bluuebunny/crossref_metadata_2025_split huggingface dataset:
O8 Suppressed vancomycin reaction in a patient receiving parenteral corticosteroids
Authors: Mulholland Peter , Heuchan A-M 
Published: June 2019

BackgroundA baby boy, (37 +6 weeks, 3 kg) was admitted on day 1 of life with an ante-natal diagnosis of a right side congenital diaphragmatic hernia (CDH). The patient was commenced on Extra Corporeal Membrane Oxygenation (ECMO), inhaled nitric oxide and parenteral nutrition. Baby was commenced on morphine, midazolam, vecuronium, dopamine, milrinone and adrenaline infusions. In addition to routine empirical antibiotics hydrocortisone at a dose of 2.5 mg/kg four times daily was commenced to treat hypotension. On day 8 a continuous vancomycin infusion was commenced in line with the network protocol.1 Two days later the infusion was stopped after a level of 41 mg/L aws recorded (therapeutic range 15–25 mg/L). Treatment was recommenced at a lower rate and all following levels were within normal limits. On day 20 of life the patient was noted to have a widespread maculopapular erythematous rash which was most florid on the upper chest, feet and hands. The patient was apyrexial but had a persistently raised CRP. A dermatology review was undertaken and the patient was prescribed a total body application of Daktacort cream. The clinical pharmacist also suggested, and prescribed, a one off dose of alimemazine. The following day the rash had become progressively worse and the possibility of a vancomycin reaction was considered. An internet image search showed that the rash was typical of vancomycin. The most common reaction to vancomycin is ‘red man syndrome’2 however this is associated with rapid infusion at a rate greater than 10 mg/min. Patient’s vancomycin rate was equivalent to 2 mg/hour (0.035 mg/minute). Following discussion with microbiology treatment was changed from vancomycin to linezolid.InvestigationsA review of the patient’s medication history showed a total of 11 different continuous drug infusions and six intermittent medicines. It was noted that the hydrocortisone, which had been weaning over a period of 14 days had been discontinued four days prior to the initial presentation of the rash.OutcomeFour days after cessation of the vancomycin infusion the rash had resolved. A yellow Card detailing the reaction was completed. We have since had a second patient with a similar rash appearing two days following cessation of hydrocortisone treatment.DiscussionIn seven years of using continuous vancomycin infusion in neonates we had never encountered this type of reaction in neonates. Given the proximity between the cessation of steroid treatment and the appearance of the rash, together with the rash resolving following cessation of vancomycin treatment it is likely that this was a true reaction to the drug. The possibility of a suppressed ‘red man’ type reaction to vancomycin should be considered in babies receiving concurrent steroid treatment.ReferencesWest of Scotland Neonatal Managed Clinical Networks Drug Monographs. http://www.knowledge.scot.nhs.uk/ (accessed August 2018)Summary of product characteristics – Vancomycin infusion. http://www.medicines.org.uk/ (accessed August 2018)
Relative effectiveness of different forms of exercises for treatment of chronic low back pain: protocol for a systematic review incorporating Bayesian network meta-analysis
Authors: Gao Chengfei , Chen Guanghui , Yang Hui , Hua Zhen , Xu Peng , Wong Mansang , He Chengqi 
Published: June 2019

IntroductionExercise is considered as an effective intervention in the management of patients with chronic low back pain (cLBP). However, the relative effectiveness as well as the hierarchy of exercise interventions have not been well established, although various exercise options are available. Therefore, the present protocol proposes to conduct a network meta-analysis (NMA) aiming to evaluate the effectiveness of different forms of exercise for treatment of cLBP.Methods and analysisMedline, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Central Register of Controlled Trials, and the Physiotherapy Evidence Database will be searched to identify all randomised controlled trials that evaluate the effectiveness of exercise in the treatment of cLBP. There will be no restrictions on date or language. Two authors will screen the literature and extract data independently based on predesigned rules, and evaluate the risk of bias of included studies using the Cochrane Risk of Bias Tool. Disagreements will be resolved through discussion or consultation with a senior reviewer. The primary outcomes of this study will be pain relief and improvement in function or disability for all interventions. Traditional pairwise meta-analysis and Bayesian NMA will be conducted to compare the effectiveness of different exercise interventions. The ranking probabilities for all interventions will be estimated and the hierarchy of each intervention will be summarised as surface under the cumulative ranking curve. The quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation instrument.Ethics and disseminationEthical approval and informed consent are not required since this is a protocol for a meta-analysis with no confidential personal data to be collected. The results of this NMA will be submitted to a peer-reviewed journal for publication.PROSPERO registration numberCRD42018090576.
Conjunctival colonisation and antibiotic resistance of coagulase-negativeStaphylococcusafter cataract surgery: a 6-month longitudinal study at a medical centre in Taiwan
Authors: Kang Eugene Yu-Chuan , Hou Chiun-Ho , Huang Yhu-Chering , Hsiao Ching-Hsi 
Published: June 2019

ObjectiveTo explored 6-month longitudinal changes in conjunctival colonisation and antibiotic resistance profiles of coagulase-negativeStaphylococcus(CNS) after cataract surgery with 1 month tobramycin treatment.DesignProspective cohort study between 1 August 2012, and 31 July 2013.SettingA single medical centre in Taiwan.ParticipantsA total of 128 Taiwanese patients with 46.9% of male participants.InterventionsSamples from the conjunctival sacs of both operation (OP) and non-OP eyes were obtained separately before cataract surgery and at 1, 3 and 6 months after surgery. Tobramycin (0.3%) treatment was applied four times daily for 1 month postoperatively.Main outcome measureIdentification of CNS isolates and their antibiotic susceptibility by using disk diffusion or E-test.ResultsCNS was detected in 24.2% of patients at baseline. During postoperative follow-up, the CNS colonisation rate did not decrease in either eye but showed an increasing trend in the OP eyes at 1 month (p=0.06). The colonisation rate showed no significant difference between the OP and non-OP eyes from baseline to a specific follow-up. We observed a significant increase (p<0.05) in resistance to tobramycin at 1 month and to ciprofloxacin at 3 months in the OP eyes and to trimethoprim/sulfamethoxazole at 1 month and 3 months and to oxacillin at 6 months in the non-OP eyes.ConclusionsDuring the 6-month postoperative follow-up, 0.3% tobramycin administration failed to reduce CNS colonisation but increased resistance to several antibiotics. Postoperative antibiotic treatment may be replaced by other evidence-endorsed prophylactic routines.
Survey on Combinatorial Register Allocation and Instruction Scheduling
Authors: Lozano Roberto Castañeda , Schulte Christian 
Published: June 2019

Register allocation (mapping variables to processor registers or memory) and instruction scheduling (reordering instructions to increase instruction-level parallelism) are essential tasks for generating efficient assembly code in a compiler. In the past three decades, combinatorial optimization has emerged as an alternative to traditional, heuristic algorithms for these two tasks. Combinatorial optimization approaches can deliver optimal solutions according to a model, can precisely capture trade-offs between conflicting decisions, and are more flexible at the expense of increased compilation time.
This article provides an exhaustive literature review and a classification of combinatorial optimization approaches to register allocation and instruction scheduling, with a focus on the techniques that are most applied in this context: integer programming, constraint programming, partitioned Boolean quadratic programming, and enumeration. Researchers in compilers and combinatorial optimization can benefit from identifying developments, trends, and challenges in the area; compiler practitioners may discern opportunities and grasp the potential benefit of applying combinatorial optimization.
CSS Minification via Constraint Solving
Authors: Hague Matthew , Lin Anthony W. , Hong Chih-Duo 
Published: June 2019

Minification is a widely accepted technique that aims at reducing the size of the code transmitted over the web. This article concerns the problem of semantic-preserving minification of Cascading Style Sheets (CSS)—the
de facto
language for styling web documents—based on merging similar rules.

The cascading nature of CSS makes the semantics of CSS files sensitive to the ordering of rules in the file. To automatically identify rule-merging opportunities that best minimise file size, we reduce the rule-merging problem to a problem concerning “CSS-graphs,” i.e., node-weighted bipartite graphs with a dependency ordering on the edges, where weights capture the number of characters.
Constraint solving plays a key role in our approach. Transforming a CSS file into a CSS-graph problem requires us to extract the dependency ordering on the edges (an NP-hard problem), which requires us to solve the selector intersection problem. To this end, we provide the first full formalisation of CSS3 selectors (the most stable version of CSS) and reduce their selector intersection problem to satisfiability of quantifier-free integer linear arithmetic, for which highly optimised SMT-solvers are available. To solve the above NP-hard graph optimisation problem, we show how Max-SAT solvers can be effectively employed. We have implemented our rule-merging algorithm and tested it against approximately 70 real-world examples (including examples from each of the top 20 most popular websites). We also used our benchmarks to compare our tool against six well-known minifiers (which implement other optimisations). Our experiments suggest that our tool produced larger savings. A substantially better minification rate was shown when our tool is used together with these minifiers.
Deoxycholic acid activates colonic afferent nerves via 5-HT3 receptor-dependent and -independent mechanisms
Authors: Yu Yang , Villalobos-Hernandez Egina C. , Pradhananga Sabindra , Baker Corey C. , Keating Christopher , Grundy David , Lomax Alan E. , Reed David E. 
Published: June 2019

Increased bile acids in the colon can evoke increased epithelial secretion resulting in diarrhea, but little is known about whether colonic bile acids contribute to abdominal pain. This study aimed to investigate the mechanisms underlying activation of colonic extrinsic afferent nerves and their neuronal cell bodies by a major secondary bile acid, deoxycholic acid (DCA). All experiments were performed on male C57BL/6 mice. Afferent sensitivity was evaluated using in vitro extracellular recordings from mesenteric nerves in the proximal colon (innervated by vagal and spinal afferents) and distal colon (spinal afferents only). Neuronal excitability of cultured dorsal root ganglion (DRG) and nodose ganglion (NG) neurons was examined with perforated patch clamp. Colonic 5-HT release was assessed using ELISA, and 5-HT immunoreactive enterochromaffin (EC) cells were quantified. Intraluminal DCA increased afferent nerve firing rate concentration dependently in both proximal and distal colon. This DCA-elicited increase was significantly inhibited by a 5-HT3 antagonist in the proximal colon but not in the distal colon, which may be in part due to lower 5-HT immunoreactive EC cell density and lower 5-HT levels in the distal colon following DCA stimulation. DCA increased the excitability of DRG neurons, whereas it decreased the excitability of NG neurons. DCA potentiated mechanosensitivity of high-threshold spinal afferents independent of 5-HT release. Together, this study suggests that DCA can excite colonic afferents via direct and indirect mechanisms but the predominant mechanism may differ between vagal and spinal afferents. Furthermore, DCA increased mechanosensitivity of high-threshold spinal afferents and may be a mechanism of visceral hypersensitivity. NEW & NOTEWORTHY Deoxycholic acid (DCA) directly excites spinal afferents and, to a lesser extent, indirectly via mucosal 5-HT release. DCA potentiates mechanosensitivity of high-threshold spinal afferents independent of 5-HT release. DCA increases vagal afferent firing in proximal colon via 5-HT release but directly inhibits the excitability of their cell bodies.
Portal hyperperfusion after major liver resection and associated sinusoidal damage is a therapeutic target to protect the remnant liver
Authors: Kohler Andreas , Moller Per W. , Frey Sabrina , Tinguely Pascale , Candinas Daniel , Obrist Dominik , Jakob Stephan M. , Beldi Guido 
Published: June 2019

Extended liver resection results in loss of a large fraction of the hepatic vascular bed, thereby causing abrupt alterations in perfusion of the remnant liver. Mechanisms of hemodynamic adaptation and associated changes in oxygen metabolism after liver resection and the effect of mechanical portal blood flow reduction were assessed. A pig model ( n = 16) of extended partial hepatectomy was established that included continuous observation for 24 h under general anesthesia. Pigs were randomly separated into two groups, one with a portal flow reduction of 70% compared with preoperative values, and the other as a control ( n = 8, each). In controls, portal flow [mean (SD)] increased from 74 (8) mL·min−1·100 g−1 preoperatively to 240 (48) mL·min−1·100 g−1 at 6 h after resection ( P < 0.001). Hepatic arterial buffer response was abolished after resection. Oxygen uptake per unit liver mass increased from 4.0 (1.1) mL·min−1·100 g−1 preoperatively to 7.7 (1.7) mL·min−1·100 g−1 8 h after resection ( P = 0.004). Despite this increase in relative oxygen uptake, total hepatic oxygen consumption (V̇o2) was not maintained, and markers of hypoxia and anaerobic metabolism were significantly increased in hepatocytes after resection. Reduced postoperative portal flow was associated with significantly decreased levels of aspartate aminotransferase and bilirubin and increased hepatic clearance of indocyanine green. In conclusion, major liver resection was associated with persistent portal hyperperfusion, loss of the hepatic arterial buffer response, decreased total hepatic V̇o2 and with increased anaerobic metabolism. Portal flow modulation by partial portal vein occlusion attenuated liver injury after extended liver resection. NEW & NOTEWORTHY Because of continuous monitoring, the experiments allow precise observation of the influence of liver resection on systemic and local abdominal hemodynamic alterations and oxygen metabolism. Major liver resection is associated with significant and persistent portal hyperperfusion and loss of hepatic arterial buffer response. The correlation of portal hyperperfusion and parameters of liver injury and dysfunction offers a novel therapeutic option to attenuate liver injury after extended liver resection.
Pairing vagus nerve stimulation with tones drives plasticity across the auditory pathway
Authors: Borland Michael S. , Vrana Will A. , Moreno Nicole A. , Fogarty Elizabeth A. , Buell Elizabeth P. , Vanneste Sven , Kilgard Michael P. , Engineer Crystal T. 
Published: June 2019

Previous studies have demonstrated that pairing vagus nerve stimulation (VNS) with sounds can enhance the primary auditory cortex (A1) response to the paired sound. The neural response to sounds following VNS-sound pairing in other subcortical and cortical auditory fields has not been documented. We predicted that VNS-tone pairing would increase neural responses to the paired tone frequency across the auditory pathway. In this study, we paired VNS with the presentation of a 9-kHz tone 300 times a day for 20 days. We recorded neural responses to tones from 2,950 sites in the inferior colliculus (IC), A1, anterior auditory field (AAF), and posterior auditory field (PAF) 24 h after the last pairing session in anesthetized rats. We found that VNS-tone pairing increased the percentage of IC, A1, AAF, and PAF that responds to the paired tone frequency. Across all tested auditory fields, the response strength to tones was strengthened in VNS-tone paired rats compared with control rats. VNS-tone pairing reduced spontaneous activity, frequency selectivity, and response threshold across the auditory pathway. This is the first study to document both cortical and subcortical plasticity following VNS-sound pairing. Our findings suggest that VNS paired with sound presentation is an effective method to enhance auditory processing. NEW & NOTEWORTHY Previous studies have reported primary auditory cortex plasticity following vagus nerve stimulation (VNS) paired with a sound. This study extends previous findings by documenting that fields across the auditory pathway are altered by VNS-tone pairing. VNS-tone pairing increases the percentage of each field that responds to the paired tone frequency. This is the first study to document both cortical and subcortical plasticity following VNS-sound pairing.
A Phase I Dose Escalation Study of Once-Weekly Oral Administration of Docetaxel as ModraDoc001 Capsule or ModraDoc006 Tablet in Combination with Ritonavir
Authors: de Weger Vincent A. , Stuurman Frederik E. , Koolen Stijn L.W. , Moes Johannes J. , Hendrikx Jeroen J.M.A. , Sawicki Emilia , Thijssen Bas , Keessen Marianne , Rosing Hilde , Mergui-Roelvink Marja , Huitema Alwin D.R. , Nuijen Bastiaan , Beijnen Jos H. , Schellens Jan H.M. , Marchetti Serena 
Published: June 2019

Abstract

Purpose:
Oral bioavailability of docetaxel is poor. Absorption could be improved by development of pharmaceutical formulations based on docetaxel solid dispersions, denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg) and coadministration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. In this study, the safety, MTD, recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of oral docetaxel combined with ritonavir in a once-weekly continuous schedule was investigated.

Patients and Methods:
Patients with metastatic solid tumors were included. Dose escalation was performed using a classical 3+3 design. Pharmacokinetic sampling was performed for up to 48 hours after drug administration. Safety was evaluated using CTCAE v3.0. Antitumor activity was assessed according to RECIST v1.0.

Results:
Sixty-seven patients were treated at weekly docetaxel dosages ranging from 30 to 80 mg in combination with 100- or 200-mg ritonavir. Most common toxicities were nausea, vomiting, diarrhea and fatigue, mostly of grade 1–2 severity. No hypersensitivity reactions were observed. The area under the plasma concentration–time curve (AUC0–48) of docetaxel at the RP2D of once-weekly 60-mg ModraDoc001 capsule with 100-mg ritonavir was 1,000 ± 687 ng/mL/hour and for once-weekly 60-mg ModraDoc006 tablet with 100-mg ritonavir, the AUC0–48 was 1,790 ± 819 ng/mL/hour. Nine partial responses were reported as best response to treatment.

Conclusions:
Oral administration of once-weekly docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir is feasible. The RP2D for both formulations is 60-mg ModraDoc with 100-mg ritonavir. Antitumor activity is considered promising.
PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage
Authors: Zhang Jinfang , Lee Yu-Ru , Dang Fabin , Gan Wenjian , Menon Archita Venugopal , Katon Jesse M. , Hsu Chih-Hung , Asara John M. , Tibarewal Priyanka , Leslie Nicholas R. , Shi Yang , Pandolfi Pier Paolo , Wei Wenyi 
Published: June 2019

Abstract

The function of PTEN in the cytoplasm largely depends on its lipid-phosphatase activity, though which it antagonizes the PI3K–AKT oncogenic pathway. However, molecular mechanisms underlying the role of PTEN in the nucleus remain largely elusive. Here, we report that DNA double-strand breaks (DSB) promote PTEN interaction with MDC1 upon ATM-dependent phosphorylation of T/S398-PTEN. Importantly, DNA DSBs enhance NSD2 (MMSET/WHSC1)-mediated dimethylation of PTEN at K349, which is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA-damage sites, governing efficient repair of DSBs partly through dephosphorylation of γH2AX. Of note, inhibiting NSD2-mediated methylation of PTEN, either through expressing methylation-deficient PTEN mutants or through inhibiting NSD2, sensitizes cancer cells to combinatorial treatment with a PI3K inhibitor and DNA-damaging agents in both cell culture and in vivo xenograft models. Therefore, our study provides a novel molecular mechanism for PTEN regulation of DSB repair in a methylation- and protein phosphatase–dependent manner.

Significance:
NSD2-mediated dimethylation of PTEN is recognized by the 53BP1 tudor domain to facilitate PTEN recruitment into DNA-damage sites, governing efficient repair of DNA DSBs. Importantly, inhibiting PTEN methylation sensitizes cancer cells to combinatorial treatment with a PI3K inhibitor combined with DNA-damaging agents in both cell culture and in vivo xenograft models.
This article is highlighted in the In This Issue feature, p. 1143
Evaluation of Beta 2-Microglobulin, Cystatin C, and Lipocalin-2 as Renal Biomarkers for Patients with Fabry Disease
Authors: Braga Marion Coting , Fonseca Fernando Luiz Affonso , Marins Maryana Mara , Gomes Caio Perez , Bacci Marcelo Rodrigues , Martins Ana Maria , D’Almeida Vânia 
Published: June 2019

<b><i>Background:</i></b> Since renal failure is one of the main causes of death in patients with Fabry disease (FD), renal follow-up is an important part of clinical monitoring in these patients. Despite its known limitations, serum creatinine is still the most widely used biomarker. While new renal biomarkers are described, their effectiveness has not yet been fully evaluated in relation to FD. <b><i>Objectives:</i></b> This study aimed to compare renal biomarkers commonly and rarely used in the evaluation of FD patients. <b><i>Method:</i></b> The usual biomarkers for renal monitoring (microalbuminuria, proteinuria, and creatinine) and some more rarely used (cystatin C, beta 2-microglobulin [β2M], neutrophil gelatinase-associated lipocalin/lipocalin-2) were quantified in the blood and/or urine samples of 40 FD patients, 39 controls without chronic kidney disease (CKD) paired by age and sex and 38 controls with CKD undergoing hemodialysis. <b><i>Results:</i></b> Significant statistical differences (<i>p</i> &#x3c; 0.05) were observed for cystatin C and lipocalin-2 in plasma levels, for β2M and serum creatinine levels and by estimated glomerular filtration rate when compared FD patients and control group with CKD and for proteinuria and microalbuminuria in urine samples and for lipocalin-2 in plasma levels when compared FD patients and control group without CKD. Urine creatinine (UCreat), pH, and urine specific gravity did not present a significant statistical difference between groups. <b><i>Conclusion:</i></b> Considering serum creatinine as gold standard, all renal parameters evaluated, including receiver operating characteristic curve, indicated β2M as the best biomarker, followed by cystatin C, proteinuria and microalbuminuria, while the results for lipocalin-2 and UCreat do not indicate good predictors of renal impairment. It suggests that at least 2 altered biomarkers should be considered to characterize a renal alteration, thereby establishing a better therapeutic course for FD patients. If possible, along with serum creatinine, measurement of β2M or cystatin C for renal evaluation of Fabry’s patients should be considered.