bluuebunny/crossref_metadata_2025 huggingface dataset:
When muscle Ca2+ channels carry monovalent cations through gating pores: insights into the pathophysiology of type 1 hypokalaemic periodic paralysis
Authors: Allard Bruno , Fuster Clarisse
Published: March 2018

Patients suffering from type 1 hypokalaemic periodic paralysis (HypoPP1) experience attacks of muscle paralysis associated with hypokalaemia. The disease arises from missense mutations in the gene encoding the α1 subunit of the dihydropyridine receptor (DHPR), a protein complex anchored in the tubular membrane of skeletal muscle fibres which controls the release of Ca2+ from sarcoplasmic reticulum and also functions as a Ca2+ channel. The vast majority of mutations consist of the replacement of one of the outer arginines in S4 segments of the α1 subunit by neutral residues. Early studies have shown that muscle fibres from HypoPP1 patients are abnormally depolarized at rest in low K+ to the point of inducing muscle inexcitability. The relationship between HypoPP1 mutations and depolarization has long remained unknown. More recent investigations conducted in the closely structurally related voltage‐gated Na+ and K+ channels have shown that comparable S4 arginine substitutions gave rise to elevated inward currents at negative potentials called gating pore currents. Experiments performed in muscle fibres from different models revealed such an inward resting current through HypoPP1 mutated Ca2+ channels. In mouse fibres transfected with HypoPP1 mutated channels, the elevated resting current was found to carry H+ for the R1239H arginine‐to‐histidine mutation in a S4 segment and Na+ for the V876E HypoPP1 mutation, which has the peculiarity of not being located in S4 segments. Muscle paralysis probably results from the presence of a gating pore current associated with hypokalaemia for both mutations, possibly aggravated by external acidosis for the R1239H mutation.

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Cholecystokinin selectively activates short axon cells to enhance inhibition of olfactory bulb output neurons
Authors: Liu Xiang , Liu Shaolin
Published: March 2018

Key points

Cholecystokinin (CCK) via CCK‐B receptors significantly enhances the GABAA receptor‐mediated synaptic inhibition of principal olfactory bulb (OB) output neurons.

This CCK action requires action potentials in presynaptic neurons.

The enhanced inhibition of OB output neurons is a result of CCK‐elevated inhibitory input from the glomerular circuit.

CCK modulation of the glomerular circuit also leads to potentiated presynaptic inhibition of olfactory nerve terminals and postsynaptic inhibition of glomerular neurons.

Selective excitation of short axon cells underlies the CCK‐potentiated glomerular inhibition.

Neuropeptides such as cholecystokinin (CCK) are important for many brain functions, including sensory processing. CCK is predominantly present in a subpopulation of excitatory neurons and activation of CCK receptors is implicated in olfactory signal processing in the olfactory bulb (OB). However, the cellular and circuit mechanisms underlying the actions of CCK in the OB remain elusive. In the present study, we characterized the effects of CCK on synaptic inhibition of the principal OB output neurons mitral/tufted cells (MTCs) followed by mechanistic analyses at both circuit and cellular levels. First, we found that CCK via CCK‐B receptors enhances the GABAA receptor‐mediated spontaneous IPSCs in MTCs. Second, CCK does not affect the action potential independent miniature IPSCs in MTCs. Third, CCK potentiates glomerular inhibition resulting in increased GABAB receptor‐mediated presynaptic inhibition of olfactory nerve terminals and enhanced spontaneous IPSCs in MTCs and glomerular neurons. Fourth, CCK enhances miniature IPSCs in the excitatory external tufted cells, although neither in the inhibitory short axon cells (SACs) nor in periglomerular cells (PGCs). Finally, CCK excites all tested SACs and a very small minority of GABAergic neurons in the granule cell layer or in periglomerular cells, but not in deep SACs. These results demonstrate that CCK selectively activates SACs to engage the SAC‐formed interglomerular circuit and thus elevates inhibition broadly in the OB glomerular layer. This modulation may prevent the system from saturating in response to a high concentration of odourants or facilitate the detection of weak stimuli by increasing signal‐to‐noise ratio.
Time and sex dependent effects of magnesium sulphate on post‐asphyxial seizures in preterm fetal sheep
Authors: Bennet Laura , Galinsky Robert , Draghi Vittoria , Lear Christopher A. , Davidson Joanne O. , Unsworth Charles P. , Gunn Alistair J.
Published: March 2018

Key points

We evaluated the effect of magnesium sulphate (MgSO4) on seizures induced by asphyxia in preterm fetal sheep.

MgSO4 did not prevent seizures, but significantly reduced the total duration, number of seizures, seizure amplitude and average seizure burden.

Saline‐asphyxia male fetuses had significantly more seizures than female fetuses, but male fetuses showed significantly greater reduction in seizures during MgSO4 infusion than female fetuses.

A circadian profile of seizure activity was observed in all fetuses, with peak seizures seen around 04.00–06.00 h on the first and second days after the end of asphyxia.

This study is the first to demonstrate that MgSO4 has utility as an anti‐seizure agent after hypoxia–ischaemia. More information is needed about the mechanisms mediating the effect of MgSO4 on seizures and sexual dimorphism, and the influence of circadian rhythms on seizure expression.

Seizures are common in newborns after asphyxia at birth and are often refractory to anti‐seizure agents. Magnesium sulphate (MgSO4) has anticonvulsant effects and is increasingly given to women in preterm labour for potential neuroprotection. There is limited information on its effects on perinatal seizures. We examined the hypothesis that MgSO4 infusion would reduce fetal seizures after asphyxia in utero. Preterm fetal sheep at 0.7 gestation (104 days, term = 147 days) were given intravenous infusions of either saline (n = 14) or MgSO4 (n = 12, 160 mg bolus + 48 mg h−1 infusion over 48 h). Fetuses underwent umbilical cord occlusion (UCO) for 25 min, 24 h after the start of infusion. The start time for seizures did not differ between groups, but MgSO4 significantly reduced the total number of seizures (P < 0.001), peak seizure amplitude (P < 0.05) and seizure burden (P < 0.005). Within the saline‐asphyxia group, male fetuses had significantly more seizures than females (P < 0.05). Within the MgSO4‐asphyxia group, although both sexes had fewer seizures than the saline‐asphyxia group, the greatest effect of MgSO4 was on male fetuses, with reduced numbers of seizures (P < 0.001) and seizure burden (P < 0.005). Only 1 out of 6 MgSO4 males had seizures on the second day post‐UCO compared to 5 out of 6 MgSO4 female fetuses (P = 0.08). Finally, seizures showed a circadian profile with peak seizures between 04.00 and 06.00 h on the first and second day post‐UCO. Collectively, these results suggest that MgSO4 may have utility in treating perinatal seizures and has sexually dimorphic effects.
Differential effects of vision upon the accuracy and precision of vestibular‐evoked balance responses
Authors: Mackenzie Stuart W. , Reynolds Raymond F.
Published: March 2018

Key points

Effective balance control requires the transformation of vestibular signals from head‐ to foot‐centred coordinates in order to move the body in an appropriate direction.

This transformation process has previously been studied by analysing the directional accuracy of the averaged sway response to multiple electrical vestibular stimuli (EVS).

Here we studied trial‐by‐trial variability of EVS responses to measure any changes in directional precision which may be masked by the averaging process.

We found that vision increased directional variability without influencing the mean sway direction, demonstrating that response accuracy and precision are dissociable.

These results emphasise the importance of single trial analysis in determining the efficacy of vestibular control of balance.

Vestibular information must be transformed from head‐ to‐foot‐centred coordinates for balance control. This transformation process has previously been investigated using electrical vestibular stimulation (EVS), which evokes a sway response fixed in head coordinates. The craniocentric nature of the response has been demonstrated by analysing average responses to multiple stimuli. This approach misses any trial‐by‐trial variability which would reflect poor balance control. Here we performed single‐trial analysis to measure this directional variability (precision), and compared this to mean performance (accuracy). We determined the effect of vision upon both parameters. Standing volunteers adopted various head orientations (0, ±30 and ±60 deg yaw) while EVS‐evoked response direction was determined from ground reaction force vectors. As previously reported, mean force direction was orientated towards the anodal ear, and rotated in line with head yaw. Although vision caused a ∼50% reduction in response magnitude, it had no influence on the direction of the mean sway response, indicating that accuracy was unaffected. However, individual trial analysis revealed up to 30% increases in directional variability with the eyes open. This increase was inversely correlated with the size of the force response. The paradoxical observation that vision reduces the precision of the balance response may be explained by a multi‐sensory integration process. As additional veridical sensory information becomes available, this lessens the relative contribution of vestibular input, causing a simultaneous reduction in both the magnitude and the precision of the response to EVS. Our novel approach demonstrates the importance of single‐trial analysis in revealing the efficacy of vestibular reflexes.
Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics
Authors: Beattie Kylie A. , Hill Adam P. , Bardenet Rémi , Cui Yi , Vandenberg Jamie I. , Gavaghan David J. , de Boer Teun P. , Mirams Gary R.
Published: March 2018

Key points

Ion current kinetics are commonly represented by current–voltage relationships, time constant–voltage relationships and subsequently mathematical models fitted to these. These experiments take substantial time, which means they are rarely performed in the same cell.

Rather than traditional square‐wave voltage clamps, we fitted a model to the current evoked by a novel sum‐of‐sinusoids voltage clamp that was only 8 s long.

Short protocols that can be performed multiple times within a single cell will offer many new opportunities to measure how ion current kinetics are affected by changing conditions.

The new model predicts the current under traditional square‐wave protocols well, with better predictions of underlying currents than literature models. The current under a novel physiologically relevant series of action potential clamps is predicted extremely well.

The short sinusoidal protocols allow a model to be fully fitted to individual cells, allowing us to examine cell–cell variability in current kinetics for the first time.

Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to predict how ion currents contribute to cellular electrophysiology is in turn critically dependent on our characterisation of ion channel kinetics – the voltage‐dependent rates of transition between open, closed and inactivated channel states. We present a new method for rapidly exploring and characterising ion channel kinetics, applying it to the hERG potassium channel as an example, with the aim of generating a quantitatively predictive representation of the ion current. We fitted a mathematical model to currents evoked by a novel 8 second sinusoidal voltage clamp in CHO cells overexpressing hERG1a. The model was then used to predict over 5 minutes of recordings in the same cell in response to further protocols: a series of traditional square step voltage clamps, and also a novel voltage clamp comprising a collection of physiologically relevant action potentials. We demonstrate that we can make predictive cell‐specific models that outperform the use of averaged data from a number of different cells, and thereby examine which changes in gating are responsible for cell–cell variability in current kinetics. Our technique allows rapid collection of consistent and high quality data, from single cells, and produces more predictive mathematical ion channel models than traditional approaches.
Activity‐dependent synaptic integration and modulation of bilateral excitatory inputs in an auditory coincidence detection circuit
Authors: Lu Yong , Liu Yuwei , Curry Rebecca J.
Published: March 2018

Key points

Binaural excitatory inputs to coincidence detection neurons in nucleus laminaris (NL) play essential roles in interaural time difference coding for sound localization.

Here, we show that the two excitatory inputs are physiologically nearly completely segregated. Synaptic integration shows linear summation of EPSPs, ensuring high efficiency of coincidence detection of the bilateral excitatory inputs.

We further show that the two excitatory inputs to single NL neurons are symmetrical in synaptic strength, kinetics and short‐term plasticity.

Modulation of the EPSCs by metabotropic glutamate receptors (mGluRs) is identical between the two excitatory inputs, maintaining balanced bilateral excitation under neuromodulatory conditions.

Unilateral hearing deprivation reduces synaptic excitation and paradoxically strengthens mGluR modulation of EPSCs, suggesting activity‐dependent anti‐homeostatic regulation, a novel synaptic plasticity in response to sensory manipulations.

Neurons in the avian nucleus laminaris (NL) receive bilateral excitatory inputs from the cochlear nucleus magnocellularis, via morphologically symmetrical dorsal (ipsilateral) and ventral (contralateral) dendrites. Using in vitro whole‐cell patch recordings in chicken brainstem slices, we investigated synaptic integration and modulation of the bilateral inputs to NL under normal and hearing deprivation conditions. We found that the two excitatory inputs onto single NL neurons were nearly completely segregated, and integration of the two inputs was linear for EPSPs. The two inputs had similar synaptic strength, kinetics and short‐term plasticity. EPSCs in low but not middle and high frequency neurons were suppressed by activation of group I and II metabotropic glutamate receptors (mGluR I and II), with similar modulatory strength between the ipsilateral and contralateral inputs. Unilateral hearing deprivation by cochlea removal reduced the excitatory transmission on the deprived dendritic domain of NL. Interestingly, EPSCs evoked at the deprived domain were modulated more strongly by mGluR II than at the counterpart domain that received intact input in low frequency neurons, suggesting anti‐homeostatic regulation. This was supported by a stronger expression of mGluR II protein on the deprived neuropils of NL. Under mGluR II modulation, EPSCs on the deprived input show transient synaptic facilitation, forming a striking contrast with normal hearing conditions under which pure synaptic depression is observed. These results demonstrate physiological symmetry and thus balanced bilateral excitatory inputs to NL neurons. The activity‐dependent anti‐homeostatic plasticity of mGluR modulation constitutes a novel mechanism regulating synaptic transmission in response to sensory input manipulations.
The new trasmuted C.D.F. based on Gompertz function
Authors: Kyurkchiev Nikolay V.
Published: March 2018

In this paper we find application of some new cumulative distribution functions transformations to construct a family of sigmoidal functions based on the Gompertz logistic function.We prove estimates for the Hausdorff approximation of the shifted Heaviside step function by means of these families.Numerical examples, illustrating our results are given.
On the Kumaraswamy-Dagum-Log-Logistic sigmoid functions with applications to population dynamics
Authors: Pavlov Nikolay , Golev Angel , Iliev Anton , Rahnev Asen , Kyurkchiev Nikolay V.
Published: March 2018

he Kumaraswamy-Dagum distribution is a flexible and simple model with applications to income and lifetime data.We prove upper and lower estimates for the Hausdorff approximation of the shifted Heaviside function by a class of Kumaraswamy-Dagum-Log-Logistic cumulative distribution function - (KD-CDF). Numerical examples, illustrating our results are given.
Electric Power and Natural Gas Synergism
Authors: Langston Lee S.
Published: March 2018

This article explains research and development in the field of gas turbine power plants. Natural gas fueled gas turbines driving generators are proving to be the most versatile and effective energy converter in the engineer's arsenal of prime movers. Continued research and development are making these gas turbine power plants even more effective, flexible, and efficient. Gas turbine plants can operate under either base load operations or in quick start/fast shutdown modes. The reliable and dispatchable backup capacity of fast-reacting fossil technology to hedge against variability of electrical supply was a key to successful renewable use in the 26 countries studied. The article concludes that the use of versatile electric power gas turbines fueled by natural gas will continue to grow in the world. In the United States, with recent shale discoveries and fracking of natural gas, such use should increase, with or without the emphasis on renewables.
Deaminase-Dead Mouse APOBEC3 Is an
In Vivo
Retroviral Restriction Factor
Authors: Stavrou Spyridon , Zhao Wenming , Blouch Kristin , Ross Susan R.
Published: March 2018

The apolipoprotein B editing complex 3 (APOBEC3) proteins are potent retroviral restriction factors that are under strong positive selection, both in terms of gene copy number and sequence diversity. A common feature of all the members of the APOBEC3 family is the presence of one or two cytidine deamination domains, essential for cytidine deamination of retroviral reverse transcripts as well as packaging into virions. Several studies have indicated that human and mouse APOBEC3 proteins restrict retrovirus infection via cytidine deaminase (CD)-dependent and -independent means. To understand the relative contribution of CD-independent restriction
in vivo
, we created strains of transgenic mice on an APOBEC3 knockout background that express a deaminase-dead mouse APOBEC3 due to point mutations in both CD domains (E73Q/E253Q). Here, we show that the CD-dead APOBEC3 can restrict murine retroviruses
in vivo
. Moreover, unlike the wild-type protein, the mutant APOBEC3 is not packaged into virions but acts only as a cell-intrinsic restriction factor that blocks reverse transcription by incoming viruses. Finally, we show that wild-type and CD-dead mouse APOBEC3 can bind to murine leukemia virus (MLV) reverse transcriptase. Our findings suggest that the mouse APOBEC3 cytidine deaminase activity is not required for retrovirus restriction.

IMPORTANCE
APOBEC3 proteins are important host cellular restriction factors essential for restricting retrovirus infection by causing mutations in the virus genome and by blocking reverse transcription. While both methods of restriction function
in vitro
, little is known about their role during
in vivo
infection. By developing transgenic mice with mutations in the cytidine deamination domains needed for enzymatic activity and interaction with viral RNA, we show that APOBEC3 proteins can still restrict
in vivo
infection by interacting with reverse transcriptase and blocking its activity. These studies demonstrate that APOBEC3 proteins have evolved multiple means for blocking retrovirus infection and that all of these means function
in vivo
.
Transmission, Human Population, and Pathogenicity: the Ebola Case in Point
Authors: Delgado Rafael , Simón Fernando
Published: March 2018

The 2013–2016 Ebola outbreak in West Africa has been the largest ever of a known disease in a new context that produced an unprecedented impact and is changing the international approach to responding to public health emergencies. The unprecedented scale of the outbreak, the use of advanced technology for detecting and characterizing the infectious agent, along with the opportunity to treat patients in modern facilities have greatly increased our knowledge of the disease and its transmission. Also, for the first time, an important international effort has been deployed to control the spread of the epidemic by providing care to patients and by adopting basic measures of public health control. Apart from supportive treatment and intensive therapy with fluids and electrolytes, no new compounds have been proved to be clinically effective to treat Ebola virus disease; however, a specific vaccine has shown significant protection in clinical trials in Guinea, opening an expectation for controlling future outbreaks.
Global Regulation by CsrA and Its RNA Antagonists
Authors: Romeo Tony , Babitzke Paul
Published: March 2018

The sequence-specific RNA binding protein CsrA is employed by diverse bacteria in the posttranscriptional regulation of gene expression. Its binding interactions with RNA have been documented at atomic resolution and shown to alter RNA secondary structure, RNA stability, translation, and/or Rho-mediated transcription termination through a growing number of molecular mechanisms. In
Gammaproteobacteria
, small regulatory RNAs (sRNAs) that contain multiple CsrA binding sites compete with mRNA for binding to CsrA, thereby sequestering and antagonizing this protein. Both the synthesis and turnover of these sRNAs are regulated, allowing CsrA activity to be rapidly and efficiently adjusted in response to nutritional conditions and stresses. Feedback loops between the Csr regulatory components improve the dynamics of signal response by the Csr system. The Csr system of
Escherichia coli
is intimately interconnected with other global regulatory systems, permitting it to contribute to regulation by those systems. In some species, a protein antagonist of CsrA functions as part of a checkpoint for flagellum biosynthesis. In other species, a protein antagonist participates in a mechanism in which a type III secretion system is used for sensing interactions with host cells. Recent transcriptomics studies reveal vast effects of CsrA on gene expression through direct binding to hundreds of mRNAs, and indirectly through its effects on the expression of dozens of transcription factors. CsrA binding to base-pairing sRNAs and novel mRNA segments, such as the 3′ untranslated region and deep within coding regions, predict its participation in yet-to-be-discovered regulatory mechanisms.
Bacterial Iron Homeostasis Regulation by sRNAs
Authors: Chareyre Sylvia , Mandin Pierre
Published: March 2018

While iron is essential to sustain growth, its excess can be detrimental to the cell by generating highly toxic reactive oxygen species. Regulation of iron homeostasis thus plays a vital role in almost all living organisms. During the last 15 years, the small RNA (sRNA) RyhB has been shown to be a key actor of iron homeostasis regulation in bacteria. Through multiple molecular mechanisms, RyhB represses expendable iron-utilizing proteins, promotes siderophore production, and coordinates Fe-S cluster cofactor biogenesis, thereby establishing a so-called iron-sparing response. In this review, we will summarize knowledge on how sRNAs control iron homeostasis mainly through studies on RyhB in
Escherichia coli
. The parallel roles and modes of action of other sRNAs in different bacteria will also be described. Finally, we will discuss what questions remain to be answered concerning this important stress response regulation by sRNAs.
Carbohydrate Utilization in Bacteria: Making the Most Out of Sugars with the Help of Small Regulatory RNAs
Authors: Durica-Mitic* Svetlana , Göpel* Yvonne , Görke Boris
Published: March 2018

Survival of bacteria in ever-changing habitats with fluctuating nutrient supplies requires rapid adaptation of their metabolic capabilities. To this end, carbohydrate metabolism is governed by complex regulatory networks including posttranscriptional mechanisms that involve small regulatory RNAs (sRNAs) and RNA-binding proteins. sRNAs limit the response to substrate availability and set the threshold or time required for induction and repression of carbohydrate utilization systems. Carbon catabolite repression (CCR) also involves sRNAs. In
Enterobacteriaceae
, sRNA Spot 42 cooperates with the transcriptional regulator cyclic AMP (cAMP)-receptor protein (CRP) to repress secondary carbohydrate utilization genes when a preferred sugar is consumed. In pseudomonads, CCR operates entirely at the posttranscriptional level, involving RNA-binding protein Hfq and decoy sRNA CrcZ. Moreover, sRNAs coordinate fluxes through central carbohydrate metabolic pathways with carbohydrate availability. In Gram-negative bacteria, the interplay between RNA-binding protein CsrA and its cognate sRNAs regulates glycolysis and gluconeogenesis in response to signals derived from metabolism. Spot 42 and cAMP-CRP jointly downregulate tricarboxylic acid cycle activity when glycolytic carbon sources are ample. In addition, bacteria use sRNAs to reprogram carbohydrate metabolism in response to anaerobiosis and iron limitation. Finally, sRNAs also provide homeostasis of essential anabolic pathways, as exemplified by the hexosamine pathway providing cell envelope precursors. In this review, we discuss the manifold roles of bacterial sRNAs in regulation of carbon source uptake and utilization, substrate prioritization, and metabolism.
A cohort study reporting normal oximetry values in healthy infants under 4 months of age using Masimo technology
Authors: Evans Hazel J , Karunatilleke Anne S , Grantham-Hill Sarah , Gavlak Johanna C
Published: March 2018

Objective

To determine sleeping saturation indices in healthy infants using a modern pulse oximeter with motion artefact extraction technology.

Design

Prospective cohort.

Setting

Home.

Subjects

Healthy term infants.

Intervention

Nocturnal pulse oximetry at home at 1 month of age (Recording 1) and repeated at age 3–4 months (Recording 2). Parents documented sleep times. Visi-Download software (Stowood Scientific) analysed data with artefact and wake periods removed.

Main outcome measures

Saturations (SAT50), desaturation index >4% (DI4) and >3% (DI3) from baseline/hour, delta index 12 s (DI12s), minimum saturations (SATmin), percentage time with saturations below 90% and 92%.

Results

Forty-five babies were studied at 1 month and 38 babies at 3–4 months. Mean (CI) SAT50, DI4, DI3, DI12s and SATmin (CI) were 97.05 (96.59 to 97.52), 16.16 (13.72 to 18.59), 25.41 (22.00 to 28.82), 0.96 (0.88 to 1.04) and 80.4% (78.8% to 82.0%) at 1 month, respectively, and 97.65 (97.19 to 98.12), 8.12 (6.46 to 9.77), 13.92 (11.38 to 16.47), 0.72 (0.65 to 0.78) and 84.7% (83.3% to 86.1%) at 3–4 months. Median (CI) percentage times with saturations below 90% and 92% were 0.39 (0.26 to 0.55) and 0.82 (0.60 to 1.23), respectively, at 1 month and 0.11 (0.06 to 0.20) and 0.25 (0.17 to 0.44) at 3–4 months. For paired samples (n=32) DI4 (P=0.006), DI3 (P=0.03), DI12s (P=0.001), percentage time with saturations below 90% (P=0.001) and 92% (P=0.000) all fell significantly and SATmin (P=0.004) rose between the two recordings.

Conclusion

Desaturation indices are substantially higher in young infants than older children where a DI4 over 4 is considered abnormal. These decrease by 3–4 months of age but still remain elevated compared with older children.
Genomics for paediatricians: promises and pitfalls
Authors: Hammond Carrie Louise , Willoughby Josh Matthew , Parker Michael James
Published: March 2018

In recent years, there have been significant advances in genetic technologies, evolving the field of genomics from genetics. This has huge diagnostic potential, as genomic testing increasingly becomes part of mainstream medicine. However, there are numerous potential pitfalls in the interpretation of genomic data. It is therefore essential that we educate clinicians more widely about the appropriate interpretation and utilisation of genomic testing.
A cluster randomised controlled trial to determine the effect of community mobilisation and advocacy on men’s use of violence in periurban South Africa: study protocol
Authors: Christofides Nicola J , Hatcher Abigail M , Pino Angelica , Rebombo Dumisani , McBride Ruari Santiago , Anderson Althea , Peacock Dean
Published: March 2018

Objective

This paper describes the design and methods of a cluster randomised controlled trial (C-RCT) to determine the effectiveness of a community mobilisation intervention that is designed to reduce the perpetration of violence against women (VAW).

Methods and analysis

A C-RCT of nine intervention and nine control clusters is being carried out in a periurban, semiformal settlement near Johannesburg, South Africa, between 2016 and 2018. A community mobilisation and advocacy intervention, called Sonke CHANGE is being implemented over 18 months. It comprises local advocacy and group activities to engage community members to challenge harmful gender norms and reduce VAW. The intervention is hypothesised to improve equitable masculinities, reduce alcohol use and ultimately, to reduce VAW. Intervention effectiveness will be determined through an audio computer-assisted self-interview questionnaire with behavioural measures among 2600 men aged between 18 and 40 years at baseline, 12 months and 24 months. The primary trial outcome is men’s use of physical and/or sexual VAW. Secondary outcomes include harmful alcohol use, gender attitudes, controlling behaviours, transactional sex and social cohesion. The main analysis will be intention-to-treat based on the randomisation of clusters. A qualitative process evaluation is being conducted alongside the C-RCT. Implementers and men participating in the intervention will be interviewed longitudinally over the period of intervention implementation and observations of the workshops and other intervention activities are being carried out.

Ethics and dissemination

Ethical approval was obtained from the University of the Witwatersrand Human Research Ethics Committee and procedures comply with ethical recommendations of the United Nations Multi-Country Study on Men and Violence. Dissemination of research findings will take place with local stakeholders and through peer-reviewed publications, with data available on request or after 5 years of trial completion.

Trial registration number

NCT02823288; Pre-result.
Projecting the effects of tobacco control policies in the USA through microsimulation: a study protocol
Authors: Tam Jamie , Levy David T , Jeon Jihyoun , Clarke John , Gilkeson Scott , Hall Tim , Feuer Eric J , Holford Theodore R , Meza Rafael
Published: March 2018

Introduction

Smoking remains the leading cause of preventable death in the USA but can be reduced through policy interventions. Computational models of smoking can provide estimates of the projected impact of tobacco control policies and can be used to inform public health decision making. We outline a protocol for simulating the effects of tobacco policies on population health outcomes.

Methods and analysis

We extend the Smoking History Generator (SHG), a microsimulation model based on data from the National Health Interview Surveys, to evaluate the effects of tobacco control policies on projections of smoking prevalence and mortality in the USA. The SHG simulates individual life trajectories including smoking initiation, cessation and mortality. We illustrate the application of the SHG policy module for four types of tobacco control policies at the national and state levels: smoke-free air laws, cigarette taxes, increasing tobacco control programme expenditures and raising the minimum age of legal access to tobacco. Smoking initiation and cessation rates are modified by age, birth cohort, gender and years since policy implementation. Initiation and cessation rate modifiers are adjusted for differences across age groups and the level of existing policy coverage. Smoking prevalence, the number of population deaths avoided, and life-years gained are calculated for each policy scenario at the national and state levels. The model only considers direct individual benefits through reduced smoking and does not consider benefits through reduced exposure to secondhand smoke.

Ethics and dissemination

A web-based interface is being developed to integrate the results of the simulations into a format that allows the user to explore the projected effects of tobacco control policies in the USA. Usability testing is being conducted in which experts provide feedback on the interface. Development of this tool is under way, and a publicly accessible website is available athttp://www.tobaccopolicyeffects.org.
Development of the Combined Assessment of Risk Encountered in Surgery (CARES) surgical risk calculator for prediction of postsurgical mortality and need for intensive care unit admission risk: a single-center retrospective study
Authors: Chan Diana Xin Hui , Sim Yilin Eileen , Chan Yiong Huak , Poopalalingam Ruban , Abdullah Hairil Rizal
Published: March 2018

Introduction

Accurate surgical risk prediction is paramount in clinical shared decision making. Existing risk calculators have limited value in local practice due to lack of validation, complexities and inclusion of non-routine variables.

Objective

We aim to develop a simple, locally derived and validated surgical risk calculator predicting 30-day postsurgical mortality and need for intensive care unit (ICU) stay (>24 hours) based on routinely collected preoperative variables. We postulate that accuracy of a clinical history-based scoring tool could be improved by including readily available investigations, such as haemoglobin level and red cell distribution width.

Methodology

Electronic medical records of 90 785 patients, who underwent non-cardiac and non-neuro surgery between 1 January 2012 and 31 October 2016 in Singapore General Hospital, were retrospectively analysed. Patient demographics, comorbidities, laboratory results, surgical priority and surgical risk were collected. Outcome measures were death within 30 days after surgery and ICU admission. After excluding patients with missing data, the final data set consisted of 79 914 cases, which was divided randomly into derivation (70%) and validation cohort (30%). Multivariable logistic regression analysis was used to construct a single model predicting both outcomes using Odds Ratio (OR) of the risk variables. The ORs were then assigned ranks, which were subsequently used to construct the calculator.

Results

Observed mortality was 0.6%. The Combined Assessment of Risk Encountered in Surgery (CARES) surgical risk calculator, consisting of nine variables, was constructed. The area under the receiver operating curve (AUROC) in the derivation and validation cohorts for mortality were 0.934 (0.917–0.950) and 0.934 (0.912–0.956), respectively, while the AUROC for ICU admission was 0.863 (0.848–0.878) and 0.837 (0.808–0.868), respectively. CARES also performed better than the American Society of Anaesthesiologists-Physical Status classification in terms of AUROC comparison.

Conclusion

The development of the CARES surgical risk calculator allows for a simplified yet accurate prediction of both postoperative mortality and need for ICU admission after surgery.
Health outcomes of patients with chronic disease managed with a healthcare kiosk in primary care: protocol for a pilot randomised controlled trial
Authors: Ng Grace , Tan Sze Wee , Tan Ngiap Chuan
Published: March 2018

Introduction

The rising prevalence of chronic disease is leading to an increase in the demand for primary care services and a shortage of primary care physicians globally. Addressing these challenges calls for innovations in the healthcare delivery model with greater use of healthcare technology tools. We previously examined the feasibility of using an automated healthcare kiosk for the management of patients with stable chronic disease in the primary care setting. The aim of this follow-up study is to evaluate the health outcomes of patients with chronic disease who are on kiosk management compared with patients who are on routine management by nurse clinicians.

Methods and analysis

The pilot study will be a two-armed randomised controlled trial of 120 patients with well-controlled chronic disease on 4-monthly follow-up visits over a 12-month period. Patients with prior diagnoses of hypertension, hyperlipidaemia and/or diabetes will be included in the study and will be randomly assigned to intervention or control groups to receive kiosk or nurse management, respectively. The main primary outcome measure is the overall chronic disease control of the patients. Other primary outcome measures are the blood pressure and low-density lipoprotein cholesterol levels for patients without diabetes, and blood pressure, low-density lipoprotein cholesterol and haemoglobin A1c levels for patients with diabetes. Secondary outcome measures are visit duration, patient satisfaction with the management process, health-related quality of life and the occurrence of any adverse event. Data will be captured longitudinally at baseline, 4 months, 8 months and 12 months, and will be analysed using multiple regression models.

Ethics and dissemination

The study has been approved by the Singapore Health Services (SingHealth) Centralised Institutional Review Board (2017/2715). Findings of the study will be submitted for publication in peer-reviewed journals and presented at national and international conferences.

Trial registration number

NCT03274089; Pre-results.
Comparison of incidence, rate and length of all-cause hospital admissions between adults with normoglycaemia, impaired fasting glucose and diabetes: a retrospective cohort study in Geelong, Australia
Authors: Sajjad Muhammad Amber , Holloway Kara L , de Abreu Lelia L F , Mohebbi Mohammadreza , Kotowicz Mark A , Pedler Daryl , Pasco Julie A
Published: March 2018

Objective

To determine whether adults with normoglycaemia, impaired fasting glucose (IFG) and diabetes differed according to the incidence, rate, length and primary reasons for hospital admission.

Design

Retrospective cohort study.

Setting

Barwon Statistical Division, Geelong, Australia.

Participants

Cohort included 971 men and 924 women, aged 20+ years, participating in the Geelong Osteoporosis Study. Glycaemic status was assessed at cohort entry using fasting plasma glucose, use of antihyperglycaemic medication and/or self-report.

Primary and secondary outcome measures

Primary outcome measure was any admission to the major tertiary public hospital in the study region over the follow-up period. Secondary outcome measures were admission rate and length (days).

Results

Over a median follow-up of 7.4 years (IQR 5.3–9.6), participants with diabetes, compared with those with normoglycaemia, were two times as likely to be hospitalised (OR 2.07, 95% CI 1.42 to 3.02), had a higher admission rate (incidence rate ratio 1.61, 95% CI 1.17 to 2.23) and longer hospital stay (third quartile difference 7.7, 95% CI 1.3 to 14.1 and ninth decile difference 16.2, 95% CI 4.2 to 28.3). IFG group was similar to normoglycaemia for the incidence, rate and length of admission. Cardiovascular disease-related diagnoses were the most common primary reasons for hospitalisation across all glycaemic categories.

Conclusions

Our results show increased incidence, rate and length of all-cause hospital admission in adults with diabetes as compared with normoglycaemia; however, we did not detect any associations for IFG. Interventions should focus on preventing IFG-to-diabetes progression and reducing cardiovascular risk in IFG and diabetes.
Why we need more poetry in palliative care
Authors: Davies Elizabeth A
Published: March 2018

Objectives

Although many well-known poems consider illness, loss and bereavement, medicine tends to view poetry more as an extracurricular than as a mainstream pursuit. Within palliative care, however, there has been a long-standing interest in how poetry may help patients and health professionals find meaning, solace and enjoyment. The objective of this paper is to identify the different ways in which poetry has been used in palliative care and reflect on their further potential for education, practice and research.

Methods

A narrative review approach was used, drawing on searches of the academic literature through Medline and on professional, policy and poetry websites to identify themes for using poetry in palliative care.

Results

I identified four themes for using poetry in palliative care. These concerned (1) leadership, (2) developing organisational culture, (3) the training of health professionals and (4) the support of people with serious illness or nearing the end of life. The academic literature was mostly made up of practitioner perspectives, case examples or conceptual pieces on poetry therapy. Patients’ accounts were rare but suggested poetry can help some people express powerful thoughts and emotions, create something new and feel part of a community.

Conclusion

Poetry is one way in which many people, including patients and palliative care professionals, may seek meaning from and make sense of serious illnesses and losses towards the end of life. It may have untapped potential for developing person-centred organisations, training health professionals, supporting patients and for promoting public engagement in palliative care.
Palliative stenting for oesophagogastric cancer: tumour and host factors and prognosis
Authors: Park James Hugh , Woodley Niall , McMillan Donald C , Glen Paul
Published: March 2018

Objectives

Palliative self-expandable metallic stent (SEMS) insertion is common in patients not suitable for resection of oesophagogastric (OG) cancer. Factors which may determine survival, however, are not clear. The present study examined the relationship between tumour and host factors, including the systemic inflammatory response and survival of patients undergoing palliative SEMS insertion.

Methods

Patients with a diagnosis of OG cancer who were considered suitable for palliative SEMS only without systemic therapy were identified. Patient characteristics including Eastern Cooperative Oncology Group performance status, radiological stage and modified Glasgow Prognostic Score (mGPS: 0—C-reactive protein (CRP) ≤10 mg/L; 1—CRP >10 mg/L; 2—CRP >10 mg/L; albumin <35 g/L) were recorded prospectively. The relationship between such characteristics and 3-month survival was examined.

Results

203 patients were included in the final analysis. All patients died during follow-up, with median survival from diagnosis 75 days (IQR 47–157). 78% of patients were systemically inflamed (mGPS >1). On multivariate analysis, only poor performance status (HR 1.23, p=0.025), metastatic disease (HR 2.27, p<0.001) and mGPS (HR 1.25, p=0.021) were associated with shorter survival. The combination of performance status and mGPS stratified 3-month survival of patients without metastatic disease from 88% to 20% (p<0.001) and patients with metastases from 43% to 6% (p=0.059). Similar results were observed when analysis was restricted to patients with oesophageal and junctional cancer (M0: 83%–20%, p=0.008; M1: 33%–8%, p=0.082).

Conclusion

Performance status, metastatic disease and mGPS are independent predictors of survival in patients with OG cancer undergoing palliative SEMS insertion. These routinely available markers provide a rational system on which to base decisions regarding prognosis and treatment.
Blood transfusion practice in the UK and Ireland: a survey of palliative care physicians
Authors: Neoh Karen , Stanworth Simon , Bennett Michael I
Published: March 2018

Objectives

Red cell (blood) transfusions are used in palliative care to manage patients with symptomatic anaemia or when patients have lost blood. We aimed to understand current blood transfusion practice among palliative medicine doctors and compare this with National Institute for Health and Care Excellence (NICE) guidance. NICE guidance advocates more restrictive transfusion practice but is based on clinical trials in non-palliative care contexts; the extent to which these findings should be applied to palliative care remains unclear.

Methods

Four clinical vignettes of common clinical palliative care scenarios were developed. Members of the Association for Palliative Medicine were invited to complete the survey. Results were compared with acceptable responses based on current NICE recommendations and analysed to determine the influence of respondents’ gender, experience or work setting.

Results

27% of 1070 members responded. Overall, ideal or acceptable responses were selected by less than half of doctors to all four vignettes. Doctors were more liberal in prescribing blood transfusions than NICE guidance would advocate. Senior doctors were less likely to choose an acceptable response than junior colleagues.

Conclusion

Palliative care practice is varied and not consistent with a restrictive blood transfusion policy. More recently trained doctors follow less liberal practices than senior colleagues. More direct evidence of benefits and harms of blood transfusion is needed in palliative care to inform practice.
European evidence-based guidelines on pancreatic cystic neoplasms
Authors:   The European Study Group on Cystic Tumours of the Pancreas
Published: March 2018

Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring <40 mm without an enhancing nodule. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter ≥40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule >5 mm, and MPD diameter >10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN.