text:
The standard BDT model is constructed algorithmically to be consistent with both the existing term structure of zero-coupon yields, and (optionally) the term structure of yield volatilities. That is, the main aim of the tree building procedure is to derive a binomial representation for the level of the short-term interest rate such that zero-coupon bond prices computed from the tree are exactly equal to the set of zero coupon prices that are directly observable in the market. If desired, the model can also be constructed so that the implied interest rate distribution at each time step matches an observed interest rate volatility curve.
A general method for constructing binomial trees for the short rate is described fully in Hull and White (1996), Rebonato (1998), and Jamshidian (1991). Clewlow and Strickland (1998) present a comprehensive summary of the Jamshidian construction method, and that reference is the main source of the discussion that follows.
Consider constructing a binomial tree for the short rate that spans a period between time 0 and time T. The entire period can be split into an arbitrary number of i = 1 to N periods such that the length of each period is equal to Dt = T / N. With two discrete outcomes possible from every node, there are a total of i + 1 nodes at each of the i 'th timesteps. This general binomial representation is shown in the following figure, where each node is indexed as (i,j).
The number of states at each timestep is indexed by j. At the initial branch in the tree (i = 0), there is only 1 state and that is indexed as j = 0. At the end of the first period, the short rate has either increased to state j = 1 or decreased to state j = -1. In general, the rate at any arbitrary node i, j (that is not at the extreme top or bottom of the tree) will either move to a node indexed as i + 1, j + 1 (after an up-jump) or i + 1, j - 1 (after an down-jump). The extreme top and bottom nodes are indexed as N, N and N, -N, respectively.
As at time 0, we assume that both the term structure of zero coupon rates and rate volatilities are known. These curves are typically defined for a discrete number of points, and some interpolation scheme will be used to determine rates for maturity dates that are not explicitly included in the input data. Assuming that the zero rate for maturity i is defined as ZR(i ), then a discount function can be defined as:
P(0,i ) = the time-0 price of a zero-coupon bond with unit face value that matures at time i
Dt = the length (in years) of the timestep assumed in the tree construction
Note that this representation of the discount function assumes that the input zero rates are defined with a compounding frequency that matches the chosen length of the timesteps used in the construction of the tree.
The variable of interest at each node in the tree is the short-term interest rate that will apply over the next time interval, r i, j. This rate is known at the beginning of each period and defines the current one period discount rate:
DFi,j = the time i discount factor for state j
Dt = the length (in years) of the timestep assumed in the tree construction
With this background, we can now consider the general intuition behind the tree building process set out by Jamshidian (1991). The technique is referred to as a forward induction process, and involves working through each successive branch in the tree searching for the collection of short-term interest rates which will return a zero-coupon bond price that is consistent with the observed bond price. Further, if the model is also fitted to observed yield volatilities then the chosen set of rates must be consistent with both yields and volatilities.
Jamshidian shows that the level of the short rate at the i'th step in the tree is characterised by:
U(i ) = the median of the lognormal distribution for r at step i
s(i ) = the short-rate volatility at step i
z(i ) = the value of a standard Wiener process
Clewlow and Strickland (1998) show that for each step i in the binomial tree, the expression in the above equation can be operationalized to give an expression for the short rate at each node in the tree. That is,
The remainder of the tree building process is then related to determining the appropriate values for both U(i ) and s(i ) such that the resulting tree is arbitrage-free. That is achieved in part using the concept of state prices (also referred to as Arrow-Debreu prices), which are defined as the time zero value of a pure security that provides a payoff of $1 if node (i, j) is reached, and zero otherwise:
the time zero state price for node (i, j)
PV = present value operator
Zero-coupon bond prices can also be defined in terms of the entire vector of state prices at step i :
State prices can therefore be interpreted as the discounted probability of reaching any node in the tree, and they represent the basic building blocks that can be used to value any financial claim through time. Further, given that the state price at node (0, 0) is equal to 1 by definition and by assuming that the risk-neutral probabilities of an up-jump and down-jump are both equal to 1/2, then we can construct the state prices at all successive nodes 'within' the tree using the following relation:
The state prices for the top and bottom nodes in the tree at each step i are given by:
Consider first just fitting a BDT tree to a set of known zero-bond prices. By assuming a constant volatility (s(i ) = s), the expression in equation (from above) for the short rate is only a time-varying function of U(i ). At each step i in the tree, we have computed all j state prices and are attempting to determine the no-arbitrage short rate at all j nodes. We do so by searching for the rates that satisfy the requirement that:
That is, given that the current value of a zero-coupon bond maturing at time (i + 1) . Dt is known, we can use a technique such as Newton-Raphson to solve for the only unknown in the above equation, U(i ).
Although the BDT model was initially derived specifically using the binomial lattice framework, several authors have subsequently shown that the model implies the following stochastic differential equations for the evolution of the short rate through time. These processes can be directly compared to the equivalent expressions for the Hull-White and Black-Karasinski models discussed in the following sections. The original specification of the model, fit to both the term structure of zero rates and the term structure of volatilities is:
r = the instantaneous short rate at time t
q(t) = value of the underlying asset at option expiry
s(t) = time dependent short rate volatility
When the BDT model is restricted to fit the initial term structure only, the expression in the above equation reduces to:
s = the constant short rate volatility
Copyright 2013 Hedgebook Ltd.


text:
"Name one genius that ain't crazy."
It's finally happened. Kanye West has actually gone insane. His mind has always been in a perpetual state of motion, constantly redirecting his attention from music to art to fashion to Twitter and to God-knows what else. On his latest The Life of Pablo, Kanye's ego has finally the better of him. The rollout for TLOP was an absolute shit show of empty promises and false starts (it still is). The album itself is an absolute mess. I'm not even confident it's finished. In fact, I hope it really isn't finished. If TLOP actually turns out to be an experiment on how the music media will seemingly eat up anything he shits out on both Tidal and Twitter, then I will certainly tip my "Yeezus" cap to him. Until then, I cannot sit here and defend this record.
Not that he needs me to. For all the shit Kanye West gets for is actions outside the studio (some of it deserved, most of it not), people tend to forget that he is a truly gifted musician. Kanye West is a man with a unique gift of musical knowledge and a golden touch for sampling and producing. He is a smart person brimming with ideas and enthusiasm, who can be as articulate as a professor when he wants to be. That's why it's frustrating that Kanye West would release such a deliberately half-hassed product, but I like to think he knows what he's doing. It's like Kanye knows that even if he farts in a microphone, critics will love it anyway. After listening to some of these lyrics, he did exactly that. He spewed a lot of that sort of crap on Yeezus, but at least on that record, the music had purpose and razor-sharp focus. Every word he spoke came across like an exorcising of demons, and we all bought it. On TLOP, the lyrics are cringe-worthy just for the sake of being cringe-worthy, and now I find myself wondering if everything that was said on Yeezus was just as cheap and insincere. As attention-getters, the X-rated lyrics work, but in the end, many of the songs suffer for the ignorance.
But it's not just the lyrics that are way sub-par. The music, 90% of it not even produced by West himself, is consistently inconsistent and relentlessly frustrating. You keep waiting for songs like "FML" and "Highlights", which have SO much potential, to become fully realized. Instead, they feel tossed aside from a man bored with his own creation.
Take the track "30 Hours" for example. Initially, it's one of the best songs on the album, as Kanye raps like he's still wearing pink polos over a beat that would fit right in on The College Dropout. It's hard-hitting, direct, and damn good. That is, until it isn't. Like a NJ Transit train headed to Penn Station, Kanye inexplicably stops. He just gives up on the song, turning a potential show-stopper into a glorified demo. Instead of finishing the song out, he blabbers on about bonus tracks, mumbles a barely conceived verse idea, and even answers his damn cell phone. He just leaves all of that in there! Critics will tell you this is art – the sound of a scatterbrained man at work – but I'm here to tell you this is bullshit. Any track that features Andre 3000 but doesn't actually have Andre 3000 rapping (or doing anything, really) on the song is bullshit. The two rappers had a chance at a banger, but instead settled for an under-cooked piece of meat. It's the story of this album, really. Kanye settles; he never attacks. And he wants Tidal users to pay $20 for this? Come on, man. Would you buy a car with no wheels for $50,000?
Now, that's not to say that TLOP doesn't have its moments of clarity. Like I said, it's easy to forget that Kanye West is a gifted producer. The skeletal "Ultralight Beam" delivers on Kanye's Twitter promise of this album being a "gospel album." Ever the curator, Kanye lets the young Chance the Rapper steal the spotlight with the most captivating verse on a Kanye West album since Nicki Minaj's ferocious debut on "Monsters". The first true taste of TLOP back in January, "Real Friends," is another understated but beautiful gem, with a moody, haunting piano setting the scene for Kanye to once again play the bad friend and even worse family member. It's one of those songs that reminds you why you root for Kanye in the first place. The best song on TLOP by far is "No More Parties in LA," and it's one of the best songs of the year so far. It's a perfect example of what makes Kanye West so great, and also what makes this album so frustration because of how it could've been so much more. Kanye, along with Kendrick Lamar(!), just let loose on this track. The three samples on here, including Junie Morrison's "Suzie Thundertussy," have no right being on the same track together, yet it sounds so seamless and captivating. It's the most fully realized this album gets, and I can guarantee you're going to be hearing a lot more of it blaring out of car stereos this summer.
I want to sit down with Kanye West. I want to tell him that he's capable of so much more. We all know this, and I think he knows it too. So, why is he settling for this? I want to know why he isn't pushing himself to be better, like all the greats. Or maybe he's pushing to hard… no one man should have all that power, right? I'm not looking for the old Kanye; I'm just looking for a sign that the man is still willing to continue to push himself musically, and not merely settle. Give me a chance to interview him, to buy him a beer he desperately seems to need. I want to ask him all these things and more. He'd probably tell me to fuck off, and if he did, I'd be happy because at least that would mean the fire isn't out.

subset: commoncrawl


text:
Listen to this archived episode of The Model Railway Show through
streaming audio at TrainLife!
The Terry and Gerry Show
In this episode…
Terry Gaskin, rapid transit modeler and layout builder.
Gerry Cornwell, owner of the Mt. Albert Scale Lumber Company.
Modeling the EL in O
Mass transit is not generally modeled – especially not in North America.
But consider this: Commuter trains, street cars and subways are often the only trains that people interact with today. Millions of us will take a commuter train or subway to work, five days a week – but not see a freight train at all.
As we think about ways to attract more people to the hobby, perhaps one way is to show them it's possible to model something that's relevant to their life experience.
If so, then we can look to Chicago native Terry Gaskin for inspiration. Terry is modeling one of the most famous such systems in North America – the Chicago Elevated, in O scale. You can follow his progress on his CTA O Scale L Layout blog, too.
Terry joins Jim to talk about why he chose the elevated as a layout subject and the benefits and hurdles of rapid transit modeling. He also shares some ideas for operating such a system, so that when the layout's finished the trains don't just shuttle back and forth.
What's up with Wood
With modern manufacturing materials such as the goop used in the 3D printing process, it's useful to remember that traditional materials have an important place in the hobby too.
Take wood, for instance. Wood is one of the most basic building materials for modellers around the world. Wood is easy to cut, saw, drill, sand, shape and glue. It takes paint or stain beautifully. No workshop should be without a good supply of wood – good wood.
One modeler who thinks a lot about wood is Gerry Cornwell. Gerry is the owner of the Mt. Albert Scale Lumber Company – the go-to source for most hobbyists looking for beautiful, scale wood… which many modelers then distress and destroy to create contest-winning structures (but that's another story).
Gerry joins Trevor to explain how Mt. Albert got started two decades ago, the attraction of modeling in wood, and how his company makes such tiny pieces so precise. (It's not done by HO scale crews using tiny table saws!)
(By the way, if you're in southern Ontario on November 3rd, 2012, the Mt. Albert Scale Lumber Company will be open and running demonstrations as part of the 12th annual Hamilton and District Layout Tour, organized by the HOMES Model Railway Club and Museum.)
How to listen:
Right-click (Windows) or hold Control and click (Mac OS) on the following link for downloading options:
Episode 41 (mp3)
Follow this link for more Episode Guides.
Show off your good taste in podcast listening:
Visit The Model Railway Show swag shop!
Listen to archived episodes at TrainLife.
Join the discussion on The Model Railway Show Facebook Page.
Next time on The Model Railway Show:
Trevor talks to Don Goodman-Wilson about NMRAnet – an emerging standard for layout control.
Jim speaks with John Landis about modeling another unique Chicago railroad, that operated underground.


text:
Would you believe that most, repeat most brands and organizations indulge themselves in something called Unsocial Media Promotion in the name of Social Media Marketing?
Yet, it's not hard to believe because :
1. We are so used to selling / promoting products for so long that we can't think beyond it
2. Not many people know what Social Media Marketing is actually!
It has been our experience and observation that while social media opens up a brand new, dynamic and revolutionary strategic marketing process, most social media practitioners are using it as an extension of old, conventional, tactical marketing tool – simply as a Promotional tool with excessive one-way dialogue. And so, there is nothing social about it nor it is Marketing!
Therefore, though we see a very high page likes (sometimes) – through paid ads – we hardly see any engagements happening.
And as you know, in social media, engagement is the only measurement criterion.
They don't realize that social media engagement measures the activities of their fans and friends – likes, shares, comments, tags, etc - and has almost nothing to do with their posts and pictures? The more they talk, the less is the engagement!
So, how do we move from Unsocial Media Promotions to Social Media Marketing?
Concentrate on the "Social" and the "Marketing" part - that is put emphasis
- on multi-way communication - between you, the brand and your fans, friends, customers, end-users, influencer and brand advocates.
- don't forget your elementary marketing lessons of 4Ps and 3Cs of Product, Price, Place & Promotion and Customer, Competition & Competencies.
In your social media marketing planning, implementation and analysis put a lot of emphasis on in-depth market research (on customers, targets, competition, market trends, etc) and have a structured content management process in place. This should be reviewed every week to see that you are reaching the desired engagement level.
All the best.
(C) Susmita Das Gupta


text:
NDC Partnership
The NDC Partnership is a global initiative to help countries achieve their national climate commitments and ensure financial and technical assistance is delivered as efficiently as possible.
Project Site: http://ndcpartnership.org/
The NDC Partnership is a new coalition of governments and international institutions working together to ensure countries receive the tools and support they need to achieve ambitious climate and sustainable development targets as fast and effectively as possible.
The NDC Partnership launched during the COP22 conference in Marrakech, Morocco on November 15, 2016.


text:
Studies of long-term potentiation (LTP) and long-term depression (LTD) strongly suggest that individual synapses can be bidirectionally modified. A central question is the biochemical mechanisms that make LTP and LTD persistent. Previous theoretical models have proposed that the autophosphorylation properties of CaMKII could underlie a bistable molecular switch that maintains LTP, and there is experimental support for this mechanism. In contrast, there has been comparatively little theoretical or experimental work regarding the mechanisms that maintain LTD. Several lines of evidence indicate that LTD is not simply a reversal of previous LTP but rather involves separate biochemical reactions. These findings indicate that a minimal model of the synapse must involve a tristable system. Here, we describe a phosphatase (PP2A) switch, which together with a kinase switch form a tristable system. PP2A can be activated by a Ca2+-dependent process but can also be phosphorylated and inactivated by CaMKII. When dephosphorylated, PP2A can dephosphorylate itself. We show that these properties can lead to a persistent increase in PP2A during LTD (as reported experimentally), thus forming a phosphatase switch. We show that the coupled PP2A and CaMKII switches lead to a tristable system in which the kinase activity is high in the LTP state; the PP2A activity is high in the LTD state, and neither activity is high in the basal state. Our results provide an explanation for the recent finding that inhibition of PP2A prevents LTD induction.
Substantial progress has been made in understanding how synaptic activity produces bidirectional modifications of synaptic strength [long-term potentiation (LTP) and long-term depression (LTD)]. Single synapse analysis has shown that LTP and LTD occur at individual synapses (O'Connor et al., 2005; Petersen et al., 1998; Sobczyk and Svoboda, 2007). It has been further shown that LTP and LTD are associated with an increase and decrease of spine volume, respectively (Zhou et al., 2001; Matsuzaki et al., 2004). Thus, the biochemical machinery at individual synapses must be capable of at least three stable states.
A CaMKII switch has been strongly implicated in LTP. Activation of this kinase during LTP occurs by an autophosphorylation reaction at Thr286 of the α subunit (Fukunaga et al., 1995; Barria et al., 1997). Once this site becomes phosphorylated, the enzyme can phosphorylate itself even in the absence of Ca2+ (Miller and Kennedy, 1986). Theoretical models have shown that such autophosphorylation could sustain the autophosphorylated state; CaMKII could thus form a bistable switch (Lisman, 1985; Zhabotinsky, 2000; Lisman and Zhabotinsky, 2001; Miller et al., 2005). Consistent with this, genetic deletion of Thr286 blocks LTP and memory (Giese et al., 1998). More recent work shows that interfering with CaMKII during the maintenance phase of LTP can reverse LTP (Sanhueza et al., 2007). There is thus considerable evidence that CaMKII is critical for LTP, though other kinases may also have important roles (Pastalkova et al., 2006).
Less progress has been made in understanding the maintenance of LTD. In one class of models (Lisman, 1989), LTD is viewed as a reversal of LTP and occurs because CaMKII is dephosphorylated. However, while there is evidence that reversal of CaMKII occurs during depotentiation of experimentally induced LTP (Huang et al., 2001; Kang-Park et al., 2003), it now seems clear that LTD is fundamentally different from depotentiation (Zhuo et al., 1999). The first indication of this came from the finding that a phosphatase inhibitor reversed LTD when applied after LTD induction, but has no effect when applied under basal conditions (Mulkey et al., 1993). These results suggest that LTD alters the balance of phosphatase and kinase activities in favor of the phosphatase. Direct biochemical assays of phosphatase activity indicate that LTD induces a transient activation of PP1 and a persistent activation of the PP2A (Thiels et al., 1998). These reactions lead to changes in GluR phosphorylation (Lee et al., 2003). Importantly, the dephosphorylation of Ser845 during LTD is not the opposite of the phosphorylation changes that occur during LTP, which involves the phosphorylation of a Ser831 by CaMKII (Lee et al., 2000). Together, these results leave little doubt that LTD is not simply a reversal of LTP but rather involves a different set of reactions. We have therefore sought to understand how known properties of PP2A might lead to its persistent activation during LTD and, more generally, how a tristable biochemical system might be formed that could account for both LTP and LTD.
Materials and Methods
CaMKII switch.
In the model, Ca2+ influx through NMDAR activates both kinase (K) and protein phosphatase (P), which have different IC50 for Ca2+. The reaction scheme for CaMKII is described in Figure 1A. K and pK are the unphosphorylated and phosphorylated forms, and the * indicates active enzyme. The kinase activity is turned on by phosphorylation, which is produced either by Ca2+ stimulation or autocatalytic phosphorylation. The distinction between inter and intramolecular autocatalytic reactions is not considered here to simplify the problem. Phosphatase (PP2A) inactivates pK by dephosphorylation. Assuming that enzymes kinetics follows Michealis–Menten scheme, the rate equation is expressed as where terms in the right-hand side are, in order, for autophosphorylation of kinase, dephosphorylation by phosphatase, basal kinase activity and Ca2+-dependent phosphorylation. k1, k2, k3 and k4 are rate constants for each reaction. Km1, Km2, and Km are equilibrium constants for kinase, phosphatase and Ca2+, respectively. In the last term, the Hill coefficient of 4 is adapted from considering 4 binding of Ca2+ to activate CaMKII; calmodulin (CaM) has effectively two binding sites of Ca2+ and two Ca2+/CaM are required to initiate phosphorylation of CaMKII (De Koninck and Schulman, 1998). K0 and P0 indicate the basal concentration of active kinase and phosphatase, respectively. The resting Ca2+ concentration is set to 0.1 μm.
The total amount of K and P are conserved:
Phosphatase switch.
The reaction scheme for phosphatase is described in Figure 1B (see Results, Background: experimental findings regarding PP2A control for the reactions assumed). pP is phosphorylated (inactive) form. The activity of phosphatase is turned on by dephosphorylation either from Ca2+-dependent reaction pathways or from autocatalytic intermolecular dephosphorylation. pK inactivates phosphatase by phosphorylation. Then, the rate equation is as follows: where terms on the right-hand side indicate, in order, autodephosphorylation of phosphatase, phosphorylation by kinase (CaMKII or other constitutive kinases) and Ca2+-dependent dephosphorylation. k11, k12, k13 and k14 are rate constants for each reaction. Km11 and Km12 are equilibrium constants for kinase and phosphatase. The Hill coefficient of 3 in the last term in Equation 4 describes the Ca2+-dependence of the dephosphorylation of the phosphatase. This may occur by several different pathways. To the extent that calcineurin is involved, the Hill coefficient is 3 (Stemmer and Klee, 1994). PP2A can also be activated via two Ca2+ bound to the PP2A regulatory subunit, B′′/PR72 (Ahn et al., 2007), and, thus, the Hill coefficient is 2. Our simulations did not reveal strong differences depending on whether the Hill coefficient is 2 or 3.
AMPAR trafficking.
We have taken a simplified view of AMPAR trafficking to provide a readout of the kinase and phosphatase switches. AMPAR is inserted to the synaptic membrane with the rate constant k21 and removed with rate constant k22. The reaction scheme for AMPAR is described as follows: Then the rate equation is where A and Aint indicate the AMPAR on the synaptic membrane and the internalized AMPAR. The total AMPAR is assumed to be conserved on the time scale of these simulations. Since the activities of kinase and phosphatase are thought to be key players in the insertion and the removal of AMPAR, k21 and k22 are dependent on their activities. There is considerable biological complexity to this control involving multiple phosphorylation sites on GluR1 and stargazin (Barria et al., 1997; Tomita et al., 2005); as a first approximation, k21 and k22 are assumed to be proportional to the concentration of active kinase and phosphatase, respectively. where c1 and c2 are scaling factors (or proportional constants), c3 and c4 are rate constants for the processes independent of kinase and phosphatase activities. We stipulate that the excitatory postsynaptic potential (EPSP) is proportional to the amount of AMPAR on the synaptic membrane.
Parameters of the model are listed in supplemental Table S1, available at www.jneurosci.org as supplemental material. One of the key requirements for tristability is the correct balance between autocatalytic activities and mutual inhibitions of enzymes. Maximal kinase and phosphatase activities had to be at the same general level; too weak or too strong mutual inhibitions abolished tristability (see supplemental materials, available at www.jneurosci.org). Parameters in Equations 1 and 2 were adjusted to balance each switch to achieve tristability. Other parameter values did not change the qualitative features of the system (i.e., tristability). Therefore, other parameter values were chosen to reproduce basic aspects of LTP and LTD and then used consistently for all calculations. The numerical simulations were done with the fourth-order Runge–Kutta method using Matlab (version 7.0, The MathWorks).
Background: experimental findings regarding PP2A control
The key idea we wish to introduce is that biochemical properties of PP2A could allow this enzyme to form a phosphatase switch that could underlie the maintenance of LTD. In this section, we briefly review relevant biochemical evidence.
An important observation regarding the regulation of PP2A is that it has autocatalytic dephosphorylation properties analogous to the autocatalytic kinase activity of CaMKII. The first to report the intermolecular self-activating mechanism of PP2A, called autodephosphorylation, was (Chen et al., 1992). The PP2A holoenzyme is composed of 3 subunits: the structural subunit (A), the regulatory subunit (B), and the catalytic subunit (C). Various combinations of A, B, and C subunits and multiple phosphorylation sites make it possible for PP2A to control multiple substrates in a finely tuned manner (Colbran, 2004). Chen et al. (1992) witnessed that the limited phosphate incorporation onto Tyr307 of the catalytic subunit of PP2A by tyrosine kinase p60v-src was maximized by the application of phosphatase inhibitor. They proposed that an autocatalytic activity of PP2A reverses the incorporation of phosphate by further showing thioATP (the phosphate thioester form is resistant to dephosphorylation) instead of ATP, gave rise to the maximal incorporation. Importantly, similar autodephosphorylation properties of PP2A were found at the Ser/Thr sites phosphorylated by CaMKII. Specifically, phosphorylation of B'α subunit, a regulatory B subunit of PP2A, can undergo autodesphosphorylation (Fukunaga et al., 2000).
Two types of results demonstrate that interactions of PP2A and CaMKII lead to functional regulation of each other. The first is the ability of PP2A to dephosphorylate CaMKII (Fukunaga et al., 2000). Dephosphorylation of CaMKII leads to a loss of its Ca2+-independent activity (Miller and Kennedy, 1986). Most importantly, from the viewpoint of the switch model we will develop, CaMKII can phosphorylate and thereby inactivate PP2A (Fukunaga et al., 2000).
LTD is initiated by Ca2+ entry through NMDA channels and this entry is necessary for the activation of PP2A (Thiels et al., 1998). Many potential enzymatic pathways may couple this Ca2+ entry to PP2A. For instance, PP2A can be activated by Ca2+ through striatin (Moreno et al., 2000; Benoist et al., 2006) and/or B′′/PR72 (Ahn et al., 2007). Striatin is a Ca2+/calmodulin-binding protein associated with dendritic spines and PSDs (Moreno et al., 2000; Benoist et al., 2006). It physically binds to PP2A and regulates PP2A activity in a Ca2+/calmodulin dependent manner. B′′/PR72 is a regulatory B subunit of PP2A which has Ca2+ binding sites and is enriched in the striatum and hippocampus (Ahn et al., 2007). Still another possibility is that Ca2+ can activate PP2A via PKC-dependent pathways (Zhang et al., 2007). Finally, it is possible that PP2A is activated when it is dephosphorylated by calcineurin (PP2B) or PP1. The latter is activated during LTD by a calcineurin-I1 pathway (Mulkey et al., 1994). Given the lack of information that establishes the relative roles of these pathways, we have modeled a single Ca2+-dependent pathway for the activation of PP2A; this can be considered the lumped action of the known Ca2+-dependent pathways.
Although there has been consideration of the interplay of CaMKII and PP2A during LTP (Kikuchi et al., 2003), the importance of these reactions in the maintenance of LTD has not been previously considered. In the next section we show that the autocatalytic properties of PP2A could form the basis of a phosphatase switch that underlies LTD maintenance and that is compatible with a kinase switch that underlies LTP.
Tristability of the synapse
CaMKII and PP2A have autocatalytic properties and inhibit each other. These key reactions are schematized in Figure 1C. Thus, the system is such that both kinase and phosphatase are driven by autocatalytic enzyme activities that provide positive feedback to their activation. However, there is also mutual inhibition that prevents strong simultaneous activation of both enzymes. As we will show through simulation, these reactions can yield three stable states.
Theoretical and experimental studies suggest that the intracellular Ca2+ level determines whether LTP or LTD is induced (Lisman, 1989; Neveu and Zucker, 1996); a moderate level of Ca2+ drives the system to the LTD state, whereas a high level drives the system to the LTP state. Following previous models and experimental data (Stemmer and Klee, 1994; De Koninck and Schulman, 1998; Lisman and Zhabotinsky, 2001; Miller et al., 2005), we assume that initiation of CaMKII autophosphorylation requires a much higher Ca2+ level than the initiation of phosphatase activation. As we will show, this leads to different states after different levels of Ca2+ stimulation.
The results of simulations of the model described in Materials and Methods are shown in Figure 2. The LTP simulation results are illustrated as a black trace in Figure 2A. Starting from the initial basal state, a high Ca2+ pulse (4 μm for 2 s; gray area) drove the EPSP magnitude to the potentiated state, which was sustained even after Ca2+ removal. The change of phosphatase and kinase activities is shown in the left panel of Figure 2B. Both enzymes were nearly inactive in the basal state. During high Ca2+ elevation, the kinase became strongly activated. After the end of the induction period, Ca2+ returned to basal levels, but the kinase stayed in the on-state. The high kinase activity suppressed phosphatase activity below baseline levels (Fig. 2B, inset; LTP graph), consistent with experimental results (Fukunaga et al., 2000).
Fig. 2A (left) shows how the basal state is affected by moderate Ca2+ elevation (2.2 μm for 2 s); as shown in the red trace, LTD is induced. The right panel of Figure 2B shows how enzyme activities are affected by LTD. Both enzymes were nearly inactive in the initial basal state. During the moderate Ca2+ elevation, the phosphatase activity became dominant because it is more sensitive to Ca2+ than the kinase. After Ca2+ returned to the resting level, the phosphatase stayed in the on-state and suppressed the basal kinase activity (Fig. 2B, inset, right panel).
We next tested whether these three states are indeed stable. To be considered a stable state, it must be resistant to small perturbations. First, the basal state was tested. Different levels of Ca2+ pulses (step size, 0.1 μm for 2 s) were applied on top of the resting Ca2+ concentration (0.1 μm) and responses were plotted (Fig. 2C). The basal state returned to its original state after termination of small Ca2+ perturbations ranging from 0.1–0.5 μm. To test the stability of LTP and LTD states, similar small perturbations were applied. Again, both LTP and LTD states returned to their original states at the end of the perturbations (data not shown). Together, these results demonstrate that the basal state can undergo LTP or LTD depending upon the Ca2+ stimulation, and that each of the states is resistant to small perturbations. The system as whole is thus tristable. The results account for three experimental observations: the activation of CaMKII and inactivation of PP2A during LTP and the activation of PP2A during LTD (Fukunaga et al., 1993, 2000; Thiels et al., 1998).
To further characterize the transitions between states, we systematically varied the concentration of Ca2+ pulses. For Ca2+ concentrations between 0.1 and 0.5 μm, the system stayed in basal state. In the range between 0.6 and 2.5 μm, the basal state underwent LTD while it underwent LTP in the Ca2+ concentration >3.0 μm. Between 2.6 and 2.9 μm of Ca2+, neither LTP nor LTD was inducible. Thus, a curve similar to the BCM curve (Bienenstock et al., 1982) is generated by plotting the final level of EPSP against Ca2+ concentration (Fig. 2D).
The reversal of LTP and LTD has been reported in experimental studies (Muller et al., 1995; Huang et al., 2001). The reverse of LTP and LTD is called depotentiation and dedepression, respectively. We tested whether such reversal could occur in our model. As shown in Figure 2E, this was the case. After LTP was induced from the basal state by high Ca2+ elevation (4 μm for 2 s), a moderate level of Ca2+ (2.2 μm for 1.4 s) reversed the potentiated state back to basal level (depotentiation). Stimulation with moderate Ca2+ (2.2 μm for 2 s) induced LTD, after which dedepression by high Ca2+ (2.93 μm for 2 s) reversed it (dedepression).
Phase space analysis
To understand the dynamics of the model graphically, nullclines at different Ca2+ concentrations (basal level, LTP induction and LTD induction) were plotted (Fig. 3). At resting Ca2+ level, nullclines (Fig. 3, left panel) intersected at five points; three were stable points (filled circles at top left, bottom left and bottom right) and two were unstable (open circles). Small arrows indicate how the system moves to one of the stable points from any arbitrary point. In the basal state, the system was stable at the bottom left point. During LTP induction, the Ca2+ elevation deformed the nullclines to create only one stable state. After Ca2+ removal, nullclines formed three stable states again, but the system stayed in the bottom right stable point (LTP) (Fig. 3, top right panel). During LTD induction, the moderate level of Ca2+ elevation deformed nullclines to create one stable state. After Ca2+ removal, nullclines formed three stable states again and the system moved to top left stable point (LTD) (Fig. 3, bottom right panel). Phase space analysis for depotentiation and dedepression is described in supplemental materials, available at www.jneurosci.org as supplemental material.
Although there has been substantial investigation of how a bistable kinase switch could account for a stable transition between the basal and LTP states, there has been relatively little experimental or theoretical work on the process that maintains LTD. The simulations presented show that biochemical mechanisms of PP2A, notably its autodephosphorylation properties, allow it to function as a bistable switch that could underlie LTD. We have further shown that the phosphatase and kinase switches can be coupled, giving rise to a tristable system. Transitions between states are triggered by moderate and high Ca2+ elevations that occur during LTD and LTP respectively (Lisman, 1989; Neveu and Zucker, 1996). Moreover, the model reproduces the BCM function (Bienenstock et al., 1982).
The proposed mechanism of persistent phosphatase activation is based on the principle of autocatalysis, specifically autodephosphorylation, for which there is direct experimental support. Thus, during LTD, PP2A is largely dephosphorylated and active; any PP2A that is phosphorylated by basal CaMKII activity is rapidly dephosphorylated by the remaining unphosphorylated PP2A, thereby maintaining a stable LTD state. It can be seen that the underlying principle is similar to that of the CaMKII switch responsible for LTP in which any site dephosphorylated by basal phosphatase activity is rephosphorylated by the remaining phosphorylated CaMKII.
In an earlier model of bidirectional modification, a single storage variable, the phosphorylation of CaMKII, could be bidirectionally modified, thereby accounting for LTP and LTD (Lisman, 1989). However, as reviewed in the Introduction, such a model does not account for the very different kinds of biochemical reactions observed during LTP and LTD. The current model can account for these observations because there are two interacting molecular switches, a kinase switch and a phosphatase switch. These switches are both stable and therefore can account for the maintenance of LTP and LTD. Other theoretical models have succeeded in describing how different levels of Ca2+ trigger LTP or LTD, but have avoided the issue of how LTP and LTD are maintained, focusing only on the induction processes (Migliore et al., 1995; Castellani et al., 2001, 2005; Zhabotinsky et al., 2006).
Limitations of the model
Several limitations of our model should be noted. Both LTP and LTD are synapse-specific modifications and it is therefore important to specify how the underlying biochemistry is localized to a particular synapse. In the case of the CaMKII, the localization of CaMKII in the PSD makes it likely that the CaMKII switch is actually localized in the PSD (Strack et al., 1997; Chen et al., 2005; Mullasseril et al., 2007). PP2A is present both in the cytoplasm and the PSD, but the current model is not explicit regarding the localization.
A second limitation stems from uncertainty about how Ca2+ activates PP2A during LTD induction. The calcineurin-I1-PP1 cascade could lead to PP2A dephosphorylation and thus activation (see review in Results), genetic deletion of forms of calcineurin either has no effect on LTD (Zhuo et al., 1999) or produces only a partial block of LTD (Zeng et al., 2001). Perhaps most likely is that multiple pathways are involved. As mentioned in Results, PP2A can be activated by Ca2+ through striatin, a Ca2+/calmodulin-binding protein associated with dendritic spines and PSDs (Moreno et al., 2000; Benoist et al., 2006) and/or B′′/PR72, a regulatory B subunit of PP2A which has Ca2+ binding sites and is enriched in the striatum and hippocampus (Ahn et al., 2007). Still another possibility is that Ca2+ can activate PP2A via PKC-dependent pathways (Zhang et al., 2007). There is also uncertainty about the targets of PP2A. LTD affects the balance of PKA and PP1 activities and thereby leads to a reduction of Ser845 on GluR1. How this might be controlled by PP2A activity remains unclear. We speculate that PP2A may dephosphorylate cofilin, thereby leading to a reduction of F-actin and the associated AKAP-PKA complex which alter the balance of PKA and PP1. A final limitation is that the proposed model is applicable only to early LTD because the protein synthesis required for late LTD (Sajikumar and Frey, 2003) is not taken into consideration.
Data accounted for and predictions
Our model suggests a mechanism for the persistent activation PP2A induced by LTD induction (Thiels et al., 1998). No previous explanation of this persistence has been proposed. A critical prediction of our model is that PP2A activation should be necessary for LTD induction and maintenance. After finishing our simulations (Nicholls et al., 2008) reported that this is the case; specific inhibition of PP2A blocks NMDAR-dependent LTD without affecting LTP, depotentiation and mGluR LTD. Whether PP2A is also required for LTD maintenance (this is tested by inhibiting the enzyme after induction) has not been tested. Further experiments may test the role of autodephosphorylation, the reaction that provides the positive feedback that maintains PP2A activity. Mutant of this site to a pseudophosphorylated form this should block LTD; mutation to a nonphosphorylatable form should lock the synapse in the LTD state.
This work was supported by National Institutes of Health (NIH) Grant R01 NS027337-19 and National Institute of Neurological Disorders and Stroke–NIH Grant R01 NS050944. We thank Drs. Edwin Richard, Nikolai Otmakhov, and David Brautigan (University of Virginia, Charlottesville, VA) for helpful comments on this manuscript; and Drs. Kong-Fatt Wong (Princeton University, Princeton, NJ), Irv Epstein, Anatol Zhabotinsky, and Paul Miller for useful discussions.
- Correspondence should be addressed to John E. Lisman, Department of Biology, Brandeis University, Waltham, MA 02454. lisman{at}brandeis.edu


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- Research article
- Open Access
- Open Peer Review
Effect of a multi-faceted quality improvement intervention on inappropriate antibiotic use in children with non-bloody diarrhoea admitted to district hospitals in Kenya
© Opondo et al; licensee BioMed Central Ltd. 2011
- Received: 11 April 2011
- Accepted: 25 November 2011
- Published: 25 November 2011
There are few reports of interventions to reduce the common but irrational use of antibiotics for acute non-bloody diarrhoea amongst hospitalised children in low-income settings. We undertook a secondary analysis of data from an intervention comprising training of health workers, facilitation, supervision and face-to-face feedback, to assess whether it reduced inappropriate use of antibiotics in children with non-bloody diarrhoea and no co-morbidities requiring antibiotics, compared to a partial intervention comprising didactic training and written feedback only. This outcome was not a pre-specified end-point of the main trial.
Repeated cross-sectional survey data from a cluster-randomised controlled trial of an intervention to improve management of common childhood illnesses in Kenya were used to describe the prevalence of inappropriate antibiotic use in a 7-day period in children aged 2-59 months with acute non-bloody diarrhoea. Logistic regression models with random effects for hospital were then used to identify patient and clinician level factors associated with inappropriate antibiotic use and to assess the effect of the intervention.
9, 459 admission records of children were reviewed for this outcome. Of these, 4, 232 (44.7%) were diagnosed with diarrhoea, with 130 of these being bloody (dysentery) therefore requiring antibiotics. 1, 160 children had non-bloody diarrhoea and no co-morbidities requiring antibiotics-these were the focus of the analysis. 750 (64.7%) of them received antibiotics inappropriately, 313 of these being in the intervention hospitals vs. 437 in the controls. The adjusted logistic regression model showed the baseline-adjusted odds of inappropriate antibiotic prescription to children admitted to the intervention hospitals was 0.30 times that in the control hospitals (95%CI 0.09-1.02).
We found some evidence that the multi-faceted, sustained intervention described in this paper led to a reduction in the inappropriate use of antibiotics in treating children with non-bloody diarrhoea.
Trial registration
International Standard Randomised Controlled Trial Number Register ISRCTN42996612
- Neonatal Sepsis
- Partial Intervention
- Control Hospital
- Multilevel Logistic Regression Model
- Restricted Randomisation
Diarrhoea remains one of the leading causes of mortality in childhood, accounting for 15% of the approximately 8.7 million deaths of under-5 year olds worldwide in 2008 alone [1]. Current best-practice guidance for treatment of diarrhoea is contained within the World Health Organisation's strategy for Integrated Management of Childhood Illness (IMCI), a strategy adopted by over 100 countries worldwide [2]. This strategy is intended to foster correct diagnosis and treatment of common childhood illnesses in outpatient and inpatient settings with guidance for small hospitals published in the Pocket Book of Hospital Care for Children [3]. However reports indicate that success in implementation of diarrhoea case management has been varied [4–8].
Treatment guidelines for diarrhoea emphasise that patients be assessed for presence of blood in stool; non-bloody diarrhoea is to be managed with fluids only (unless co-morbidities are present which require different treatment), while bloody diarrhoea, presumed to be dysentery, should be managed with fluids and antibiotics. This is a pragmatic approach informed by the observation that most non-bloody diarrhoea episodes in the under-5 age group in low-income settings are self-limiting and are caused by pathogens not susceptible (e.g. rotavirus, astrovirus and enteric adenovirus) to antibiotic therapy or for which antibiotics are likely of little value or even deleterious (e.g. salmonellae and campylobacter) [9]. In contrast a significant proportion of episodes of bloody diarrhoea caused by shigella are associated with considerable mortality and are ameliorated by antibiotic therapy [10]. Furthermore correcting dehydration is clinically more important due to its association with adverse outcomes. Despite the fact that the guidelines are unambiguous, inappropriate antibiotic use remains common [11]. Antibiotic misuse may accelerate acquisition of antibiotic resistance [12] necessitating the use of more expensive alternative drugs [13, 14] and is a serious threat to drug therapy of infectious diseases [15, 16]. It may also be associated with missed opportunities to make correct diagnoses and as a result further increase in treatment cost. These undesirable consequences are disproportionately greater in low income countries which bear a bigger burden of infectious diseases [17]. However, research that explores the reasons for unnecessary antibiotic use in low-income settings is unusual; research that explores the effects of interventions on this outcome, particularly amongst inpatient populations, is rare. We conducted a multi-faceted intervention trial in Kenya aimed at improving key inpatient paediatric care practices spanning assessment, diagnosis and treatment of malaria, pneumonia and non-bloody diarrhoea using 14 process-of-care indicators. The effect of this intervention on these practices has been reported previously [18]. Here, we use these data to investigate whether the intervention (described subsequently) reduces inappropriate antibiotic use in the children admitted with non-bloody diarrhoea using a hierarchical modelling approach.
This trial was undertaken between 2006 and 2009 with the main end-point in 2008. It investigated whether an intervention delivered at the hospital level comprising training health workers on the use of evidence-based guidelines for paediatric care, local facilitation, and external supervision and feedback, would improve the quality of care given to children with specific diagnoses admitted to Kenya's district hospitals [18]. In this paper we explore associations between the intervention and evidence for inappropriate antibiotic use in cases of non-bloody diarrhoea. This outcome was not a pre-specified trial endpoint.
Kenya has a population of just over 39 million (2009 population census). Infant mortality rate is 54 deaths per 1000 live births and under-five mortality rate is 78 per 1000. Diarrhoea causes 20% of under-five deaths [19]. Administratively, Kenya has eight provinces each subdivided into districts; in total there were 70 districts (1999 boundary review) at the time of the study each with a district hospital providing walk-in and referral care. This study was conducted in eight district hospitals purposefully selected to represent typical variations in disease risk and hospital size from four of the eight provinces [20]. A restricted randomisation procedure was then used to assign the 8 hospitals into two groups of four in an effort to maintain balance across the groups with respect to the key characteristics considered during selection [18].
Due to the nature of the intervention it was impossible to blind the health workers or the research team delivering the intervention to the group allocations. However the caretakers of children whose case records were examined were unaware of these allocations. The admission records of children aged 1 day to 12 years hospitalised with a diagnosis of one or more of the common serious childhood illnesses including diarrhoea, dehydration, malaria, pneumonia, meningitis, malnutrition, anaemia and neonatal sepsis were selected using a random and uniform sample of admission dates between the 6-monthly surveys.
The intervention
A detailed description of the development and context of the intervention is available elsewhere [20, 21]. Briefly, it involved adaptation of evidence-based practices for assessing, classifying and managing childhood malaria, pneumonia, diarrhoea and dehydration, malnutrition, anaemia, meningitis, neonatal sepsis and prematurity to the local situation with development of management protocols disseminated by the Ministry of Health. Thus, training spanned a large number of recommendations. Recommendations for managing non-bloody diarrhoea alone included appropriate history-taking, assessment for shock and dehydration, classification of severity of dehydration and appropriate rehydration therapy, four key recommendations (of which one was a primary trial outcome-accuracy of intravenous fluid prescriptions) [18]. The use of antibiotics for non-bloody diarrhoea was actively discouraged and represented a fifth key recommendation in this area. This management plan was summarised within the clinical protocols provided within guideline booklets for clinicians and nurses and wall charts.
A training programme for health workers was developed to help implement these guidelines (called ETAT+, described in full by Irimu et al. [22]) and piloted prior to their use in this study. The full intervention had several components including: the five-and-a-half day theory and practical training (ETAT+) in recommended practices for 30-34 hospital staff at each intervention site (in total 90 nurses, 11 medical officers and 29 clinical officers providing paediatric care referred to here as 'clinicians' were trained across the four hospitals); clinical practice guidelines and job-aids for all health workers providing paediatric care; 2-3 monthly supervision of hospitals' implementation by a paediatrician from the study team to discuss progress in guideline implementation, informed by data from surveys when available (see below), and identify local strategies for problem-solving with senior hospital staff (described by Nzinga et al. [23]); a local facilitator from among the hospital staff assigned to promote guideline implementation for 18 months; six-monthly surveys to assess progress and collect data for the study; and written and face-to-face feedback on findings after each survey. Written and face to face feedback focused on key trial outcomes but also provided information on inappropriate antibiotic use for non-bloody diarrhoea amongst many other indicators of quality of care. Face to face feedback was provided by those undertaking supervision six-monthly, however the wider supervisory process (2-3 monthly) was not standardised tending to focus on key, hospital specific problems related to pre-identified key indicators [18] and follow up of locally developed action plans. While the main trial outcomes were thus the focus of intervention it was hoped that by providing a broad set of guidelines, linked to training and an increased emphasis on provision of quality care fostered by the process of supervision and feedback that a wider set of practices might improve.
A partial intervention was delivered to 'control' hospitals including: the same 1.5 days didactic training on the use of guidelines as in the full 5.5 days course that was given to 35-40 hospital staff at each site (107 nurses, 6 medical officers and 21 clinical officers in total across the four sites); the clinical practice guidelines and job-aids; and written feedback after contemporaneous surveys. The partial intervention was not typical of this setting; it was better than the support that would routinely have been provided by the Ministry of Health, notably in the provision of written performance feedback.
The study began with baseline surveys in July and August 2006 conducted over two weeks at each hospital. Subsequent surveys were done in 6-month intervals over the next 18 months during which the intervention was delivered. The main outcome for this analysis was inappropriate prescription of antibiotics to children with non-bloody diarrhoea.
Data collection procedures and tools
During each survey records of patients admitted to hospital with acute illness on a set of random dates within the preceding six months (generated using Stata™) were selected with the aim of obtaining 400 records per hospital per survey [18]. Each record was assigned a unique ID number linking to a hospital and survey, and another ID number for the attending clinician linking to clinicians' characteristics. Data were collected using a patient case-record data abstraction form. Data collectors were trained for three weeks prior to the first data collection exercise and sent to the field in four teams of four each supervised by a member of the study team [20]. It was not possible to blind the data collectors to the group allocations. However the objectivity and consistency of the collected data was improved by rotating the teams for subsequent data collection exercises. 10% of the data at each site was double-collected during each survey to assess agreement which was consistently above 95%.
Eligible sample
Exposures and outcome measures
Key characteristics of the 1, 160 children with non-bloody diarrhoea
Age (years)
Median 0.8, IQR 0.6-1.3, N = 1, 160
Male 550 (47.4%); female 441 (38.0%); not recorded 169 (11.3%), N = 1, 160
Weight (kg)
Median 8.0, IQR 6.6-9.0, N (recorded) = 728
Length of illness prior to admission (days)
Median 3.0, IQR 2.0-5.0, N (recorded) = 1, 062
Summary of characteristics of clinicians admitting the 1, 160 children (CO = clinical officer, MO = medical officer, paed = paediatrician)
Age group (years)
Experience (years)
134 (43.5%)
CO intern
107 (34.7%)
56 (18.2%)
< 1
140 (45.5%)
78 (25.3%)
58 (18.8%)
112 (36.4%)
37 (12.0%)
96 (31.2)
45 (14.6%)
23 (7.5%)
12 (3.9%)
1 (0.3%)
10 (3.3%)
> 10
8 (2.6%)
97 (31.5%)
3 (1.0%)
111 (36.0%)
2 (0.7%)
1 (0.3%)
1 (0.3%)
100 (32.5%)
Statistical analysis
All children were assumed to have received the group treatment their hospitals had been allocated to therefore the analyses described here adhere to the 'intention-to-treat' principle. The trial was a cluster randomised trial, and any analysis needs to allow for this. Given that individual level regression methods do not necessarily perform robustly when there are relatively few clusters [24], we adopted a two stage approach to the analysis [25]. The first step was to carry out an unadjusted cluster-level analysis where we calculated the observed proportions of children receiving inappropriate antibiotics at each hospital during each survey. The difference in the mean proportions in the control and intervention groups was then assessed using a t-test. An adjusted cluster-level analysis was then undertaken. A forward-and-backward stepwise variable selection procedure within a hierarchical logistic regression model was used to identify predictors of inappropriate antibiotic use from the patient-level factors in table 1 and Figure 2 and clinician-level factors in table 2. We then fit a logistic regression model using as covariates the factors found to be associated with the outcome excluding the effect we are interested in (here the effect of the intervention). We then obtained covariate-adjusted residuals based on the difference between observed proportions of children experiencing the outcome at baseline and the main end-point versus predicted proportions from the logistic model. This difference-residual was computed for each cluster (hospital) and difference between the mean difference-residual in the control and intervention groups was again assessed using a t-test. In the absence of an effect the group means of these residuals should be similar.
The second approach to the analysis was a multilevel logistic regression model to estimate the intervention effect. Details of this model are given in the appendix. The model was adjusted for survey period and other previously identified important covariates. It also included interaction terms to estimate how the effect of the intervention was modified by the different survey periods thus allowing for time. Likelihood ratio tests were carried out to decide which terms to retain in the model. Hospital and clinician intra-cluster correlation coefficients were estimated from the final model [26].
All analyses were done using Stata™ v.11 (Stata Corp., College Station, Texas) and were based on complete case-records only. Ethical approval for the trial was granted by Kenya Medical Research Institute National Ethics and Scientific review committees (SSC No. 991).
The multilevel logistic regression model with clinician and hospital random effects
Odds ratio
1st Follow-up
2nd Follow-up
3rd Follow-up
Group × Survey
Intervention × Baseline
Intervention × 1st Follow-up
Intervention × 2ndFollow-up
Intervention × 3rd Follow-up
< 0.001
Not recorded
Standard deviation
Standard deviation
Clinical practice guidelines are applied in healthcare settings with the aim of improving the process of care. Studies in a variety of settings and clinical fields generally show that guidelines improve processes and outcomes of care [27]. However most of these studies have been poor quality individually randomised studies or studies in primary healthcare settings that are not comparable to hospitals in a low income country. Guidelines are very important when new evidence makes it necessary to change practice. In cases of non-bloody diarrhoea in children guidelines discourage the use of antibiotics. Focusing on this as a process-of-care measure for diarrhoea case management we sought to determine whether this outcome was influenced by an intervention promoting the uptake of a set of practice guidelines aimed at health workers caring for children admitted to hospital. This outcome is relevant to our setting because childhood diarrhoea and dehydration are leading causes of death, and contemporary evidence favours effective supportive treatments such as rehydration while discouraging antibiotic therapy except in cases of dysentery [9]. Furthermore inappropriate use of antibiotics is a waste of important resources that a low-income country can ill afford. While other interventions are also important in reducing the burden of disease and costs attributable to diarrhoea, such as staff hand-washing that was also promoted within the intervention, our study design did not allow us to evaluate any effect of the intervention on these practices.
We used two approaches to the analysis of the data: an adjusted t-test to assess evidence of a difference in mean effect between the full intervention and control (partial intervention) hospitals-a simple but robust approach [25]-and a hierarchical logistic regression model for these repeated survey data. The latter method allows for the clustering within the data in acknowledgement of the reality that the hospital is the unit of intervention, but can be faulted for underestimating higher-level variances for binary covariates when lower-level units (clusters) are few relative to higher-level units (individuals) [24]. Imbalances may also occur between intervention and control groups with respect to covariates predictive of the outcome when the number of higher-level units is relatively small.
Both procedures provide comparable weak evidence of a possibly substantial intervention effect, with the individual level model indicating that children in the intervention hospitals had just under one-third the odds of receiving antibiotics inappropriately compared to those in the control hospitals by the trial endpoint. This evidence of an intervention effect complements that derived from analyses of the trial's main outcomes (structure indicators of availability of key resources supporting service delivery, process errors in management of pneumonia, malaria and diarrhoea/dehydration, and outcome indicators of adherence to key policy recommendations) [18] and suggests broader benefits than so far reported. A new finding was some evidence that the intervention effectiveness was modified by survey period; this suggests a dose-dependent effect on the outcome. Thus the accelerated improvement in the intervention arm compared with the control arm suggests a true effect of the full intervention. For ethical reasons no comparable data are available from hospitals without any form of intervention although baseline data perhaps indicate typical prevalence of inappropriate antibiotic use. It is therefore not possible to determine if the less marked improvement in hospitals receiving the partial intervention was also an intervention effect or represented just a secular trend. Nevertheless this, along with other results of the trial [18], represents the first evaluation of a complex intervention in our setting and evidence that it promotes good paediatric care practice.
Restricted randomisation was used to create the group allocations. It must be acknowledged that when randomising only 8 units of analysis the potential for residual confounding, even after identifying and adjusting for other associations with the outcome as above, is considerable. Still, the model showed no evidence that the baseline differences in the outcome between the hospitals was more than would have been expected by chance (OR 0.85, p-value 0.843). Furthermore the objective nature of the exposures and outcome further strengthen the analysis. Interestingly between-clinician differences contributed almost two-thirds of overall variability in the data, suggesting that hospitals as organisations do not necessarily promote consistent practice amongst clinicians within them.
We found that children with crackles had increased odds of receiving inappropriate antibiotics. Crackles are commonly associated in health worker training with lower respiratory tract infection. However in the national (and international) guidelines provided and used in training the diagnosis of pneumonia, which requires treatment with antibiotics, does not depend on observing crackles. Rather, it should be made in children with elevated respiratory rates or other signs of respiratory distress. Our results and anecdotal experience however suggest clinicians generally find this diagnostic advice difficult to accept. Nevertheless, and interestingly, in these data the clinicians recording the presence of crackles did not record a diagnosis of pneumonia; in the analysis this therefore was classified as inappropriate antibiotic use. Absence of information on crackles was also associated with inappropriate antibiotic use. An alternative or complementary hypothesis is that clinicians who carefully record clinical signs, and find them to be negative, are more likely to adhere to guidelines. Qualitative research might be particularly useful to examine such hypotheses and facilitate understanding of inappropriate antibiotic use in hospitalised children with diarrhoea.
Limitations of the study
The main limitation from the study design is the relatively small sample of 8 hospitals. This is likely to be insufficient in characterising the diversity of patients, clinicians and hospitals in the country. However feasibility issues make working with large numbers of hospitals difficult in low-income settings [21]. Missing data is another problem, and this is especially true of clinician-level data. This may explain why few clinician-level variables were important in the combined adjusted models. Adjustment for baseline values was an important part of the analysis; however missing and poor quality data was most prevalent at the baseline survey and this may have led to misclassification of patients as not needing antibiotics more often than in subsequent surveys; the effect of this would be to overestimate the true change of the outcome over the course of the intervention.
A limitation arising from the analysis strategy and procedures include the use of the stepwise variable selection procedure, which in performing a large number of tests increases the probability of 'false positive' findings and models based on chance findings [28]. Models constructed using this procedure tend to have very small p-values and may be sensitive to small changes in the underlying data, and may also be poor at predicting outcomes in different situations from those generating the data from which they are based. Another limitation is the fact that this was a post-hoc analysis which was not specifically anticipated in the original study design; the data available from the study may therefore not be sufficient for answering the questions posed.
Finally, patients' signs and symptoms not included in the case record were deemed to have been unavailable to the clinician to help in making a diagnosis and were coded as 'not recorded'. This category obviously contained a mix of patients with and without the sign/symptom. A bias may have arisen if there was an association between the missing observations and the outcome [29]. Multiple imputation can be used to further explore this issue.
We are not aware of any other studies evaluating an intervention intending to improve care for multiple, common and life-threatening illnesses in children admitted to hospitals in low-income settings using a randomised controlled design. The intervention provided training on evidence-based paediatric care with facilitation, supervision and feedback delivered at the hospital level. In the analyses presented we show that the intervention substantially reduced the odds of a child being inappropriately treated with antibiotics for non-bloody diarrhoea, an improvement in care that is in addition to the findings of improvement in most of the 14 process of care indicators forming the primary endpoint for the trial [18]. Most previous intervention studies to improve care, in both developed and developing countries, have focused on single diseases and have often demonstrated only modest improvements in practices, The data we bow report indicates even wider benefits of the intervention than suggested in the main study results implying that the intervention effects may cut across all diseases covered by the guideline package approach. Other ongoing analyses of the intervention suggest that it requires modest financial investments for comparatively substantial improvements in quality of care. Enhanced medical education focusing on rational use of antibiotics is necessary to improve clinicians' prescribing habits; we have shown that it is possible to change practices using an integrated approach and that perhaps, at hospital level, this is preferable to the recent focus on disease-specific interventions within low-income settings.
Appendix: the hierarchical logistic regression model
Let Y ijk be the outcome of patient i who was attended to by clinician j in hospital k. Let x 1 be a binary variable representing the intervention group, x 2 a binary variable representing the survey (baseline vs. final post-intervention), and x 3 an interaction parameter to represent how the intervention is modified by successive surveys. We also define z l as any other covariate(s) associated with the outcome to be adjusted for in the model.
with clinician-level random-effects u j ~ N(0, σu j 2), and, conditional on u j , hospital-level random-effects u jk ~ N(0, σu jk 2).
showing that the relationship between the outcome and the intervention has a slope of β 1 + β 3 S and random intercept α + β 2 S + Σ l γ l z ijkl + u j + u jk .
in the intervention group (x 1 = 1). The difference between these two patients is the intervention effect at baseline, which is β1.
in the intervention group. The intervention effect due to this survey is β 1 + β 3 s. To obtain the baseline-adjusted intervention effect we find the difference between effects at these two study points, which is β 3 s - the interaction between the intervention and survey s.
The authors are grateful to the staff of all the hospitals included in the study and colleagues from the Ministry of Public Health and Sanitation, the Ministry of Medical Services and the KEMRI-Wellcome Trust Research Programme for their assistance in the conduct of this study. We acknowledge the Director of KEMRI, with whose permission this work is published.
Funds from a Wellcome Trust Senior Fellowship awarded to Dr. Mike English (#076827) made this work possible. Dr. Charles Opondo is supported by a Wellcome Trust Master's Fellowship (#089349). The funders had no role in the design, conduct, analyses or writing of this study or in the decision to submit for publication.
Authors' Affiliations
- Black RE, Cousens S, Johnson HL, Lawn JE, Rudan I, Bassani DG, Jha P, Campbell H, Walker CF, Cibulskis R, Eisele T, Liu L, Mathers C, Child Health Epidemiology Reference Group of WHO and UNICEF: Global, regional, and national causes of childhood mortality in 2008: a systematic analysis. Lancet. 2010, 375: 1969-1987. 10.1016/S0140-6736(10)60549-1.View ArticlePubMedGoogle Scholar
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- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/11/109/prepub
Pre-publication history
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


text:
Oscars: Philippines Unveils Shortlist of Contenders for Foreign Language Category
Titles include two films by director Erik Matti, Brillante Mendoza's "Thy Womb" and "Dance of the Steel Bars," inspired by viral YouTube footage of inmates dancing in a Filipino prison.
The Film Academy of the Philippines has announced its shortlist of local titles competing to become the country's submission for this year's foreign language category Oscar.
Based on sheer numbers, director Erik Matti would appear to have the best odds of becoming the Philippines' official entry. Of the eight films selected by the FAP, two are from the director: comedy horror Tiktik: The Aswang Chronicles and hitman thriller, On the Job, which premiered in the Directors' Fortnight at Cannes in May.
PHOTOS: 50 Never-Before-Seen Portraits From Cannes
Another festival favorite, Brillante Medoza made the cut with his social drama Thy Womb, which bowed in competition at the 69th Venice International Film Festival.
As is often the case for national submissions, historical biopics figure prominently on the list: namely, Supremo starring Alfred Vargas as Philippine hero Andres Bonifacio and El Presidente about the life of Emilio Aguinaldo, the country's first president.
The other selections include Dance of the Steel Bars, inspired by real-life footage of inmates dancing at a prison in Cebu, which became a viral sensation on YouTube; road rage comedy Tuhog by Veronica Velasco; and redemptive child abuse drama, Boses, from Ellen Ongkeko- Marfil.
To qualify for the Oscars' Best Foreign Language Film category, movies must have been commercially exhibited in their country for at least seven days during the period of October 2012 to September 2013. The FAP says it may still add more films to the list, if anything worthy is released this month.
To date, no Philippine film has ever won or been nominated in the Best Foreign Language category.


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American National Announces Employee Changes in Greensboro
For more information, contact:
Jeffrey V. Haley
President & Chief Executive Officer
American National Bank and Trust Company
FOR IMMEDIATE RELEASE: January 16, 2014
DANVILLE, VA American National Bank and Trust Company announced today the following employee changes and promotions in the Greensboro Region:
Rhonda P. Joyce has been named Senior Vice President & Market President for the Greensboro Region. An alumna of the University of North Carolina at Chapel Hill, Joyce joined American National (formerly MidCarolina Bank) in 2003 to start their loan production office in Greensboro. Joyce has been in banking for more than 27 years in Greensboro. The current Chair of the Board of the YMCA of Greensboro, she is also on the Board of the Greensboro Chamber Operating Group, on the Board of Directors of the Guilford Merchants Association and FirstPoint, a member of Summit Rotary, a member of the Womens Professional Forum, a graduate of Leadership Greensboro and a member of Stoney Creeks Ladies Golf Association.
Mary Bridges-Hicks has been promoted to Vice President. With more than 30 years of banking experience, Bridges-Hicks has served in branch management, relationship management and mortgage lending. An alumna of High Point College, she currently serves as a Relationship Manager and Mortgage Lender for the Greensboro Region.
Jennifer Stetler has been promoted to Vice President. Stetler currently serves as a Relationship Manager and Business Development Officer for the Greensboro Region. Her 17 years in banking have included various roles in sales, retail, small business lending and banking management. Prior to her career in banking, Stetler served our country as an active duty member of the U.S. Air Force. She has worked with numerous volunteer organizations, including the Big Brothers Big Sisters program, Habitat for Humanity and United Way. An 11-year member of Kiwanis International, she also currently serves as Immediate Past President for the Nat Greene Kiwanis Club of Greensboro and as Chairwoman of the Board for Our Lady of Grace Catholic School of Greensboro. Stetler is a graduate of Leadership Greensboro and an ambassador for the Greensboro Chamber of Commerce.
Melody Albright has been promoted to Assistant Vice President. Albright currently serves as a Loan Compliance Specialist. An alumna of Greensboro College, she has nine years of banking experience in loan operations, commercial lending and compliance. Having previously worked as a real estate paralegal, she is a North Carolina Bar-Certified Paralegal. In addition, Albright serves as President of the Pilot Club of Greensboro, a service organization that assists people with brain injuries and brain disease.
As one of our key markets, Greensboro is an important focus for us, said Jeffrey V. Haley, President & Chief Executive Officer. We are excited about the significant growth we have experienced under the exceptional leadership of Rhonda Joyce and look forward to continuing this momentum.
About American National
American National Bankshares Inc. is a multi-state bank holding company with total assets of approximately $1.3 billion. Headquartered in Danville, Va., American National is the parent company of American National Bank and Trust Company. American National Bank is a community bank serving southern and central Virginia and north central North Carolina with 25 banking offices and two loan production offices. American National Bank and Trust Company also manages an additional $607 million of trust, investment and brokerage assets in its Trust and Investment Services Division. Additional information about the company and the bank is available on the bank's website at www.amnb.com.
Shares of American National are traded on the NASDAQ Global Select Market under the symbol "AMNB."
# # #


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Top 10 Anime Characters That Are Better Than The Hero
Dan Paradis
Written by Alex Crilly-McKean They may not take centre stage but boy do they cast a large shadow. Welcome to WatchMojo.com and today we are counting down our picks for the top ten anime characters that are better than the hero. For this list, we'll be looking at anime characters who regardless of their influence on the show, manage to outshine the lead character in their respective series. We will be going into spoiler territory here, so a spoiler alert is now in effect. Special thanks to our user AlexCrilly-Mckean for submitting the idea on our interactive suggestion tool: WatchMojo.comsuggest
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Top 10 Anime Characters That Are Better Than The Hero
They may not take centre stage but boy do they cast a large shadow. Welcome to WatchMojo.com and today we are counting down our picks for the top ten anime characters that are better than the hero.
For this list, we'll be looking at anime characters who regardless of their influence on the show, manage to outshine the lead character in their respective series. We will be going into spoiler territory here, so a spoiler alert is now in effect.
#10: Lockon Stratos
"Gundam 00" (2007-09)
There's no denying that Setsuna is a gifted pilot, and his zero tolerance for those that prolong its conflicts make him something of a compelling protagonist. However, that introverted, brooding architype has been done to death, which was probably what made Lockon so appealing. A fellow Meister and ace pilot in his own right, he was certainly one of the few individuals that tried to see the best in people in such harsh times. That compassionate nature of his mixed together with a much more compelling tragic past and equally painful ending ensured that his star burned a lot brighter that Setsuna's.
#9: Arataka Reigen
"Mob Psycho 100" (2016)
Supposedly the 'Greatest Psychic of the 21st Century', Reigen is for all intents and purposes a con-man without any spiritual connection at all. But by god is he charming. Excelling when it comes to persuasion, bribery and anything to do with manipulation, you would think that this would make for a rather detestable character. However, due to his hilariously eccentric personality and genuine care for Mob, he manages to steal the show. Which in itself is a pretty impressive feat given his protégé is the strongest Esper in existence and all Reigen has is a green belt in martial arts.
#8: Ruri Gokou
"Oreimo" (2010-13)
Not going to lie Kyousuke, you f*cked up bro. Going by the name of Kuroneko and donning an edgey-gothic-lolita attire, she's a little hard to approach. Her social insecurities and hatred for the moe side of nerd culture made her a stark contrast to Kirino, though we would later learn that above all else she has a good heart. What we're trying to say here is that instead of ending up in a relationship with your sister you may have wanted to try a little harder romantically with this far more delicate and lovable lady – you IDIOT.
#7: Levi
"Attack on Titan" (2013-)
Nothing personal Eren, I mean the whole transforming into a Titan and smashing the faces of your foes to pieces is all well and good but...you just aren't Levi. One of the most highly skilled members of the Survey Corp, Levi may be short in stature but he makes up for it with his absolute authority and beastly skills with the three dimensional manoeuvre gear. Seriously this guy is so good with those blades that when he goes full on beast mode it means that some poor Titan is about to end up as a bloody stain!
#6: Kakashi Hatake
"Naruto" series (2002-)
From beginning to end this sometimes perverted, sometimes lazy, always awesome ninja has served as the guiding hand for Naruto, Sasuke and Sakura. With his mastery of the Sharingan and extensive knowledge of Jutsu he not only taught valuable lessons about being a Shinobi to his young charges but was always on the front lines when the Hidden Leaf Village was in danger. Throw in a tortured past with his old friend turned enemy Obito and you have a ninja who has managed to evolve throughout the series' extensive runtime, at least a smidge more than Naruto.
#5: Satsuki Kiryuin
"Kill La Kill" (2012-14)
Don't get us wrong, we love Ryuko. She's spunky, fiery and makes for an excellent protagonist. It's just that we found Satsuki's redemption arc far more investing compared to Ryuko's drive for vengeance. Originally the baddest broad on the block whose ruthlessness, sword skills and Kamui made her nearly undefeatable, her clashes with Ryuko, not to mention the unsettling relationship she had with her mother, made her character far more layered. Balancing a superiority complex with a very unhappy home-life, the wicked sister of our hero soon became the one to root for.
"Death Note" (2006-07)
Whether you found Light's actions to be villainous or necessary for the sake of true justice, it made his nemesis all the more intriguing. An unorthodox genius whose intellect and skill when it came to detective work was unsurpassed, L was truly Light's equal in a deadly game of wits. So much so that with his untimely demise some would say that the series dipped in quality. Regardless, the cat and mouse feud these two opposites had was truly the highlight of the series, even if L was a weirdo.
#3: Kamina
"Gurren Lagann" (2007)
Going from meek child all the way to saviour of the cosmos, Simon's heroic journey was certainly worthy of praise. Alas, this transformation wouldn't have happened if he didn't have a role model to look up to, and you couldn't get a better one than Kamina. His bravado borders on the insane, his stubbornness knows no bounds, he refuses to wear a shirt and he even made out with Yoko! Truly standing at the top as the pinnacle of anime manliness, no matter how hard the series tried, there's no one who can replace Kamina.
#2: Ban
"The Seven Deadly Sins" (2014-)
There's no doubt that Meliodas is a worthy leader for the sins, both for his noble heart and his monstrous strength, but when it comes to charisma you just can't beat the Fox's Sin of Greed. Aside from pulling off a wardrobe that no sane creature should be able to pull off, Ban brings so much to the table simply by being a certified badass.
He may get his body crushed on a regular basis, but due to his immortality he just keeps on coming back for more.
Before we reveal our number one pick, here are a few honourable mentions.
Sky High
"Tiger & Bunny" (2011)
Minene Uryuu
"Mirai Nikki" (2011-12)
Asuka Langley
"Neon Genesis Evangelion" (1995-96)
#1: Homura Akemi
"Puella Magi Madoka Magica" (2011)
Everybody has a waifu when it comes to the Madoka series…But Homura is objectively the best girl. Ok, just kidding, but it's the sacrifices of this fractured young lady that truly makes her the unsung hero of the show.
After witnessing Kyubey's villainous intentions, Homura traverses, fights against and even rewinds time itself in order to prevent Madoka's death. Throw in her unwavering determination and the fact she's nearly unsurpassed when it comes to taking out witches and you're looking at the total package.
Now if only Madoka would return those feelings.
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|medical dictionary
1. A stretching or bending of the mind toward of the mind toward an object; closeness of application; fixedness of attention; earnestness. "Intention is when the mind, with great earnestness, and of choice, fixes its view on any idea." (Locke)
2. A determination to act in a certain way or to do a certain thing; purpose; design; as, an intention to go to new York. "Hell is paved with good intentions." (Johnson)
3. The object toward which the thoughts are directed; end; aim. "In [chronical distempers], the principal intention is to restore the tone of the solid parts." (Arbuthnot)
4. The state of being strained. See Intension.
5. <logic> Any mental apprehension of an object.
6. <medicine> First intention, to unite after suppuration.
Synonyms: Design, purpose, object, aim, intent, drift, purport, meaning. See Design.
Origin: F. Intention, L. Intentio. See Intend, and cf. Intension.
(01 Mar 1998)
intensive management, intensive properties, intensive psychotherapy < Prev | Next > intentional replantation, intention spasm
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Talk:Volcano Uncroaking
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Was GG "Good Game" or "Gotta Go"? Abb3w 01:16, 6 June 2011 (EDT)
- It was accepted as "Good Game" from memory, back on the OoTS forums at the time. While "Gotta Go" sort of fits in with him making a move to possibly leave somewhere before ducking into the portal, I think "Good Game" really fits in better at many other levels. --Charles 09:15, 7 June 2011 (EDT)
- Fair enough. Of course, this is Erfworld, where double meanings abound; and Parson's talking to Charlie, who might be able to catch both of them. Abb3w 14:06, 7 June 2011 (EDT)
Deleted "It is unclear if the parts of the previous uncroaked army (of Jetstone and Marbit troops) which was destroyed is part of this decrypted force, and if so, whether the decrypted uncroaked units return as uncroaked or their original unit type and level." Artwork consistently portrays uncroaked units as being dusted when destroyed, rather than returning to being croaked. Units leaving no bodies are unavailable for decryption (cf: Bogroll).


text: 4Corners 3,859 Report post Posted June 30, 2013 Where would you rank this all time on a list sports controversies? Has to be at the top, right? Off the top of my head, you'd have to consider: Sandusky/Paterno/Penn St (which I would rank #1 for now) Rae Carruth Pete Rose gambling Baseball steroids era Baylor basketball murder/cover up SpyGate Duke LAX What am I leaving off? Edit: Add OJ, Lance Armstrong scandal, Mike Vick dog fighting, Black Sox scandal Share this post Link to post Share on other sites


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Two short remarks: 1. Rather than having mutually exclusive "SVG " and "SVGZ" tables, I believe the SFNT'ish approach would be to have one "SVG " table with two (or more) different formats: One raw, one compressed. 2. It would conversely be interesting to see an XML encoding for the information in SFNT tables (I'm primarily thinking GPOS, GSUB, and friends, as each table has to be specified separately). The last time I checked [oh dear, that is close to two years ago!], there was only one tool around for doing such conversions, and its XML format was completely undocumented. :-( Lars HellströmReceived on Monday, 27 June 2011 15:38:28 UTC
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