bluuebunny/crossref_metadata_2025 huggingface dataset:
Reproducing an Early-20th-Century Wave Machine
Authors: Daffron John A. , Greenslade Thomas B.
Published: August 2016

Physics students often have problems understanding waves. Over the years numerous mechanical devices have been devised to show the propagation of both transverse and longitudinal waves (Ref. 1). In this article an updated version of an early-20th-century transverse wave machine is discussed. The original, Fig. 1, is at Creighton University in Omaha, NE. The new version, by the authors, is shown in Fig. 2. It was designed in such a way that it can be built relatively easily. Sliders that rest on a rotating helical rail move up and down in approximate simple harmonic motion. When the helix is at rest, the tops of the sliders form a good approximation to a sine wave. In the original, the sliders are double-ended knitting needles, and the handle was taken from an earlier piece of apparatus.
Of mice and microbes
Authors: Servick Kelly
Published: August 2016

The zoo of bacteria and viruses each lab animal harbors may confound experiments.
Reverse osmosis molecular differentiation of organic liquids using carbon molecular sieve membranes
Authors: Koh Dong-Yeun , McCool Benjamin A. , Deckman Harry W. , Lively Ryan P.
Published: August 2016

Carbon sieving to separate the similar

Separating organic molecules, particularly those with almost equal sizes and similar physical properties, can be challenging and may require energy-intensive techniques such as freeze fractionation. Taking inspiration from reverse osmosis of aqueous fluids, Koh
et al.
describe the synthesis, characterization, and mass transport performance of carbon molecular sieve membranes for the separation of liquid-phase organic molecules at room temperature. This technique is capable of separating very similar isomers, such as
ortho
- and
para
-xylene, on an industrial scale.

Science
, this issue p.
804
Northward migration of the eastern Himalayan syntaxis revealed by OSL thermochronometry
Authors: King Georgina E. , Herman Frédéric , Guralnik Benny
Published: August 2016

Unlinking erosion from uplift in Tibet

Conventional wisdom suggests that the locations of gorges or “knickpoints” along the edges of large plateaus remain fixed because erosion drives tectonic uplift. Nowhere should this be more evident than the rapidly uplifting and eroding Tibetan plateau. However, King
et al.
found evidence for slow migration of a major knickpoint along the Parlung River in eastern Tibet. They used a new method with exceptional time resolution for determining regional cooling rates called multi–OSL (optically stimulated luminescence) thermochronology. It appears that the Parlung knickpoint is steadily moving upstream as a response to tectonic uplift that is unrelated to the local erosion rates.

Science
, this issue p.
800
Design, synthesis, and testing toward a 57-codon genome
Authors: Ostrov Nili , Landon Matthieu , Guell Marc , Kuznetsov Gleb , Teramoto Jun , Cervantes Natalie , Zhou Minerva , Singh Kerry , Napolitano Michael G. , Moosburner Mark , Shrock Ellen , Pruitt Benjamin W. , Conway Nicholas , Goodman Daniel B. , Gardner Cameron L. , Tyree Gary , Gonzales Alexandra , Wanner Barry L. , Norville Julie E. , Lajoie Marc J. , Church George M.
Published: August 2016

Recoding and repurposing genetic codons

By recoding bacterial genomes, it is possible to create organisms that can potentially synthesize products not commonly found in nature. By systematic replacement of seven codons with synonymous alternatives for all protein-coding genes, Ostrov
et al.
recoded the
Escherichia coli
genome. The number of codons in the
E. coli
genetic code was reduced from 64 to 57 by removing instances of the UAG stop codon and excising two arginine codons, two leucine codons, and two serine codons. Over 90% functionality was successfully retained. In 10 cases, reconstructed bacteria were not viable, but these few failures offered interesting insights into genome-design challenges and what is needed for a viable genome.

Science
, this issue p.
819
Coordinative alignment of molecules in chiral metal-organic frameworks
Authors: Lee Seungkyu , Kapustin Eugene A. , Yaghi Omar M.
Published: August 2016

Stop wiggling and hold that pose

X-ray crystallography can be the definitive method for determining the structure and chirality of small organic molecules, but orientational disorder in the crystal can limit its resolution. Lee
et al.
used a chiral metal-organic framework containing formate ligands that can bind and align molecules covalently to reduce this motion (see the Perspective by Öhrström). The structure and absolute configuration—i.e., which spatial arrangement of atoms is the
R
or
S
isomer—of several organic molecules can thus be measured. These range from small molecules, such as methanol, to complex plant hormones, such as gibberellins that have eight stereocenters or jasmonic acid, whose absolute configuration had not previously been directly established.

Science
, this issue p.
808
; see also p.
754
Diagnostics for Zika virus on the horizon
Authors: Speer Scott D. , Pierson Theodore C.
Published: August 2016

The immune response to Zika virus informs antibody-based diagnostics and therapeutics
Progress lies in precision
Authors: Desmond-Hellmann Sue
Published: August 2016

Too often, I feel as though I live in two worlds. One is populated by scientists working on advanced tools, such as big data, sequencing, and data-based disease surveillance. The other is populated by public health professionals working on the demanding challenges of combating infectious diseases, empowering women and girls, and ensuring that more children survive and thrive. If we want to achieve the ambitions set out by the United Nations for global health and development by 2030, we need to bring these two worlds closer together through a new concept—precision public health.
Multivalent and Multipathogen Viral Vector Vaccines
Authors: Lauer Katharina B. , Borrow Ray , Blanchard Thomas J.
Published: August 2016

The presentation and delivery of antigens are crucial for inducing immunity and, desirably, lifelong protection. Recombinant viral vectors—proven safe and successful in veterinary vaccine applications—are ideal shuttles to deliver foreign proteins to induce an immune response with protective antibody levels by mimicking natural infection. Some examples of viral vectors are adenoviruses, measles virus, or poxviruses. The required attributes to qualify as a vaccine vector are as follows: stable insertion of coding sequences into the genome, induction of a protective immune response, a proven safety record, and the potential for large-scale production. The need to develop new vaccines for infectious diseases, increase vaccine accessibility, reduce health costs, and simplify overloaded immunization schedules has driven the idea to combine antigens from the same or various pathogens. To protect effectively, some vaccines require multiple antigens of one pathogen or different pathogen serotypes/serogroups in combination (multivalent or polyvalent vaccines). Future multivalent vaccine candidates are likely to be required for complex diseases like malaria and HIV. Other novel strategies propose an antigen combination of different pathogens to protect against several diseases at once (multidisease or multipathogen vaccines).
Complete Genome Sequence of
Brachyspira hyodysenteriae
Type Strain B-78 (ATCC 27164)
Authors: Mirajkar Nandita S. , Johnson Timothy J. , Gebhart Connie J.
Published: August 2016

Reported herein is the complete genome sequence of the type strain B-78 (ATCC 27164) of
Brachyspira hyodysenteriae
, the etiological agent of swine dysentery. The 3.1-Mb genome consists of a 3.056-Mb chromosome and a 45-kb plasmid, with 2,617 protein-coding genes, 39 RNA genes, and 40 pseudogenes.
Rapid Identification of OXA-48 and OXA-163 Subfamilies in Carbapenem-Resistant Gram-Negative Bacilli with a Novel Immunochromatographic Lateral Flow Assay
Authors: Pasteran Fernando , Denorme Laurence , Ote Isabelle , Gomez Sonia , De Belder Denise , Glupczynski Youri , Bogaerts Pierre , Ghiglione Barbara , Power Pablo , Mertens Pascal , Corso Alejandra
Published: August 2016

We assessed a novel immunochromatographic lateral flow assay for direct identification of OXA-48-like carbapenemases and accurate differentiation of allele variants with distinct substrate profiles (OXA-48 or OXA-163 subfamilies). The assay allowed rapid (less than 4 min) and reliable direct confirmation of OXA-163- and/or OXA-48-like enzymes (with 100% sensitivity and 100% specificity) from cultured colonies that were recovered from both solid medium and spiked blood culture bottles.
Drone Transport of Microbes in Blood and Sputum Laboratory Specimens
Authors: Amukele Timothy K. , Street Jeff , Carroll Karen , Miller Heather , Zhang Sean X.
Published: August 2016

Unmanned aerial vehicles (UAVs) could potentially be used to transport microbiological specimens. To examine the impact of UAVs on microbiological specimens, blood and sputum culture specimens were seeded with usual pathogens and flown in a UAV for 30 ± 2 min. Times to recovery, colony counts, morphologies, and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS)-based identifications of the flown and stationary specimens were similar for all microbes studied.
Evaluation of the Aptima HIV-1 Quant Dx Assay Using Plasma and Dried Blood Spots
Authors: Sahoo Malaya K. , Varghese Vici , White Elizabeth , Winslow Meg , Katzenstein David A. , Shafer Robert W. , Pinsky Benjamin A.
Published: August 2016

HIV-1 RNA quantitation in plasma, or virus load testing, is the primary method by which the response to antiretroviral therapy is monitored. Here we describe evaluation of the Aptima HIV-1 Quant Dx assay (Aptima) performed on the automated Panther system. The clinical performance of Aptima was compared to that of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test v2.0 (CAP/CTM) using 162 EDTA plasma samples collected from patients undergoing HIV-1 monitoring. Overall agreement was 84.0% (136/162), with a kappa statistic of 0.723 (standard error, 0.047; 95% confidence interval [CI], 0.630 to 0.815), indicating substantial agreement. Using the 86 clinical samples quantifiable by both methods, Passing-Bablok regression revealed a regression line of
Y
= (1.069 ×
X
) − 0.346 (95% CI of the slope [1.003 to 1.139] and intercept [−0.666 to −0.074]), and Bland-Altman analysis demonstrated a mean difference (Aptima-CAP/CTM) of −0.075 log
10
copies/ml (95% limits of agreement of −0.624 to 0.475), consistent with negative bias. Comparison of Aptima results for paired dried blood spot (DBS) and plasma specimens archived from participants in the Peninsula AIDS Research Cohort Study (PARC) demonstrated an overall agreement of 94.7% (90/95) when 1,000 copies/ml was used as the threshold. In conclusion, the Aptima HIV-1 Quant Dx assay provides a suitable alternative for HIV-1 monitoring in plasma and DBS.
Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4
+
T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy
Authors: Liu Bingfeng , Zou Fan , Lu Lijuan , Chen Cancan , He Dalian , Zhang Xu , Tang Xiaoping , Liu Chao , Li Linghua , Zhang Hui
Published: August 2016

Despite the advent of combined antiretroviral therapy (cART), the persistence of viral reservoirs remains a major barrier to curing human immunodeficiency virus type 1 (HIV-1) infection. Recently, the shock and kill strategy, by which such reservoirs are eradicated following reactivation of latent HIV-1 by latency-reversing agents (LRAs), has been extensively practiced. It is important to reestablish virus-specific and reliable immune surveillance to eradicate the reactivated virus-harboring cells. In this report, we attempted to reach this goal by using newly developed chimeric antigen receptor (CAR)-T cell technology. To generate anti-HIV-1 CAR-T cells, we connected the single-chain variable fragment of the broadly neutralizing HIV-1-specific antibody VRC01 to a third-generation CAR moiety as the extracellular and intracellular domains and subsequently transduced this into primary CD8
+
T lymphocytes. We demonstrated that the resulting VC-CAR-T cells induced T cell-mediated cytolysis of cells expressing HIV-1 Env proteins and significantly inhibited HIV-1 rebound after removal of antiviral inhibitors in a viral infectivity model in cell culture that mimics the termination of the cART in the clinic. Importantly, the VC-CAR-T cells also effectively induced the cytolysis of LRA-reactivated HIV-1-infected CD4
+
T lymphocytes isolated from infected individuals receiving suppressive cART. Our data demonstrate that the special features of genetically engineered CAR-T cells make them a particularly suitable candidate for therapeutic application in efforts to reach a functional HIV cure.

IMPORTANCE
The presence of latently infected cells remains a key obstacle to the development of a functional HIV-1 cure. Reactivation of dormant viruses is possible with latency-reversing agents, but the effectiveness of these compounds and the subsequent immune response require optimization if the eradication of HIV-1-infected cells is to be achieved. Here, we describe the use of a chimeric antigen receptor, comprised of T cell activation domains and a broadly neutralizing antibody, VRC01, targeting HIV-1 to treat the infected cells. T cells expressing this construct exerted specific cytotoxic activity against wild-type HIV-1-infected cells, resulting in a dramatic reduction in viral rebound
in vitro
, and showed persistent effectiveness against reactivated latently infected T lymphocytes from HIV-1 patients receiving combined antiretroviral therapy. The methods used in this study constitute an improvement over existing CD4-based CAR-T technology and offer a promising approach to HIV-1 immunotherapy.
Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells
Authors: Schmiedel Dominik , Tai Julie , Levi-Schaffer Francesca , Dovrat Sarah , Mandelboim Ofer
Published: August 2016

TheHerpesviridaefamily consists of eight viruses, most of which infect a majority of the human population. One of the less-studied members is human herpesvirus 6 (HHV-6) (Roseolovirus), which causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by lifelong latency. Reactivation frequently occurs in immunocompromised patients, such as those suffering from HIV infection or cancer or following transplantation, and causes potentially life-threatening complications. In this study, we investigated the mechanisms that HHV-6 utilizes to remain undetected by natural killer (NK) cells, which are key participants in the innate immune response to infections. We revealed viral mechanisms which downregulate ligands for two powerful activating NK cell receptors: ULBP1, ULBP3, and MICB, which trigger NKG2D, and B7-H6, which activates NKp30. Accordingly, this downregulation impaired the ability of NK cells to recognize HHV-6-infected cells. Thus, we describe for the first time immune evasion mechanisms of HHV-6 that protect lytically infected cells from NK elimination.

IMPORTANCEHuman herpesvirus 6 (HHV-6) latently infects a large portion of the human population and can reactivate in humans lacking a functional immune system, such as cancer or AIDS patients. Under these conditions, it can cause life-threatening diseases. To date, the actions and interplay of immune cells, and particularly cells of the innate immune system, during HHV-6 infection are poorly defined. In this study, we aimed to understand how cells undergoing lytic HHV-6 infection interact with natural killer (NK) cells, innate lymphocytes constituting the first line of defense against viral intruders. We show that HHV-6 suppresses the expression of surface proteins that alert the immune cells by triggering two major receptors on NK cells, NKG2D and NKp30. As a consequence, HHV-6 can replicate undetected by the innate immune system and potentially spread infection throughout the body. This study advances the understanding of HHV-6 biology and the measures it uses to successfully escape immune elimination.
Stimulation of the Replication of ICP0-Null Mutant Herpes Simplex Virus 1 and pp71-Deficient Human Cytomegalovirus by Epstein-Barr Virus Tegument Protein BNRF1
Authors: Lu Yongxu , Orr Anne , Everett Roger D.
Published: August 2016

It is now well established that several cellular proteins that are components of promyelocytic leukemia nuclear bodies (PML NBs, also known as ND10) have restrictive effects on herpesvirus infections that are countered by viral proteins that are either present in the virion particle or are expressed during the earliest stages of infection. For example, herpes simplex virus 1 (HSV-1) immediate early (IE) protein ICP0 overcomes the restrictive effects of PML-NB components PML, Sp100, hDaxx, and ATRX while human cytomegalovirus (HCMV) IE protein IE1 targets PML and Sp100, and its tegument protein pp71 targets hDaxx and ATRX. The functions of these viral regulatory proteins are in part interchangeable; thus, both IE1 and pp71 stimulate the replication of ICP0-null mutant HSV-1, while ICP0 increases plaque formation by pp71-deficient HCMV. Here, we extend these studies by examining proteins that are expressed by Epstein-Barr virus (EBV). We report that EBV tegument protein BNRF1, discovered by other investigators to target the hDaxx/ATRX complex, increases the replication of both ICP0-null mutant HSV-1 and pp71-deficient HCMV. In addition, EBV protein EBNA-LP, which targets Sp100, also augments ICP0-null mutant HSV-1 replication. The combination of these two EBV regulatory proteins had a greater effect than each one individually. These findings reinforce the concept that disruption of the functions of PML-NB proteins is important for efficient herpesvirus infections.

IMPORTANCE
Whether a herpesvirus initiates a lytic infection in a host cell or establishes quiescence or latency is influenced by events that occur soon after the viral genome has entered the host cell nucleus. Certain cellular proteins respond in a restrictive manner to the invading pathogen's DNA, while viral functions are expressed that counteract the cell-mediated repression. One aspect of cellular restriction of herpesvirus infections is mediated by components of nuclear structures known as PML nuclear bodies (PML NBs), or ND10. Members of the alpha-, beta-, and gammaherpesvirus families all express proteins that interact with, degrade, or otherwise counteract the inhibitory effects of various PML NB components. Previous work has shown that there is the potential for a functional interchange between the viral proteins expressed by alpha- and betaherpesviruses, despite a lack of obvious sequence similarity. Here, this concept is extended to include a member of the gammaherpesviruses.
The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling
Authors: Varghese Finny S. , Thaa Bastian , Amrun Siti Naqiah , Simarmata Diane , Rausalu Kai , Nyman Tuula A. , Merits Andres , McInerney Gerald M. , Ng Lisa F. P. , Ahola Tero
Published: August 2016

Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a high-throughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH
2
-terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the
in vivo
efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle.

IMPORTANCE
Chikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug
in vivo
. Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections.
Tectonic settings of continental crust formation: Insights from Pb isotopes in feldspar inclusions in zircon
Authors: Delavault Hélène , Dhuime Bruno , Hawkesworth Chris J. , Cawood Peter A. , Marschall Horst ,   and the Edinburgh Ion Microprobe Facility
Published: August 2016

Most crustal rocks derive from preexisting crust, and so the composition of newly generated (juvenile) continental crust, and hence the tectonic settings of its formation, have remained difficult to determine, especially for the first billion years of Earth’s evolution. Modern primitive mantle–derived magmas have distinct U/Pb ratios, depending on whether they are generated in intraplate (mean U/Pb = 0.37) or in subduction settings (mean U/Pb = 0.10). The U/Pb ratio can therefore be used as a proxy for the tectonic settings in which juvenile continental crust is generated. This paper presents a new way to see back to the U/Pb ratios of juvenile continental crust that formed hundreds to thousands of millions of years ago, based on ion probe analysis of Pb isotopes in alkali feldspar and plagioclase inclusions within well-dated zircons. Pb isotope data are used to calculate the time-integrated U/Pb ratios (i.e., 238U/204Pb = µ) for the period between the Hf model age and the U-Pb crystallization age of the zircons. These time-integrated ratios reflect the composition of the juvenile continental crust at the time it was extracted from the mantle, and so they can be used as a proxy for the tectonic setting of formation of that crust. Two test samples with Proterozoic Hf model ages and Paleozoic crystallization ages have feldspar inclusions with measured Pb isotope ratios that overlap within analytical error for each sample. Sample Z7.3.1 from Antarctica has Pb isotope ratios (mean 206Pb/204Pb = 16.88 ± 0.08, 1σ) that indicate it was derived from source rocks with low U/Pb ratios (∼0.11), similar to those found in subduction-related settings. Sample Temora 2 from Australia has more radiogenic Pb isotope ratios (mean 206Pb/204Pb = 19.11 ± 0.23, 1σ) indicative of a source with higher U/Pb ratios (∼0.36), similar to magmas generated in intraplate settings. Analysis of detrital populations with a range of Hf model ages (e.g., Hadean to Phanerozoic), and for which zircons and their inclusions represent the only archive of their parent magmas, should ultimately open new avenues to our understanding of the formation and the evolution of the continental crust through time.
The outcome of antenatal ultrasound diagnosed anomalies of the kidney and urinary tract in a large Danish birth cohort
Authors: Andrés-Jensen Liv , Jørgensen Finn Stener , Thorup Jorgen , Flachs Julie , Madsen Jan Lysgaard , Maroun Lisa Leth , Nørgaard Pernille , Vinicoff Pablo Gustavo , Olsen Beth Härstedt , Cortes Dina
Published: August 2016

Objective

Antenatal ultrasound diagnosed anomalies of the kidney and urinary tract (AUDAKUT) are reported in 0.3%–5% on prenatal ultrasound (US) and 0.3%–4.5% on postnatal US. The anterior-posterior diameter of the renal pelvis (APD) is an essential measurement. Series with low threshold values of APD prenatally and postnatally will include healthy infants. It is important to avoid follow-up of such infants.

Interventions

In 2006, new Danish guidelines for AUDAKUT were introduced.

Aim of study

Investigations of incidences and type of AUDAKUT based on Danish guidelines, including long-term follow-up.

Design

Cohort study.

Setting

Copenhagen University Hospital Hvidovre and Copenhagen University Hospital Rigshospitalet, Denmark.

Patients

Consecutive cases with AUDAKUT in the second and third trimesters, which were either terminated before 22 completed weeks of gestation or born in the 8-year period January 2006–December 2013. Patients were followed until June 2014.

Results

50 193 live born children and 24 terminated fetuses (0.05%) were included. The prevalence of AUDAKUT was only 0.39% prenatally, 0.29% at first postnatal US and 0.22% at the end of follow-up, including terminated cases. The greater the prenatal and postnatal APD, the higher risk of febrile urinary tract infection (fUTI) and surgical intervention, and lower probability of resolution. 25% of the identified patients had fUTI and/or surgery.

Conclusions

We recommend threshold values of APD at least 10 mm in the third trimester and in general at least 12 mm at first postnatal US for intensive follow-up. In this largest to date unselected birth cohort of AUDAKUT, the incidences of clinically significant AUDAKUT were in the lowest range of those previously published.
AN AUDIT OF PAEDIATRIC VANCOMYCIN DOSING
Authors: Mohsin-Shaikh Soomal , Lumb Poonam
Published: August 2016

Aim

To audit whether a new paediatric vancomycin guideline is being adhered to and if therapeutic levels are being achieved.

Method

Data on doses, age, weight, vancomycin levels, time taken and renal function were collected prospectively by reviewing drug charts of paediatric patients on vancomycin. The patients were followed for their whole vancomycin journey in order to observe if the guidelines were followed throughout. Data were collected between 7th and 30th January 2015. The data were analysed using an excel spreadsheet.

Standards

▸ 100% of patients <1 month without renal failure should be prescribed an initial dose of 15 mg/kg three times a day

▸ 100% of patients ≥1 month without renal failure should be prescribed an initial dose of 20 mg/kg three times a day

▸ 100% of patients of all ages with renal impairment (defined as Glomerular filtration rate <50 ml/min) should be prescribed a single dose of 10 mg/kg

▸ 90% of patients should have their vancomycin levels taken at the correct time (pre-third dose)

▸ 80% of the third dose trough levels should be in range (10–15 mg/L)

▸ In 90% of patients with levels out of range, appropriate action should be taken to correct their levels.

Results

Data from 15 patients were collected resulting in 62 vancomycin levels.

Three of six standards were met. Standards 1 and 3 could not be assessed as no patients were under the age of 1 month or had renal impairment. 100% patients were initiated on the correct staring dose meeting standard 2. One patient excluded from this standard as a clinical decision was made to start the patient on a lower starting dose of 15 mg/kg three times a day due to previous high levels. 90% of vancomycin levels had been taken at the correct time (pre-third dose) thus standard 4 was achieved. However there were 6 occasions when the levels were taken post-third dose or taken pre-maturely. These levels were not in range. Only 33% of patients had the initial level within range for standard 5; after a dose change a further 31% were in range.

For standard 6, 93% of actions taken by doctors when the vancomycin levels came back out of range were correct. This standard was achieved.

Conclusion

This audit has shown that the guidelines are being followed but the paediatric dosing of vancomycin requires modification to achieve therapeutic levels. Limitations of the audit included low patient numbers, standard 1 and 3 could not be assessed and an assumption was made that all the levels documented were taken at the correct time, unless stated. Not enough data were collected to make suggestions based on different ages. An option would be to follow recommendation that frequency of dosing is changed from three to four times a day.1 A continuous infusion of vancomycin could also be considered.
THE ROLE OF THE PHARMACIST IN PAEDIATRIC PALLIATIVE CARE
Authors: Khan Jumana , Gaze Sian , Tomlin Stephen
Published: August 2016

Aim

To explore what involvement pharmacists in the UK have in paediatric palliative care

Objectives

1. To determine the current roles and services provided by pharmacists to paediatric palliative care patients.

2. To establish how other members of the multidisciplinary team perceive the pharmacist's role and the extent to which they value the pharmacist's contributions.

3. To identify the references used by the multidisciplinary team to make clinical decisions about medication use in paediatric palliative care patients.

Methods

An online questionnaire was designed and emailed to members of the Neonatal and Paediatric Pharmacist's Group and the Association of Paediatric Palliative Medicine. The questionnaire was also sent by post to selected community pharmacists as palliative care is often provided to children in a community setting. Results were analysed using Microsoft Excel and SPSS version 22.

Results

A response rate of 27% (114/430) was achieved. Pharmacists reported supporting children receiving palliative care by supplying medicines, dealing with medication related enquiries and providing advice to nursing and medical staff on the compatibility and stability of drugs. The pharmacist's contributions were highly valued by other members of the paediatric palliative care team as a median rating of 9 (out of 10) was obtained. The results also showed that differences existed in the references used by pharmacists and other healthcare professionals–the Children's British National Formulary was the most commonly used reference across all disciplnes when caring for children requiring palliative care.

Conclusion

This is one of the first studies to outline the roles of pharmacists working in paediatric palliative care and has highlighted that pharmacists have an important input in the care of these patients.
INHALER COUNSELLING, THE REAL DEAL OR JUST FRESH AIR?
Authors: Goodwin Richard , Chander Tiranvir , Shah Neha , Tomlin Steve
Published: August 2016

Aim

To evaluate whether healthcare professionals within the local community are able to counsel paediatric patients on the essential steps required for drug delivery with multi-dose inhalers (MDI), MDIs with a spacer and turbohalers.

Method

An expert panel produced and piloted checklists for essential and good practice counselling steps. Eligible participants included healthcare professionals regularly counselling children on inhaler devices, including doctors, nurses and pharmacy team members. Participants were recruited through purposive sampling on a general paediatric ward in a major children's hospital over 2 months and local community pharmacies. Participants counselled on each technique through simulated paediatric scenarios and were assessed by a trained researcher.

Results

The audit captured 92 healthcare professionals, comprising 43 nurses, 9 doctors, 13 hospital pharmacy staff and 27 community pharmacies team members.

Overall 13% (12/92) of participants counselled on all the essential criteria for an MDI inhaler. Pharmacy teams within the hospital and community saw the highest competency levels with 31% (4/13) and 30% (8/27) of staff able to discuss the essential steps respectively, no doctors or nurses were able to indentify all steps.

10% (9/92) of participants were able to counsel on all essential steps for a MDI with a spacer device, with no nurse nor doctor achieving all steps. Hospital pharmacy staff were most likely to discuss all the essential steps with 6/13 staff competent and 3/27 community pharmacy team members counselled on the required steps. Commonly omitted steps included shaking the inhaler and leaving sufficient time between doses.

Competency levels for turbohaler counselling were low, only 5 participants were able to counsel on the essential steps required. Commonly omitted or incorrect descriptions surrounded the priming of the device and incorrect inhalation technique.

Conclusion

Our findings mirror those of previously published studies with an adult focused counselling set,these concluded that less than 10% of healthcare professionals were competent with an MDI.1 Though respiratory conditions represent a large proportion of paediatric consultants, healthcare staff are failing to equip patients and carers with the knowledge and skills to utilise even the most common inhaler devices. With the NHS spending £900 million on inhalers2 and hospital admissions increasing dramatically3 more needs to be done to improve inhaler literacy within the local healthcare community.

A comprehensive review of training methods needs to be undertaken to ensure these meet the requirements of the local healthcare community. A renewed emphasis on asthma care is required including standard methods for counselling on inhalers.

A competency document should be created to assess and validate healthcare professionals to ensure the delivery of accurate and high quality inhaler counselling.
THE IMPACT OF FIXED CONCENTRATIONS SEDATION INFUSIONS ON FLUID OVERLOAD IN CRITICALLY ILL CHILDREN
Authors: Sutherland Adam , Jemmett Elizabeth , Playfor Stephen
Published: August 2016

Introduction

Fluid overload of 10% at 48 hrs (100 ml/kg additional fluid) is strongly associated with morbidity in critically ill children.1 Contributors include fluid resuscitation, acute kidney injury, and administration of intravenous drugs. Acute Kidney Injury has been observed to be more prevalent in infants.2 Drug infusions are historically prepared according to bodyweight to run at large volumes to facilitate end-of-bed calculation and administration. We report the impact of using standardised concentrations on fluid overload in critically ill children in a tertiary general PICU.

Methods

Administration of sedation infusions was prospectively documented using purposive sampling until a population-representative sample for age and weight was obtained. Infusion volumes were calculated in ml/kg/day for different weight groups – 0–5 kg, 5–20 kg and <20 kg – and compared with equivalent volumes for weight-based infusions.

Results

33 patients received sedation infusions over a 5 week period. Overall drug volumes were reduced by 50.3%(41.3 to 58.7%) from 5.19 ml/kg to 2.65 ml/kg. Greatest reduction was seen in the smallest patients (total reduction 68% (16.72 ml/kg vs 5.36 ml/kg). Midazolam volumes in patients >20 kg was observed to increase (0.75 ml/kg vs. 0.95 ml/kg) but this did not have an impact on overall fluid burden.

Conclusions

Weight based sedation infusions may contribute to fluid overload related morbidity, especially in infants. An infant on morphine and midazolam at standard doses (20 mcg/kg/hr and 90 mcg/kg/hr respectively) will receive 16.7 ml/kg/day (33.4% of critical fluid overload at 48 hrs) when using weight-based infusions. Using standard concentrations reduces this volume to 5.36 ml/kg/day (10.7% of critical fluid overload at 48 hrs).
IMPACT OF A COMPUTERISED OUTPATIENT PRESCRIPTION PRINTING SYSTEM (COPPS) ON MELATONIN PRESCRIBING IN A COMMUNITY CHILD HEALTH CLINIC
Authors: Webb Liz , Skingle Jum
Published: August 2016

Aim

COPPS is a computerised outpatient prescription printing system for WP10 prescriptions. It aims to improve the quality and safety of service, as patients will be provided with a legible, complete prescription to take to a community pharmacy of their choice. Patients requiring specialist medicines will have their medicines dispensed more promptly by the hospital pharmacy or medicines home care provider. The software ensures prescriptions contain all the required information to allow safe dispensing, reducing frequency of delays. Hospital pharmacy staff have more time to explain their medicines to patients, promoting shared decision making and improved adherence leading to better health outcomes and reduced waste and harm; provide information at the time of prescribing to increase adherence to agreed care pathways and prescribing practice. It facilitates attribution of prescribing, improves governance and is more easily audited and reported; capture the costs of medicines dispensed for out-patients which will be measured using information from the hospital pharmacy computer system and CASPA.

The aim of this audit was to evaluate the effect the introduction of COPPS has had on compliance with the UHB formulary, local melatonin pathway and its impact on expenditure for melatonin within the community child health clinic. The pathway states that the starting dose is 2 mg Circadin® tablet or liquid melatonin 1 mg/1 ml if necessary for individual patients.

Method

Community Child Health prescribing data shows their highest expenditure is on melatonin. This was therefore chosen to test the impact of COPPS for a pilot study.

Six months prescribing data (September 14–March 15) was obtained from COPPS. This was compared to data obtained for WP10's from hospital forms analysis for the same months the previous year (September 13–March 14)

Results

A 55% reduction was seen in the prescribing of non-formulary melatonin and a reduction in expenditure on melatonin by 18% or £16,000. The estimated annual reduction is £23,000.

There was also a significant increase in adherence to the agreed medication pathway for melatonin.

Conclusion

COPPS provides information for establishment of a robust and expediated audit of medication costs and pathway compliance as shown by the melatonin results. It encourages prescribers to pick medicines from the UHB formulary and provides information that can be used to assess compliance to agreed pathways. In addition pharmacies are provided with accurate legible prescriptions and the patient receives printed copy of the prescription for the GP. A similar approach will now be used to assess the data for Attention Deficit Hyperactivity Disorder (ADHD). COPPS has recently been rolled out to another UHB community child health clinic and the local special schools and further outpatient clinics will follow. A patient satisfaction survey in the outpatient clinics will be developed and audited.
LONG-COURSE ORAL CORTICOSTEROID TOXICITY IN CHILDREN
Authors: Aljebab Fahad , Choonara Imti , Conroy Sharon
Published: August 2016

Background

Long courses of oral corticosteroids are commonly used in children in the management of conditions such as nephrotic syndrome, leukaemia, asthma and others. Various adverse drug reactions (ADRs) are known to occur with their use. This systematic review aimed to identify the most common and serious ADRs and to determine their relative risk levels.

Methods

A literature search of several databases; Embase, Medline, International Pharmaceutical Abstracts, CINAHL, the Cochrane Library and PubMed was performed to identify all studies where corticosteroids had been administered to paediatric patients ranging from 28 days to 18 years of age for at least 15 days of treatment. Each database was searched from their earliest dates to March 2014. All types of studies that provided clear information on ADRs were included.

Results

91 relevant studies were found from 27 countries. These studies represented a total of 6653 children and contained reports of 4124 ADRs, the majority in patients with leukaemia, haemangioma and asthma. Oral prednisolone was the most commonly prescribed corticosteroid (74% of patients). The three most frequent ADRs were weight gain, Cushingoid features and growth retardation. The incidence rates of patients with these three ADRs were 22.4%, 20.6% and 18.9%, respectively. Increased susceptibility to infection was the most serious ADR. 24 children died from infections, ten from varicella zoster and the others from different microorganisms.

Conclusions

Weight gain, Cushingoid features and growth retardation were the most frequent ADRs seen when long-course oral corticosteroids were given to children. In addition, increased susceptibility to infection was the most common cause of mortality.
ONCE DAILY GENTAMICIN DOSE BANDING IN NEWBORNS WITH SIGNS OF EARLY ONSET OF NEONATAL SEPSIS (EONS), BASED ON INITIAL BIRTH WEIGHT AND GESTATIONAL AGE
Authors: Windscheif Paul-Michael , Welsh Rhoda , Smith Laura , Nicoll Ian , Anthony Mark
Published: August 2016

Aim

Prospective assessment of safety of dose banding of once daily gentamicin in newborns with signs of EONS in their first days of life.

Method

All neonates admitted on the level-3 neonatal unit, with at least three consecutive once daily gentamicin doses, started no later than 48 hrs after birth were included. The dose was based on initial birth weight and not adjusted to daily changes of the bodyweight(W). A gentamicin trough level of 2 mg/L was permitted. Neonates with hypoxic ischaemic encephalopathy at birth were not started on a gentamicin regimen. Data was taken from a database system registered as a service evaluation.

Of more than 1200 admitted neonates eighty nine (60 boys, 29 girls; born between Feb 2014 and Jul 2015) received at least three consecutive gentamicin doses for EONS soon after birth (within first 24 hrs: 96.6%), while the majority of antibiotic courses started with a gentamicin regimen were stopped within 36 hrs. 23 (25.8%) neonates with a gestational age (GA) of less than 30 weeks started on 5 mg/kg 48-hourly. Neonates 30 weeks and older started on weight based dosing range: Up to 3 kg: 48 (53.9%) neonates on 5 mg/kg 24 hourly. Between 3–3.5 kg: 13 (14.6%) at fixed 15 mg 24 hourly; between 3.5–4 kg: 5 (5.6%) neonates at fixed 17.5 mg 24 hourly. The first trough level (95.5%) was taken before the third dose. Daily weight (W) was recorded. Routine blood samples was recorded including creatinine, C-reactive protein and a routine sample was sent for investigation of bacterial growth.

Results

The first trough level for neonates up to 30 weeks on 48 hourly regimen (GA-mean 27, range 24–29; W-mean 0.96 kg, range 0.54–1.4 kg; W-change 3.9%) was for all less than 2 mg/L (mean 0.66 mg/L, range 0.2–1.3). For neonates 30 weeks and older, up to 3 kg: (GA-mean 34, range 30–41; W-mean 2.16 kg, range 1.09–2.86 kg; W-change 2.9%) on 24 hourly regimen the level was for 37(82%) up 2 mg/L (mean 1.6 mg/L, range 0.2–2; for 3 cases no level; eight cases 2 up to 3 mg/L of which 3 results cannot be explained with change of a disease status). Neonates between 3–3.5 kg: (GA-mean 38, range 33–42; W-mean 3.3 kg, range 3–3.48 kg; W-change 0.96%) on 24 hourly regimen: all except for one less than 2 mg/L (mean 1.3 mg/L, range 0.4–2; one at 2.7 with hyperinsulinaemia). Between 3.5–4 kg: (GA-mean 39, range 36–41; W-mean 3.78 kg, range 3.6–3.9 kg; W-change 1.3%) on 24 hourly regimen: all less than 2 mg/L (mean 1.1 mg/L, range 0.4–1.7). None of the samples for 73(82%) neonates sent for bacterial investigation showed bacterial growth over 5 days.

Conclusion

Dose banding for gentamicin in EONS is a promising safe option for dosing neonates. There needs to be a revision and re-evaluation in context of the disease profile of the population of a newborn unit as indicated by results for dosing neonates 30 weeks and older but less than 3 kg.
PAEDIATRIC STANDARDISED CONCENTRATION INFUSIONS – A NATIONAL SOLUTION
Authors: Howlett Moninne , Curtin Michael , Doherty Dermot , Gleeson Paula , Sheerin Michelle , Breatnach Cormac
Published: August 2016

Aim

Wide scale implementation of paediatric standardised concentration infusions (SCIs) and the use of smart pump technology has been slow despite international safety agency recommendations. Implementation rates in European hospitals fall far below those in the United States, where for the last decade accreditation has been linked to implementation.1 2 Multidisciplinary collaboration is essential, with pharmacy input and the creation of a smart pump drug library recognised as often being limiting, yet crucial factors, to implementation.3 Following on from the successful development and implementation of a paediatric drug library of standardised concentrations in the paediatric intensive care unit (PICU), operating theatres and cardiac ward of a large tertiary children's hospital, a project was set up to further develop this library for use across multiple sites including paediatric acute transport services.

Method

Post-implementation of the original SCI drug library in the single site paediatric hospital in 2012, a database was created to record proposals for amendments and expansion of that library. A cross-site multidisciplinary collaborative working group was established with representation from PICU pharmacists, intensivists, nursing and clinical engineering to progress multisite adoption of a standardised drug library. Differences in practices across sites were identified and resolved by consensus where possible. Unresolved differences were overcome by omission or ‘hiding’ of particular drug lines at individual sites until consensus could be reached for future updates. Legally binding agreements were drawn up between sites, in conjunction with the infusion pump vendors, to prevent any future deviations from the master library.

Results

Cross-site collaboration over a number of months facilitated the successful amendment and extension of the original drug library to create a new master drug file. Individual site versions of this library, and the supporting documentation were created and disseminated. A change control management plan was developed and agreed upon.

Conclusion

Cross-site collaboration is achievable in supporting the increased implementation of standardised concentration infusions. The standardisation of practices across sites maximises both human and financial resources, and has the potential to reduce medications errors as both patients and medical staff transfer across sites.
Acute hypertension during ramucirumab infusion in two patients with advanced oesophagogastric cancer
Authors: van der Woude Stephanie O , van Laarhoven Hanneke W M
Published: August 2016

Ramucirumab, a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) pathway, in combination with paclitaxel is becoming part of standard second-line systemic therapy for advanced oesophagogastric cancer, based on the results of the REGARD and RAINBOW trials. Common well-known side effects of VEGF pathway inhibitors are hypertension and infusion-related reactions. Here, we describe hypertension as the predominant feature of an infusion-related reaction in 2 patients with metastasised oesophagogastric carcinoma treated with ramucirumab and paclitaxel as second-line treatment and propose possible explanations of this side effect previously undescribed for ramucirumab.