creatinine may, therefore, increase the power to detect treatment effects and could be incorporated in future ALS clinical trials as potential surrogate outcome.