There is increasing evidence that fluid overload and acute kidney injury (AKI) are associated but the exact cause-effect relationship remains unclear. Wang and colleagues analysed patients admitted to 30 intensive care units in China and found that fluid accumulation was independently associated with an increased risk of AKI and mortality. This commentary focuses on the close pathophysiological link between AKI and fluid overload and discusses the implications for clinical practice. It outlines some of the challenges, including the difficulty in diagnosing fluid overload reliably with current methods, and stresses the importance of personalised fluid therapy with physiological end-points to avoid the deleterious effects of fluid overload. In a recent article in Critical Care, Wang et al. analysed the data of 2526 patients admitted to 30 intensive care units (ICUs) in China and showed that even relatively small degrees of fluid overload were independently associated with an increased risk of AKI and mortality [Fluids are the second most common intervention in acutely ill patients (after oxygen). Whilst the benefits of early fluid resuscitation in patients with shock and acute kidney injury (AKI) have been accepted, uncertainty remains about the optimal type, volume and timing of fluid delivery. There is growing evidence that fluid administration beyond the correction of hypovolaemia is ortality . Others Although there is now little doubt that fluid overload is associated with AKI, it is difficult to disentangle the cause-effect relationship. Furthermore, translating the results into clinical practice is very challenging, especially since some important issues are still unresolved.First, defining fluid overload is not straightforward. By convention, most studies in the literature, including the study by Wang et al. , definedSecond, whether the consequences of fluid overload depend on the specific type of fluid has not been studied. It is plausible that fluid overload as a result of excessive crystalloid administration has a different impact compared with fluid accumulation following infusion of colloids or massive transfusion of blood products. More data are necessary. The timing of volume administration may also be relevant. A positive fluid balance of 5 litres over an initial 24-hour period followed by no further fluid gain may have a different outcome compared with the same net balance over a period of days.Third, fluid overload may result from overzealous fluid administration or oliguria or a combination of the two. The differentiation is important since fluid overload caused by excessive fluid therapy is potentially avoidable whereas fluid overload as a result of oliguria may reflect AKI and may not be easily modifiable without RRT . Most stFinally, the fact that fluid overload is associated with AKI does not prove causality. One key problem is that the effects of volume overload and the effects of AKI are similar. Both lead to multi-organ dysfunction. They also often have the same denominator, including endothelial dysfunction due to inflammation or ischaemia/reperfusion injury with decay and shedding of the glycocalyx and subsequent capillary leakage . PatientNevertheless, the study by Wang et al. does confirm what other studies have shown previously that a positive fluid balance is associated with worse outcomes. The crucial question for clinical practice is how to ensure appropriate and timely correction of hypovolaemia without causing fluid overload. Unfortunately, the tools to guide fluid management and to inform the clinical team when fluid administration is no longer beneficial are inadequate. Central venous pressure (CVP) or dynamic techniques like fluid responsiveness or echocardiography are often used. However, the CVP does not accurately reflect intravascular volume status and can be misleading . MeasuriIn the absence of any sophisticated tools to confirm euvolaemia or diagnose fluid overload, initial fluid resuscitation should be guided by an assessment of fluid responsiveness followed by fluid therapy titrated against individualized end-points , 14. TheThere is some prospect that novel biomarkers may also have a role to prevent fluid overload. Mekontso Dessap et al. randomly assigned 304 mechanically ventilated patients to a strategy driven by B-type natriuretic peptide (BNP) or usual care . PatientFluid overload, AKI and poor outcomes are clearly associated. However, whether AKI has caused fluid overload or vice versa can be difficult to determine. Better tools are necessary to measure intravascular volume status. Until then, fluid therapy needs to be personalised with physiological end-points, guided by dynamic tests like PLR manoeuvre, and monitored by using cumulative fluid balance coupled, where possible, with daily weights to avoid the adverse outcomes associated with fluid overload.


Cancer-cachexia state frequently induces both fat and protein wasting, leading to death. In this way, the knowledge of the mechanism of drugs and their side effects can be a new feature to treat and to have success, contributing to a better life quality for these patients. Metformin is an oral drug used in type 2 diabetes mellitus, showing inhibitory effect on proliferation in some neoplastic cells. For this reason, we evaluated its modulatory effect on Walker-256 tumour evolution and also on protein metabolism in gastrocnemius muscle and body composition.Wistar rats received or not tumour implant and metformin treatment and were distributed into four groups, as followed: control (C), Walker 256 tumour-bearing (W), metformin-treated (M) and tumour-bearing treated with metformin (WM). Animals were weighed three times a week, and after cachexia state has been detected, the rats were euthanised and muscle and tumour excised and analysed by biochemical and molecular assays.Tumour growth promoted some deleterious effects on chemical body composition, increasing water and decreasing fat percentage, and reducing lean body mass. In muscle tissue, tumour led to a decreased protein synthesis and an increased proteolysis, showing the higher activity of the ubiquitin-proteasome pathway. On the other hand, the metformin treatment likely minimised the tumour-induced wasting state; in this way, this treatment ameliorated chemical body composition, reduced the higher activities of proteolytic enzymes and decreased the protein waste.Metformin treatment not only decreases the tumour growth but also improves the protein metabolism in gastrocnemius muscle in tumour-bearing rats. Cancer is one of the leading causes of deaths worldwide , and manAMP-activated protein kinase (AMPK) plays an essential role maintaining the cellular energetic status, acting as a fuel gauge. This process helps cells to deal with energy stress conditions and bring them back to homoeostasis , controlDespite the fact that metformin can decrease insulin levels and tumour’s cell proliferation , few stu6 viable tumour cells, in 0.2 mL NaCl suspension, were implanted subcutaneously in the right flank, while the rats without tumour received 0.2 mL of 0.9 % NaCl injection as a sham procedure. The general UKCCCR [Male Wistar rats weighted within 60–70 g (3 weeks old) were obtained from the animal facility CEMIB/State University of Campinas and housed in a collective cage, maintained at 22 ± 2 °C and 12 h light/dark cycles. Animals were allowed to a normoprotein semi-purified diet   and watel UKCCCR , 17 guidMetformin was dissolved in drinking water (100 mg/L) which corresponded to 33 mg/Kg body weight. Metformin concentration was estimated using the allometric scaling , 19 fromBiochemical body composition assay was previously described [escribed . The samescribed . Anotherescribed . Non-colTotal serum proteins and albumin were quantified spectrophotometrically  , pH 7.4, 0.1 % Triton X-100 and the supernatant was used for protein concentration [Immediately after euthanasia, the gastrocnemius muscles were dissected, frozen in liquid nitrogen and kept at - 80 °C. A sample was then homogenised in phosphate buffer saline (PBS)  for protein synthesis assay while left muscle was incubated with 0.5 mM cycloheximide for protein degradation assay. Radioactive phenylalanine incorporated into muscle and tyrosine released in incubation buffer were assayed as described [Right gastrocnemius muscle was dissected and incubated with 0.5 μCi/mL L-[2,3,4,5,6-escribed . ProteinThr172 (2535), Akt (4685), phospho-AktThr308 (4056), goat anti-rabbit (7074), horse anti-mouse (7076)  and rabbit anti-goat (AP106P) . Images were captured using Alliance 2.7  and band intensity was quantified using UVIband -1D .Immunoblotting was performed as previously described . Proteint-test was used for comparison between two groups. Comparison among groups, we used One-way ANOVA followed by Bonferroni post-test, using GraphPad Prism version 5.00 software  and results showed as mean ± standard deviation (SD). Significance was defined as p < 0.05.The nonparametric To analyse whether tumour growth led to cachexia and whether metformin treatment, at close therapeutic dose used in T2DM patients, was able to reduce the tumour harmfull effect, we analysed the biochemical body composition parameters. As can be seen in Table Total serum protein decreased by 15 % in W compared to C, whereas WM had similar content as C rats, and increased 11 % when compared to W. Albumin content reduced around 23 % in each W and WM group, while globulin concentration decreased only in W (22 % lower) (Table p = 0.0571). In this way, the ratio of muscle protein synthesis and degradation was deeply reduced in W (93 % less) whereas in WM this effect was modulated by metformin, being 4-times higher in WM than in W group  expression increased in W but not in WM Fig. , b and c 28 KDa eCachexia is a common feature of many cancers, being responsible to worse prognosis in patients with different types of cancers , and is Some tumours release factors that can change host metabolism and induce weight loss, mainly the lean body mass . BesidesTumour cells have an increased metabolic rate compared to non-tumour cells, probably because of the highly proliferative cell activity, which depends on a good provision of nutrients mobilised from host tissues. Due to that, metabolic tumour reprogramming has been described as a new cancer hallmark  and the Animals bearing Walker 256 tumour have a reduced insulin secretion . A decreWe demonstrated that cytosolic degradation pathways, including calpain and cathepsin, were not activated in muscle of Walker 256 tumour-bearing animals, but the UPP is the main pathway by which muscle protein were degraded in these animals. The UPP handles muscle protein degradation in both human  and mousOverall, metformin treatment was able to decrease tumour growth (as the tumour/body weight ratio) and also able to decrease the harmful tumour effects on protein metabolism in skeletal muscle. As previously stated, metformin treatment is also known to inhibit mitochondrial complex I and, therefore, may be implicated in decreasing TCA intermediates . In thisDespite the fact that action mechanism of metformin is not completely understood, using it in laboratory animal models has shown remarkable antineoplastic effects . HoweverTaking all data together, we conclude that the cachectic state developed by tumour effects, mainly impairing the muscle tissue, as a consequence of higher activity of the ubiquitin-proteasome pathway, can be minimised under metformin treatment as this treatment ameliorated chemical body composition, reducing the ubiquitin-proteasome pathway, which decreased the protein waste. In summary, metformin remains a promising tool in cancer studies and how it could attenuate cachexia in tumour-bearing animals is a subject for further research.


The rationale for perioperative fluid therapy has been to preserve organ perfusion. However, conservative postoperative fluid balance (FB) is now encouraged to avoid the effects of iatrogenic fluid overload. In addition, fluid expansion has been described as a confounder of acute kidney injury (AKI) diagnosis by dilution serum creatinine (SCr).We conducted a prospective audit of FB and renal function in patients undergoing major elective surgery admitted to critical care over a 28-day period. Fluid overload was defined as: (positive FB) / (weight × 0.6) × 100%.P = 0.003), median 73 to 55 μmol/l, with decreases occurring both postoperatively and during critical care stay  were studied over a median of 3 critical care days range 1 to 7). Total FB was +3.9 l at discharge; however, 75% of this occurred intraoperatively so that positive FB in critical care was only +390 ml/day. Patients had median 9% fluid overload at discharge. Two patients had transient AKI stage 1. Overall SCr decreased significantly from preoperatively to discharge ( to 7. ToWe achieved near-neutral fluid balances after admission, but did not resolve intraoperative fluid accumulation. SCr fell significantly, even after there was no further net fluid accumulation. This suggests a decrease in creatinine generation after major surgery, rather than fluid expansion, may largely account for sCr decreases in these patients.


Vasculogenic mimicry (VM) is a brand-new tumour vascular paradigm independent of angiogenesis that describes the specific capacity of aggressive cancer cells to form vessel-like networks that provide adequate blood supply for tumour growth. A variety of molecule mechanisms and signal pathways participate in VM induction. Additionally, cancer stem cell and epithelial-mesenchymal transitions are also shown to be implicated in VM formation. As a unique perfusion way, VM is associated with tumour invasion, metastasis and poor cancer patient prognosis. Due to VM's important effects on tumour progression, more VM-related strategies are being utilized for anticancer treatment. Here, with regard to the above aspects, we make a review of advanced research on VM in cancer. IntroductionDiscovering VM–Molecule mechanisms involved in VM formation–Other relevant molecule mechanisms–CSC, EMT and VMTumour VM formation mechanismsVM and cancer therapeuticsVM and prognosis of human cancer patientsConclusion2 chain Tumour angiogenesis plays a significant role in tumour growth and metastasis, which was formerly considered the unique choice for tumour blood supply et al. in vitro. Additionally, some researchers also confirmed that VM provides an important perfusion pathway for malignant tumours through sufficient blood and nutrition supply, playing a significant role in tumour growth.Malignant solid tumours need blood supply to promote growth and metastasis. In the past, angiogenesis, one type of neovascularization in embryo development, was regarded as the only form of supporting tumour blood supply. Angiogenesis was first used by British surgeon John Hunter in 1787 to describe blood vessel growth in reindeer antlers. In 1966, Warren first described angiogenesis in melanoma, and afterwards it was investigated in other tumours Vasculogenic mimicry is linked with numerous tumour malignancies, including invasion and metastasis i) positive PAS and negative CD31 straining; (ii) the channel is lined by tumour cells rather than endothelial cells; (iii) the expression of a multipotent, stem cell-like phenotype; (iv) ECM remodelling and (v) VM has connection with the tumour microcirculation system, providing blood for tumour growth. Major VM discoveries are illustrated in TableGenerally, VM characteristics can be summarized as follows:  is a transmembrane protein expressed in many cell types, including endothelial cells, smooth muscle cells, macrophages and solid tumours VEGF-A is secreted by almost all tumour cells and belongs to the angiogenic growth factor family associated with tumour angiogenesis. Binding VEGF-A to its ligand results in the dedifferentiation of endothelial cells into its precursor, stimulating vascular channel proliferation and formation in tumours, especially in avascular regions. Findings showed that, in melanoma, VM and angiogenesis were mediated by VEGF-A The two tyrosine kinases receptors, VEGFR1 and VEGFR2, bind to VEGF and possess different characteristics. VEGFR1 has a higher VEGF binding ability but lower kinase activity compared to VEGFR2. VEGFR2 is linked with tumour angiogenesis et al. Growing tumours lack blood supply in a normal state. Hypoxia can stimulate tumour vessel structure formations in vitro. Gal-3 mediated the expression of many genes, such as VE-cadherin, interleukin-8 (IL-8) and MMP-2, which are confirmed to contribute to VM formation. Silencing Gal-3 expression inhibited VE-cadherin and IL-8 promoter activities, mainly owing to increased recruitment of early growth response-1 (EGR-1), a transcription factor participating in maintaining differentiation processes in normal tissues. EGR-1 overexpression repressed VE-cadherin, IL-8 and their promoter activities, while Gal-3 expression blocked EGR-1 binding to gene promoter and induced VM formation in tumour tissues.Galectin-3  is a β-galactosyl-binding lectin involved in biological functions including cell adhesion, cell migration, cell apoptosis and angiogenesis Cyclic adenosine monophosphate (cAMP), a second messenger regulating cell growth and differentiation, is generated by activated adenylyl cyclase acting on ATP. Several studies have proven that in aggressive melanoma, cAMP increase resulted in VM formation inhibition through multiple signalling pathways. First, cAMP stimulates PKA-independent activation of Epac/Rapl pathway to restrain vessel-like channel structure formation. Additionally, cAMP helps inhibit MMP-2 and MT1-MMP expression by suppressing ERK1/2 to block VM formation. A recent study found that forskolin resulted in increased cAMP that strongly restrained VM formation by activation of Epac/Rap1, and inhibition of ERK1/2 and PI3K/Akt functional activation et al. Nodal belongs to one transformation growth factor β (TGF-β) superfamily and plays an important role in maintaining tumourigenicity and melanoma progression. Nodal and Notch receptor were implicated in stem cell-associated plasticity development and up-regulation of Nodal expression, which was found in invasive melanoma cells et al. Cyclooxygenase (COX), a necessary enzyme in prostaglandins synthesis, consists of the isoenzymes COX-1 and COX-2. A house keeping enzyme, it mainly existed in blood vessels, stomach and other tissues. It is widely regarded as participating in the body's normal physiological processes and protection functions, such as maintaining gastrointestinal mucosa integrity and platelet function adjustment. The latter is an inducible type mainly produced by inducting various pathophysiological stimuli including chemical, physical and biological factors, thus participating in inflammatory reactions by promoting prostaglandins synthesis. As a rate-limiting enzyme of prostaglandin E2 (PGE2), COX2 shows no expression or low expression in normal tissue cells, but it is highly expressed in a variety of epithelial tumours due to environment induction. Basu Inhibitors of DNA binding 2 (Id2) is a member of the helix-loop-helix (HLH) protein family that participates in many cellular processes, including cell proliferation, differentiation, cell cycle regulation and tumourigenesis 2 chain domain III fragments, thus promoting tumour cell migration, metastasis and VM formation.Migration-inducing protein 7 (Mig-7), a cysteine-rich protein, plays an important role in tumour migration and circulation. There is evidence showing that Mig-7 is overexpressed in highly aggressive melanoma cells with VM but not in poorly aggressive melanoma without VM et al. et al. Caspase-3 is implicated in cell apoptosis Endothelin (ET)-1 is considered a practical tumour marker, the secretion of which is increased in a variety of pathological conditions and cancer patients. In primary and metastatic melanoma cell lines, the activation of a G-protein coupled receptor by ET-1 could markedly result in increased VEGFR-3, VEGF-C and VEGF-D expression. Binding ET-1 to VEGF-C was able to enhance the phosphorylation of VEGFR-3, MAPK and ATK, thereby significantly promoting tumour cell invasion and VM formation Bone morphogenetic protein 4 (BMP4) is another tumour migration and invasion regulator. Reducing BMP4 activity in melanoma cells reduced VE-cadherin and EphA2 expression and failed to promote tubular structure formation Human chorionic gonadotropin (hCG) is reportedly capable of inducing VM formation in ovarian cancer cell line OVCAR-3. hCG expression is higher under hypoxia compared to normoxia. Inhibiting HIF-1α expression using siRNA resulted in significantly decreased hCG expression in OVCAR-3. Treating OVCAR-3 with 5000 mU/ml hCG led to the induction of vessel-like networks lined by tumour cells and markedly enhanced vascular marker expression even under normoxia et al. +et al. Tumours contain a small portion of cells capable of self-renewal and multiple potential differentiation called cancer stem cells (CSCs). Lapidot et al. +/CD34+ stem cells from acute leukaemia patients were able to secret more insulin growth factor-1 and stromal cell-derived factor-1 (SDF-1) alpha, and could result in the formation of capillary-like structures (‘VM’) on Matrigel. Furthermore, there is evidence showing that in oral SCC, TRA-1-60+/beta6+ stem cells were capable of producing vascular-like structures in vivo. Additionally, in melanoma, it was shown that some phenotypes generally expressed in epithelial or endothelial cells were observed to express in VM-engaging tumour cells et al. Recently mounting studies implicated CSCs in VM formation. Mirshahi et al. in vitro. The well-differentiated cell line HepG2 failed to form VM, and no correlation was found between intrinsic VM ability and stemness gene expression et al. Epithelial-mesenchymal transition is a dedifferentiation process that plays an integral role in tumour progression. By epithelial cells transitioning into mesenchymal cells, EMT acquired mesenchymal features and lost epithelial phenotypes, mainly including epithelial marker downregulation, mesenchymal marker upregulation and cell polarity loss. EMT is reportedly involved in tumour invasion and metastasis. Cadherin switching, an important EMT marker associated with the EMT differentiation process, contains E-cadherin expression loss and N-cadherin gains. Recent studies show that transcription factors related to EMT are upregulated in VM-forming tumour cells. As a main EMT-mediated process regulator, Twist reportedly promotes breast cancer metastasis into distant regions et al. in vivo tumourigenicity in nude mice. Stable miR-200a overexpression had the opposite result. Fang et al. et al. With increasing studies on CSC's origin, more evidence indicated that differentiated tumour cell stemness can be acquired by EMT induction, which may become a new CSC origin mechanism. Xia Anti-angiogenic treatment is widely accepted as an effective anticancer therapy. Common anti-angiogenic drugs like angiostatin and endostatin play a role mainly by reducing endothelial cell proliferation or inducing endothelial cell apoptosis, but they have little effect on vessel-like structures lined by tumour cells. Furthermore, when blood vessel density is reduced due to anti-angiogenic therapy, it may lead to hypoxia. Subsequently, oxygen and nutrient deficiency as a compensatory stimulus will contribute to VM formation and indirectly promote tumour progression. Moreover, several of these drugs have a variety of side effects, thus limiting their usefulness in treatment. Therefore, further study is needed to find safe and effective therapies against the invasion and metastasis of highly aggressive tumours.et al. et al. et al. Recently, mounting studies focus on a new anticancer treatment that inhibits VM formation and is involved in various mechanisms, including antisense oligonucleotides to the Ln-5 γ2 chain, antibodies to MMP-2 or MT1-MMP, VE-cadherin downregulation, and inhibiting other VM-associated genes. Zhang et al. et al. et al. Vasculogenic mimicry provides adequate blood supply for various malignant tumours to promote tumour invasion and metastasis. Subsequent studies showed that VM was significantly linked with poor prognosis for patients with aggressive tumours As a brand-new tumour vascular pattern, VM describes the functional ability of aggressive cancer cells to express a multipotent, stem cell-like phenotype and form ECM-rich and patterned vasculogenic-like networks to provide adequate blood supply for tumour growth in a three-dimensional matrix. VM with positive PAS and negative CD31 is lined by tumour cells and independent of epithelial cells. As a unique perfusion way, VM has been observed in a variety of aggressive tumours. Many molecule mechanisms, especially VE-cadherin, EphA2, PI3K, MMPs, VEGFR1 and HIF-1a, are involved in tumour migration, invasion, and VM formation. However, their specific roles in VM still remain unclear. Furthermore, CSC and EMT are also shown to participate in VM formation. Also, CSC may be implicated in VM formation by EMT induction. There is increasing evidence showing that VM and VM density levels are linked with poor prognosis and shorter 5-year survival in cancer patients. Ordinarily, VM-forming aggressive tumours have the increased potential to metastasize to distant organs, therefore, predicting cancer progression in advance may be extremely important. Currently, more VM-related strategies are utilized for anticancer treatment by preventing VM formation, and many drugs shows an effective outcome in inhibiting it. More therapies targeting VM need to be attempted in experimental and clinical research. VM inhibitors combining with anti-angiogenic therapies may be a promising therapeutic target in anti-tumour therapy.


Endothelial glycocalyx degradation induced by fluid overload adds to the concern of a detrimental effect of uncontrolled fluid resuscitation and the risk of unnecessary fluid infusion. As a consequence, the use of new tools for monitoring response to fluids appears promising. From that perspective, the monitoring of plasma concentration of glycocalyx degradation markers could be useful. Critical Care adds an important piece of information to the debate over the need for careful monitoring of patients in order to avoid unnecessary fluids.Fluid resuscitation is common practice for patients with hypovolemia and is recommended as first-line treatment for septic shock. However, accumulating evidence suggests that uncontrolled fluid loading may be detrimental. In that respect, the study by Chappell and colleagues  in the pIn vivo, degradation of the glycocalyx with heparinase favors tight contacts between circulating leukocytes and the endothelium through denudation of the protective barrier that normally prevents this effect [During peri-operative management, Chappell and colleagues prospectively explored the consequences of acute volume loading on endothelial functions and hypothesized that high-volume infusion could alter endothelial glycocalyx. The glycocalyx consists of a variety of endothelial membrane-bound molecules, including glycoproteins and proteoglycans that form a negatively charged barrier to circulating cells and macromolecules . Numerous effect . In addis effect ).Chappell and colleagues reported that volume loading (20 mL/kg of hydroxyethyl starch (HES) 130/0.4) in elective surgery induced a release of atrial natriuretic peptide (ANP) associated with an increase of serum glycocalyx components  but that there was no effect of acute normovolemic hemodilution. The augmentation of these plasma components suggests a degradation of endothelial glycocalyx that could promote vascular leakage, leukocyte adhesion, and procoagulant status. However, this is a speculative and physiopathological conclusion, and the authors did not provide any direct evidence of glycocalyx functional alteration. The twofold increase of serum syndecan-1 concentration after volume overload is statistically significant but was very far from the 10-fold increase reported during septic shock  and the The mechanisms of glycocalyx shedding have not been directly investigated, but the authors proposed that ANP could be implicated. This hypothesis is based on a previous experimental study by the same group  and the This translational study gives interesting insights into the deleterious effects of fluid infusion in critically ill patients. Indeed, accumulative clinical studies pointed out that positive fluid balance and weight gains are associated with a worse prognosis  but the


Noise Lett. 11, 1240007 (doi:10.1142/S021947751240007X)). We have shown that dithering based on random jitter noise plus pseudorandom numbers can be used in the digital control system to radically reduce the long-term drift of the laser pulse from the trigger and to improve the accuracy of the synchronization. In this update paper, we present our new experimental results obtained by the use of the delay-controller unit to tune the timing of a KrF excimer laser as an addition to our previous numerical simulation results. The hardware was interfaced to the laser using optical signal paths in order to reduce sensitivity to electromagnetic interference and the control algorithm tested by simulations was applied in the experiments. We have found that the system is able to reduce the delay uncertainty very close to the theoretical limit and performs well in real applications. The simple, compact and flexible system is universal enough to also be used in various multidisciplinary applications.Recently, we have reported on a compact microcontroller-based unit developed to accurately synchronize excimer laser pulses (Mingesz  Very short-time observations are often aided by impulse lasers in exploring many physical, chemical, biological phenomena, pump-probe measurements, and time-resolved spectroscopy –4. A sinRather surprisingly, the presence of random noise is not necessarily bad, sometimes adding noise can even improve performance. Today, there are several applications that are based on the constructive role of noise in various multidisciplinary fields. Examples include stochastic resonance that has special importance in biology –11 and d2.The principle of the control of the entire delay can be seen in In the following, we give a brief overview of the hardware components that were used to control the laser pulse timing. Note that only a smaller part of our more universal system was required; therefore, it is possible to build an optimized, even simpler unit in similar cases. The block diagram of the experimental set-up and the simplified hardware of the delay-controller unit is shown in 1,D2,DL) are integrated on the controller unit and the KrF excimer laser is connected to the rest of the system via fibre-optical links to reduce electromagnetic interference and noise. The whole system can be monitored by a host computer via a USB interface. The time diagram of the delay-control operation is shown in The delay-controller unit is based on a C8051F120 microcontroller incorporating a 100 MHz oscillator, a counter with two capture latches (Latch1 and Latch2) and a serial communication port. Three programmable delay units  and transmitters (HFBR 1521). These elements introduce excessive jitter; therefore, first we evaluated the performance without the use of the KrF excimer laser. The desired delay was set to 1000 ns, and the jitter was measured using the time-to-digital conversion method described in the previous section. We found that the standard deviation of the jitter of the timing circuitry was 2.1 ns. In order to measure the full jitter of the system the delay control was switched off. The full delay between the laser trigger and the thyratron sense signals was measured to be 1.36 μs with a jitter of 10 ns. Owing to the statistical independence the full jitter is the root mean square of the laser jitter plus the jitter of the timing circuitry. In our case, this means that the contribution of the timing circuitry was below 2.2% of the full jitter. Lower jitter lasers may need even better performing optical receivers and transmitters. As a rule of thumb, the contribution to the total jitter can be kept below 5% if the jitter of the system is less than one-third of the laser jitter.After the testing the control circuit was tested with the KrF laser system. During the experiments, a pulse shape time-dependent desired delay was set as depicted in After 50 shots the initial value of 2 μs was changed to 2.5 μs and after the next 50 shots it was set again to 2 μs. The measurement results show clearly that high accuracy can be achieved with the developed control system while the additional jitter due to the control system is negligible.4.In addition to the results reported in our initial article, in this update paper we have demonstrated the performance of our compact microcontroller-based delay-control system driving a KrF excimer laser. We have added fibre-optic links to the original system to reduce its sensitivity to interference and noise, and we have shown that the time synchronization accuracy of the system can be maintained. Our experimental results confirm that the long-term drift of the laser delay can be removed by using the shot-to-shot jitter noise and added random dither with a simple and compact system. We have shown that the regulation can keep the accuracy close to the theoretical limit determined by the jitter of the laser. Lasers controlled by such system and algorithm can be used in many multidisciplinary applications where timing accuracy is important. Note also that the very compact and universal system can play a constructive role in general time-to-digital conversion and precision time synchronization solutions in various fields of science and engineering.


Excessive or inadequate intravenous fluid given in the perioperative period can affect outcomes. A number of guidelines exist but these can conflict with the entrenched practice, evidence base and prescriber knowledge. We conducted a multi-centre audit of intraoperative and postoperative intravenous fluid therapy to investigate fluid administration practice and frequency of postoperative electrolyte disturbances.A retrospective audit was done in five hospitals of adult patients undergoing elective major abdominal, gastrointestinal tract or orthopaedic surgery. The type, volume and quantity of fluid and electrolytes administered during surgery and in 3 days postoperatively was calculated, and electrolyte disturbances were studied using clinical records.Data from four hundred thirty-one patients in five hospitals covering 1157 intravenous fluid days were collected. Balanced crystalloid solutions were almost universally used in the operating theatre and were also the most common fluid administered postoperatively, followed by hypotonic dextrose-saline solutions and 0.9 % sodium chloride. For three common uncomplicated elective operations, the volume of fluid administered intraoperatively demonstrated considerable variability. Over half of the patients received no postoperative fluid on day 1, and even more were commenced on free oral fluids immediately postoperatively or on day 1. Postoperative quantities of sodium exceeded the recommended amounts for maintenance in half of the patients who continued to receive intravenous fluids. Potassium administration in those receiving intravenous fluids was almost universally inadequate. Hypokalaemia and hyponatraemia were the common findings.We documented the current clinical practice and confirmed that early free oral fluids and cessation of any intravenous fluids is common postoperatively in keeping with the aims of enhanced recovery after surgery programmes. Excessive sodium and water and inadequate potassium in those given intravenous fluids postoperatively is common and needs to be investigated. The variation in intraoperative fluid volume administration for three common procedures is considerable and in keeping with other international studies. Future trials of fluid therapy should include the intraoperative and postoperative phases. The fundamental goal of any intravenous fluid therapy is to restore and maintain normal fluid and electrolyte physiology in situations where patients are unable to control their own fluid intake, while minimising the risk of fluid-related complications. Excessive or inadequate intravenous fluid therapy in surgical patients is associated with adverse outcomes and can cause significant harm   were selected. In high-volume centres, the target of identifying 100 patients was reached within the first 4 months of the year. In lower volume centres, to identify the required 100 subjects, operations up to October 2013 were included. Once 100 patients were identified in each centre, collection of identifying details ceased and the medical notes were requested. Hospital C was a very high volume centre, and in order to improve the overall number of patients in the audit, an additional 50 patients were identified in hospital C and their notes requested.−1 and hypokalaemia as a serum sodium of less than 3.5 mmol.l−1. Data collection covered the period from the day of the operation up to and including postoperative day 7, and the day after intravenous fluids were completely ceased or the day of discharge if this came first. The ‘standards’ used for this audit were the GIFTASUP guidelines  . These quantities are very similar to other more recent intravenous fluid guidelines  and operation type were recorded. For each patient, we collected data on volume and fluid type administered, quantities of sodium, chloride and potassium administered per kilogram body weight per day, calculated fluid balance based on input/output charts  and serum electrolyte measurements. We defined hyponatraemia as a serum sodium of less than 135 mmol.lEach hospital was assigned a random letter (A–E) with the identity of each hospital known only to the principal investigator. No patient identifiable data was recorded and kept, and all recorded data was anonymised and encrypted using commercially available software. Data in figures is expressed either as absolute numbers with percentages or as measures of central tendency (mean or median). Measures of spread used were standard error of the mean or interquartile range, and this is indicated in the figure legends. We did not undertake any further statistical tests so as not to deviate from the observational nature of the audit.Data were collected for 431 subjects. Although we requested the notes of the first 100  patients in each hospital, during the analysis period, a number of patient notes that were requested were not available due to administrative reasons. These included being lost or in use at a different hospital department. Therefore, the final number of patient records analysed was 431  and median weight was 79 kg (range 36–210 kg). Forty-three percent of the patients underwent orthopaedic surgery, 23.5 % upper gastrointestinal and 33.5 % lower gastrointestinal, gynaecological or urological surgery. Table The audit set out to record fluid and electrolyte quantities for each postoperative day up to and including postoperative day 7. However, the quality of fluid prescription charts and fluid balance documentation was subjectively noted by the data analysing team to become progressively less complete or even present in the medical notes as length of stay progressed. Early on in the data collection process , it was therefore decided to limit further data collection to 3 days postoperatively only due to the paucity of data. We did continue to collect the date when free oral fluids were started because this information was easier to find in the narrative medical notes. Overall, 1157 intravenous fluid days have been included in the analysis over postoperative days 1, 2 and 3.During the entire time period studied, the balanced crystalloid solutions were the most common intravenous fluid . Figure When the balanced intravenous solutions are subdivided into Hartmann’s and Plasma-Lyte , Hartmann’s was the most commonly used balanced solution intraoperatively and on postoperative day 1 Fig. . This waThe type of fluid given on postoperative day 1 demonstrated a similar pattern for all clinical areas. The only difference was more hypotonic dextrose-saline was used in the intensive care unit (ICU) compared to wards or ward-based high dependency unit (HDU) see Fig. .Fig. 4Tyn = 36), total hip replacement (n = 58) and total knee replacement (n = 70). The volume of fluid administered intraoperatively (where recorded) for these index procedures demonstrated considerable variability  of all subjects. Where recorded, free fluids were ordered immediately postoperatively or on postoperative day 1 in the majority of patients , quantities of sodium and chloride exceeded maintenance requirements in approximately half of those studied (Table n = 96). We found similar trends in day 1 sodium and potassium dosing  grade or other perioperative risk scoring systems. We considered ASA grade to be insufficiently robust to determine perioperative risk, and other risk scoring systems were rarely used by anaesthetists in this audit.−1. Also, these patients were not matched in terms of perioperative risk score (e.g. ASA), co-morbidities, surgical complexity or operative time, although we did exclude non-elective patients and those with significant blood loss. Fluid balance charts were studied to help assess appropriateness of intravenous fluids. These were subjectively noted to be often of poor quality and do not record all losses, such as fluid sequestration in sepsis, so they do not provide all the information needed to assess whether the fluid administered is clinically appropriate. Fluid prescription charts were better in terms of completion.When calculating intraoperative fluid administration data for the three common procedures, our ability to determine that these were uncomplicated was based on discharge summaries and anaesthetic charts. Neither of these two methods may have recorded all the technical difficulties or other ‘complications’ during the surgery that may have mandated higher than average intravenous fluid administration volumes. In addition, the length of time spent in the operating theatre was not recorded so we were unable to present intraoperative fluid administration volumes as ml.kg.hVolumes of fluid and quantities of sodium were calculated to be excessive in reference to the maintenance requirements in a large number of patients in the postoperative period. An unknown proportion might have been septic, bleeding or hypovolaemic requiring additional replacement over and above the maintenance requirements. A detailed notes review would be required to assess how clinically appropriate the fluid volume and sodium quantity given in each case was. Enhanced recovery pathways and fluid prescription guidelines often vary between individual hospitals and even individual surgical teams in the same institution. This may explain some of the variation in practice.One of the principles of enhanced recovery after surgery protocols is an early return to oral intake to improve patient comfort, gut function and limit the detrimental effects of intravenous fluid  and 0.9 % sodium chloride as the next most common. There is increasing recognition that the traditional postoperative regime of 0.9 % sodium chloride and 5 % dextrose risks sodium, chloride and salt overload  and the different physiology occurring at the different time points.Even the use of the balanced crystalloids can result in sodium overload and some hospitals and the NICE  in response to surgical incision and trauma. Neuroendocrine changes are particularly relevant to perioperative fluids because the release of catecholamines and cortisol, vasopressin and aldosterone result in retention of sodium and water (often water in excess of sodium hence hyponatraemia), loss of potassium, reduced creatinine clearance and urine output. These effects can last well beyond the operative period into the postoperative phase.Postoperative hyponatraemia was common and is multifactorial. It is not possible to determine the causes without a detailed notes analysis of the affected patients. As Fig. −1. When only looking at those patients who received any dextrose solutions on postoperative day 1, the mean drop was 2.9 mmol.kg−1. This raises the possibility that the use of dextrose solutions on postoperative day 1 is associated with subsequent hyponatraemia (compared to other fluids) and should be avoided. It should be noted that the pre-operative mean serum sodium was lower in this group. With the relatively small number of subjects, the retrospective nature of the audit and the large number of contributory factors, it is not possible to suggest causation. From our limited data, it would appear that the use of hypotonic dextrose-saline on postoperative day 1 was not associated with hyponatraemia and therefore, the recommendation made in several fluid guidelines  but 50 % fell outside of this wide range with some patients receiving as much as 35 ml.kg−1.h−1 (Lilot et al. The range of intraoperative fluid doses for three index procedures was wide and in keeping with a recent two-centre observational study in America of fluid administration for uncomplicated elective abdominal surgery with minimal blood loss (Lilot et al. The lack of correlation between the volume of postoperative day 1 fluids and body weight is interesting. In terms of absolute volumes given, if clinicians were calculating fluid doses on a millilitre per kilogram basis, we might expect absolute volumes to increase with body weight. We saw the opposite of this with smaller patients getting larger volumes of fluids. This suggests that practitioners are thinking in terms of ‘number of bags’ for a ‘standard’ patient and not taking into account weight.Most intravenous fluid trials take place in the operating theatre. We have demonstrated the type of intravenous fluid prescribed varies depending on whether the patient is in the postoperative ward or in theatre. The type of prescriber is likely to be different as well. Some previous intravenous fluid research has excluded the first postoperative day from any analysis because fluid prescriptions during this period may have been complicated by surgery-induced fluid and electrolyte shifts and any postoperative fluid prescriptions completed by the anaesthetist (Walsh and Walsh Education of junior doctors can make an impact on their prescribing choices (De Silva et al. Our aims were to accurately document the current clinical practice of perioperative intravenous fluid prescribing and identify key areas for improvement. There is some evidence of good practice in terms of early cessation of intravenous fluid, reduced use of 0.9 % sodium chloride compared with previous audits and early free fluid orders. However, there is clearly a need for effective implementation of intravenous fluid therapy guidelines to assist prescribers in the postoperative period prescribe appropriate quantities of sodium, potassium and water relevant to the clinical need. The wide variation of intraoperative volume for three common elective procedures is of concern and needs to be investigated further. We have identified that the suboptimal use of intravenous fluid therapy is relatively common and a potential cause of excessive complications. It is of concern that a basic principle such as appropriate potassium supplementation appears to be inadequate. The publication of prominent guidelines for all involved in fluid prescribing can only help raise basic standards, while acknowledging that fluid physiology is a complex and evolving area not fully understood even by those with expertise in this field.


Since their inception, Twitter and related microblogging systems have provided a rich source of information for researchers and have attracted interest in their affordances and use. Since 2009 PubMed has included 123 journal articles on medicine and Twitter, but no overview exists as to how the field uses Twitter in research.This paper aims to identify published work relating to Twitter within the fields indexed by PubMed, and then to classify it. This classification will provide a framework in which future researchers will be able to position their work, and to provide an understanding of the current reach of research using Twitter in medical disciplines.Papers on Twitter and related topics were identified and reviewed. The papers were then qualitatively classified based on the paper’s title and abstract to determine their focus. The work that was Twitter focused was studied in detail to determine what data, if any, it was based on, and from this a categorization of the data set size used in the studies was developed. Using open coded content analysis additional important categories were also identified, relating to the primary methodology, domain, and aspect.As of 2012, PubMed comprises more than 21 million citations from biomedical literature, and from these a corpus of 134 potentially Twitter related papers were identified, eleven of which were subsequently found not to be relevant. There were no papers prior to 2009 relating to microblogging, a term first used in 2006. Of the remaining 123 papers which mentioned Twitter, thirty were focused on Twitter . The early Twitter focused papers introduced the topic and highlighted the potential, not carrying out any form of data analysis. The majority of published papers used analytic techniques to sort through thousands, if not millions, of individual tweets, often depending on automated tools to do so. Our analysis demonstrates that researchers are starting to use knowledge discovery methods and data mining techniques to understand vast quantities of tweets: the study of Twitter is becoming quantitative research.This work is to the best of our knowledge the first overview study of medical related research based on Twitter and related microblogging. We have used 5 dimensions to categorize published medical related research on Twitter. This classification provides a framework within which researchers studying development and use of Twitter within medical related research, and those undertaking comparative studies of research, relating to Twitter in the area of medicine and beyond, can position and ground their work. Since their inception in 2006, Twitter and similar microblogging systems have provided data for research, with the first academic paper on the subject appearing in 2007 . ArticleThe terms microblog and Twitter are both widely used by authors, dating from the first paper on the subject . The terA variant of blogging which allows users to quickly post short updates, providing an innovative communication method that can be seen as a hybrid of blogging, instant messaging, social networking and status notifications. The word’s origin suggests that it shares the majority of elements with blogging, therefore it can potentially be described using blogging’s three key concepts: the contents are short postings, these postings are kept together by a common content author who controls publication, and individual blog entries can be easily aggregated together.4Some writers hyphenate the term as “micro-blog” , while oTwitter is a microblogging site, originally developed for mobile phones, designed to let people post short, 140-character text updates or “tweets” to a network of others. Twitter prompts users to answer the question “What are you doing?”, creating a constantly- updated timeline, or stream, of short messages that range from humor and musings on life to links and breaking news. Twitter has a directed friendship model: participants choose Twitter accounts to “follow” in their stream, and they each have their own group of “followers”.7PubMed is a free Web literature search service developed and maintained by the National Center for Biotechnology Information (NCBI) . Since 1In common with many other papers, we used the term Twitter to encompass all microblogging systems. The work was not a traditional literature review . InsteadThis work will provide a framework with which researchers studying Twitter related topics and their applications in medical related areas will be able to position and ground their work. It will provide a single point where current work on the medical use of Twitter can be compared and contrasted. Additionally it will help to understand the scope and reach of using PubMed as a data source.Our analysis shows that Twitter related research can be classified in a variety of ways: whether it is Twitter-focused or part of a wider social media related study; whether it is based on data, and if so, the quantity of data considered; the domain in which the work is based; the methods used; and the aspect–or characteristic–of Twitter considered. These dimensions of classification provide a framework in which Twitter-related medical research can be positioned and compared with other work within the area and beyond.Researchers normally identify papers on a topic in a number of different ways such as chaining from existing papers and database searches ,13. TherInitial experimentation showed that for Google Scholar  the searGold et al  faced a It was determined for this study that a structured search using PubMed would be used to identify papers in journals. While this most certainly would not give an exhaustive list of papers on Twitter it does mean that the search is repeatable, by other researchers, allowing future studies to include papers added to PubMed. Using subscription based services (such as Scopus) would mean only some researchers could repeat the study limiting its usefulness as a benchmark.The data collection was made for the papers that were first published between 2007 (the first year academic papers on Twitter appeared) and 2011 (the last complete year before this study); inclusive of papers available online as preprints ahead of the print version (epubs).During 2010, the terms “Twitter messenging” and “Twitter messaging” were introduced into the MeSH controlled vocabulary under the headings Internet and Blogging respectively. There are no entries relating to the term microblog or its variants, although blogging is present. There are currently no papers within PubMed that are returned by searches on the MeSH terms: “Twitter messenging” or “Twitter messaging”. It should be noted that where papers have keywords, not indexed by MeSH terms, PubMed does not store these and so it is not possible to search PubMed for papers with keywords such as “Twitter” or “microblog”. Therefore, the terms Twitter, Tweet, Microblog, and Micro-blog were used as the basis for keyword searching across all fields in PubMed, and then cross-referenced and checked to remove spurious data. A total of 139 papers were initially identified which had used terms from the query in a medical context. Five of these were subsequently found to be only included in the results because one of the author’s surnames or usernames included “tweet”, and so a base corpus of 134 papers was created.Previous research  showed tFocus. Papers can be predominantly about Twitter or related microblogging such as the use of the Chinese microblog site Sina Weibo [na Weibo , or theyna Weibo . There aData. The data used in studies is varied, ranging from observations of small samples, through questionnaires, to collecting vast quantities of information via the Twitter API . The date of the study also impacts on the timeliness, quantity and quality of data.Domain. Studies are undertaken from a number of different standpoints and often within a domain or a group of domains.Method. Researchers use a variety of methodological techniques when carrying out research into Twitter.Aspect. The aspect or characteristic of Twitter considered. Many studies concentrate on looking at the message (tweets), while others study the user (tweeter), with smaller numbers look at the underlying technology and how it can be developed. A number of papers consider the concept of Twitter without any detail of its use.The overarching approach to classification was based on the approach used in a study of research on microblogging in education , with inThere were 57 corpora ,56-111 tOut of 134 papers, 36 -147 had Out of 134 articles, there were 11 -160 not The 2 papers in the corpus published in 2009 ,29 and 3In the following we consider only the Twitter-focused papers in medical related disciplines. Those papers that use Twitter or other microblogs as a primary source and topic for research as identified via PubMed. Across the papers a number of different types of data sources were reported including surveys, user profiles, tweets (posts), and individual words in tweets. The size of data set examined ranged from small, with a few items, to large scale, with billions of individual data points. Some papers were not based on data, particularly those early papers that were introducing the concept of Twitter.For some papers the abstracts indicated the data studied, for example in a paper “Use of Twitter to encourage interaction in a multi-campus pharmacy management course”  the abstMore than eighteen hundred tweets were made by students, guests, and the instructor... One hundred thirty-one students completed an optional evaluation survey.41Indicating the type of data and quantities, the full paper shows that the students posted 1775 tweets over 6 days, as well as indicating the use by other participants. The Twitter data was collected by graduate teaching assistants using a Twitter list in preference to hashtags, which the students are reported to have found cumbersome. In other papers, the abstract provides only partial information about the dataset. For example in a paper “Social media & stem cell science: examining the discourse” , the absUsing Twitter.com’s data access protocol, we collected up to 400 public messages from each user in the sample, excluding users with fewer than 25 messages. The resulting corpus contained about 2.4 million individuals from across the globe and 509 million messages authored between February 2008 and January 2010.43The paper “Implementing Twitter in a health sciences library”  is a repStratifying across the different descriptions of data we identified 4 categories which can be used to describe the datasets used to study Twitter in a medical context.Large. Studies looking at vast amounts of data that would require a team of researchers and the use of automated tools if the data is to be analyzed in a timely manner. Typically considering over a million tweets and/or a million accounts. The term “big data” is often used to describe the quantity of data in such studiesMedium. Studies using quantities of data that could realistically be analyzed manually by a dedicated researcher or a small team with limited tool support. Typically considering thousands of tweets or accounts.Small. The data handled could be reasonably handled by a researcher alongside other tasks. Typically considering surveys, groups, tweets, and user profiles, with up to a thousand items.Not data based. Papers not based on data collection and analysis.All the papers in this study are from PubMed and so the broad domain is medical, however the researchers have a number of different standpoints. Consideration was given to the selection of domains from sub-area and disciplines of medicines, but typically there are only a few papers in each sub-area, see Based on an analysis of the contents of full papers we have identified the following broader topic, or domain, areas. Some papers are allocated to more than one of these domains:Academic. Seven papers in total [in total ,40,41,48General Communication. Fourteen papers [n papers -46,50-54Medical Professional Communication. Nine papers [e papers ,47,48,55Targeted Communication. Two papers [o papers ,49 involGuides. Four of the papers [e papers -30,36 arInitially, the papers’ titles and abstracts were read to try to identify the methodological approach use by the researchers. For the papers with structured abstracts and some others this clearly indicated the approach taken. For example a paper entitled “'What's happening?' A content analysis of concussion-related traffic on Twitter”  clearly These methods were then stratified into 3 broad categories:Analytic. Where the researchers had performed some type of analysis, which may be quantitative or qualitative. Sometimes these methods are supported by existing or new techniques from artificial intelligence, mathematics and statistics to facilitate knowledge discovery and mining of information. Many of the papers use the techniques of content analysis: for example in “Pandemics in the age of Twitter: content analysis of Tweets during the 2009 H1N1 outbreak” [utbreak” , while iutbreak”  machine utbreak”  to extraDesign and Development. Where systems are proposed or built, to interact with Twitter, such systems are often demonstrators used by the authors within their own context. For example, in a paper entitled, “A new support system using a mobile device (smartphone) for diagnostic image display and treatment of stroke” [ stroke” , the met stroke” , the aut stroke”  they desExamination. Where the authors had undertaken review and survey type works, including approaches such as: case studies, categorizations, essays, ethnographic studies, interviews, and investigation. For example in a paper entitled, “Twitter as a communication tool for orthopedic surgery” [surgery” , they idsurgery” , interviAlongside the methods the aspect of Twitter primarily considered in research was identified according to the 4 categories:The messages (tweets).The users (tweeter).The underlying technology and how it can be developed.The concept of Twitter without any detail of its use.For all medical related papers it was possible to identify a primary method and primary aspect considered by the researchers and these are summarized in It is interesting to note that the majority of the papers report research using analytic methods, and the majority of this group look at the contents of the tweets sent, rather than the users. The 6 papers using examination methods such as reviews considering the concept of Twitter are the same as the 6 papers in Across PubMed 123 papers were identified that were Twitter related; this is a very tiny proportion of the more than 21 million citations held in the database. The first papers indexed by PubMed were published in 2009, 3 years after the launch of Twitter and 2 years after the first Twitter papers appeared in other disciplines. The early Twitter focused papers introduced the topic and highlighted the potential, not carrying out any form of data analysis. However subsequent studies analyzed quantities of Twitter data and one of the principal findings of this study is the size of studies that are now possible based on Twitter in the medical field. The first of the large studies of over a million pieces of data was published in November 2010 . ResearcOur research material of tweets was gathered by using the Twitter4J … an open-source Java library for the Twitter Application Programming Interface (API). The tweets were stored locally as Twitter limits online search to one week. This strategy allowed an increased sample size improving the likelihood of detecting trends. Twitter API provided approximately one per cent of all real-time tweets. Our tweet corpus included English tweets over fourteen days. The data was gathered during 4 Jan 2011 at 13:36–20:10 EST with 300,000 tweets and 582,975 words.52The Edinburgh Twitter corpus of 97 million tweets was used in one paper , howeverLimiting the papers examined in this study to those indexed in PubMed between 2007 and 2011 means that there is a body of work published since the start of 2012 that is not considered. While PubMed indexes some 5400 journals there are journals not indexed, including those not in English. A lot of papers published on the subject of Twitter are in conference proceedings. For instance, the Scopus database  returns Searching on the MeSH terms did not prove useful in highlighting relevant papers. Given the terms “Twitter messaging” and Twitter messenging” were only added to the vocabulary during 2010 this is not totally surprising, although we did expect to see some use of these terms in the most recent publications. This indicates that the MeSH vocabulary system is not being adequately used by authors and publications writing about Twitter, which is problematic given that it is the only faceted search available in PubMed.The word “twitter” is sometimes used in medical related research with its original meaning. Papers that did this were discounted from this study. Potentially papers may be incorrectly excluded, for example a paper that related both patients with twitters and who used microblogging. We do not believe this was the case in the papers considered here but it is certainly a potential limitation with the approach.Given that this paper covers only the first few years of academic research in the area of Twitter, it is likely that some of the approaches reported upon are fledgling and that over the next years the methods applied will reach a degree of maturity that will impact on the broad methodological classification presented here.The papers reviewed and categorized here were diverse in their finding and conclusions. Of the findings many were closely linked to the domain of study rather than the use of Twitter or social media in general. For example, the findings and conclusions of Golder and Macy  all relaIn the papers in the domain of professional communications, where usually papers concentrate on the concept of Twitter, rather than findings extrapolated from Twitter data, the approach was usually a review or other method classified above as examination. These tended to conclude that they had introduced Twitter and highlighted its potential. Although some were less enthusiastic.Despite the growing popularity of social media across multiple disciplines, the majority of pharmacy preceptors surveyed were not willing to use these venues in professional practice.47Papers looking at medium and large data sets often included indications that their work illustrated the potential for studies in medical related area to use Twitter and other social media data.The study adds to evidence supporting a high degree of correlation between pre-diagnostic social media signals and diagnostic influenza case data, pointing the way towards low cost sensor networks.5Also among these studies authors indicate that the abundance of data will change the way in which researchers approach their studies .This work is to the best of our knowledge the first broad study of medical related research based on Twitter and related microblogging. We have identified that medical related research in this area was first published in 2009 and that the number of papers has increased in both the following years.From the some 5400 journals indexed by PubMed, we have identified thirty papers that focus on Twitter and 57 that mention it. There are also a number of papers in which the term twitter is used with its original meaning and not at all related to microblogging. There are some papers indexed that appear to relate to Twitter but do not have abstracts further investigations shows these to be editorial or news type items as opposed to academic oriented papers. Further work will need to be undertaken to identify and classify work beyond the academic papers indexed by PubMed, this would include diverse sources such as book chapters, conference proceedings, and blog posts.While the early Twitter-focused papers were predominantly introductory explaining to the readership what Twitter was about and considering its potential, we are now seeing work reported were researchers have examined large quantities of Twitter data, using these large data sets to obtain better understanding of topics within medicine. We have classified this usage of data into 4 categories: large, medium, small, and no data. This access to large amount of data stemming from individual tweets coupled with metadata of location, time of day, networks of followers holds potential for many future studies building on existing work such as identification of the spread of infectious diseases but it has also potential for the identification of previously impossible studies based on personal thoughts put into a public space. While most studies use methods that can be broadly classed as analytic, the large quantities of data mean that analysis techniques that facilitate knowledge discovery and mining of information are starting to be used. As the number of research papers grows, the dimension of domain will need to be revisited as other stratifications may become possible.The results presented here will provide researchers with an insight into the medical domain and Twitter use, where there is work in related sub-areas that can be used to inform new studies and those that have still to be studied rigorously. The large data studies that have completed certainly have information on techniques for data collection and method for analysis that will be useful in other domains. Identifying areas where further research is needed is difficult, but we would suggest that the following are neglected areas within the realms of twitter and medicine:Outreach and investigating the reach and scope of Twitter messages. Although Prochaska et al [ka et al  have revPublic engagement. While Adams et al [ms et al  have invLegal and ethical issues. While a number of papers  discThis study provides a framework within which researchers studying the development and use of Twitter within medical related research will be able to position their work and against those undertaking comparative studies of research relating to Twitter in the area of medicine and beyond will be able to ground their work. We have provided an analysis of the use and usefulness of microblogging within medical fields at a time when social media is being increasingly used for research purposes across many domain and in a reproducible manner, which can be built upon in future as more studies are published.


Patients with non-small cell lung cancer frequently demonstrate differing clinical courses, even when they express the same tumour stage. Additional markers of prognostic significance could allow further stratification of treatment for these patients. By generating quantitative information about tumour heterogeneity as reflected by the distribution of pixel values within the tumour, CT texture analysis (CTTA) can provide prognostic information for patients with NSCLC. In addition to describing the practical application of CTTA to NSCLC, this article discusses a range of issues that need to be addressed when CTTA is included as part of routine clinical care as opposed to its use in a research setting. The use of quantitative imaging to provide prognostic information is a new and exciting development within cancer imaging that can expand the imaging specialist’s existing role in tumour evaluation. Derivation of prognostic information through the application of image processing techniques such as CTTA, to images acquired as part of routine care can help imaging specialists make best use of the technologies they deploy for the benefit of patients with cancer. Lung cancer remains the leading cause of cancer death in Western societies, with more than 75 % of cases comprising non-small cell lung cancer (NSCLC). Tumour stage is the most important prognostic variable for survival, and this parameter makes a major contribution to clinical decisions concerning the benefits of surgery, chemotherapy and/or radiotherapy for individual patients. However, patients with the same tumour stage frequently demonstrate differing clinical courses. Hence, there is a need for additional markers of prognostic significance that could for example, identify those patients with the highest likelihood of post-surgical recurrence who might benefit most from adjuvant chemotherapy Fig. , or alteComputed Tomography (CT) plays a key role in staging of NSCLC, either as a stand-alone technique or during Positron Emission Tomography, and the use of CT to provide additional prognostic markers can form a natural extension to this role. Deriving markers of prognosis from existing CT images avoids the cost and radiation exposure associated with techniques such as perfusion CT that require specialised data acquisitions. CT texture analysis (CTTA) is an image processing method that can be applied to routinely acquired images to provide additional quantitative information about tumour heterogeneity as reflected by the distribution of pixel values within the tumour. Tumour heterogeneity is an important biological characteristic related to tumour aggression and response to treatment. There is an increasing body of evidence demonstrating the ability of CTTA to provide prognostic information for patients with NSCLC and other tumours –5.At present, none of the currently available image viewing or Picture Archiving and Communication software packages has integrated CTTA into their products. A stand-alone software that implements the filtration/histogram method is available commercially Fig.  but needAlthough any CT image can in principle be analysed using CTTA, at our institution we currently restrict analysis to the low-dose CT (LDCT) component of Positron Emission Tomography (PET)/CT examinations for the following reasons: Firstly, the prognostic value of CTTA in NSCLC has been more extensively clinically validated for LDCT than for diagnostic CT images, including derivation and testing of cut-off values from separate patient cohorts . SecondlThe single CT slice that displays the largest cross-section of the tumour is selected for analysis and displayed in soft-tissue windows. When constructing the tumour region of interest (ROI), automated segmentation procedures should be used wherever possible to optimise consistency in analysis between operators. Computer automated segmentation of tumour relative to aerated lung is straightforward. When a tumour is completely surrounded by aerated lung, segmentation tools allow the operator to construct a ROI beyond the tumour edge within which the precise tumour margins are defined by the software algorithm Fig. . HoweverCTTA software typically returns a range of texture parameters for the constructed tumour ROI. For the filtration-histogram CTTA approach, these parameters characterise the histogram of pixel intensity values within the ROI for a series of filtered images highlighting features of a specified size. Each parameter has a different relationship with the size, number, brightness and variability of features in the original CT image . A choicCTTA parameters reflect variations in x-ray attenuation (measured in Hounsfield Units) within the tumour. The accuracy of CT attenuation values is checked as part of the routine quality procedures recommended by the equipment manufacturers. Nevertheless, the potential sources of variability in CTTA values between different sites have not been fully characterised. It is therefore essential to audit the prognostic performance of results acquired locally before full implementation of CTTA as a biomarker in clinical practice. If the audit indicates that selection of different CTTA parameters and/or adjustment of cut-off values is required to optimise prognostic performance, new cut-off values should be determined from one patient cohort and tested in another. Alternatively, a cross-validation procedure may be used . AuditinAcceptance of prognostic imaging biomarkers by clinicians is an essential pre-requisite to adoption into clinical practice and communication of a convincing case for the use of CTTA as a marker of prognosis is important for achieving clinical engagement. A “black box” approach which fails to enunciate the biological basis of the imaging biomarker values is unlikely to be successful even in the presence of compelling data linking the measurements to prognosis. In NSCLC, emerging evidence that points to the intra-tumour heterogeneity reflected by CTTA as being a phenotypic consequence of activation of the MAPK tumour pathway provides a clinically and therapeutic relevant foundation for CTTA as a prognostic indicator. Studies have shown CTTA values in NSCLC to be related to hypoxia, mutations in EGFR and KRAS genes, and ALK gene re-arrangements , 5, 9–12The use of quantitative imaging to provide prognostic information is a new and exciting development within cancer imaging that can expand the imaging specialist’s existing role in qualitative and semi-quantitative assessments of prognosis such as TNM staging and changes in tumour appearances during serial imaging. Parallel developments are occurring, or have already emerged, in other areas of imaging such as CT coronary calcium scoring for risk-assessment in patients with coronary artery disease. Cancer patients often need to undergo a range of investigations and there is a responsibility to maximise the clinically relevant information obtainable from these procedures, particularly when they entail ionising radiation. Derivation of prognostic information through the application of image processing techniques such as CTTA, to images acquired as part of routine care can help imaging specialists make best use of the technologies they deploy for the benefit of patients with cancer.


Although many cancers are associated with infectious agents  seems plausible, or most likely, the two diseases have arose separately.An important question is whether the DFT2 tumour is slower growing than DFT1. As the latter seems to grow very quickly, rapidly kill the animals and decimate the host population, the time of potential transmission is short. In this setting, a slower growing tumour may be fitter as the slower growth permits a longer time for transmission in an increasingly sparse population. It will be interesting to see whether slower growing phenotypes become more prevalent as the population steadily declines (Ujvari et al. We propose that the emergence of transmissible cancers requires a ‘perfect storm’ with the rare confluence of multiple host and tumour cell traits (Ujvari et al.


However, combination therapy increased cancer cell apoptosis, decreased tumour cell proliferation and enhanced survival, owing to a synergistic effect of the drugs on suppression of the PI3K pathway . Therefore, this model represents a valuable preclinical system for advancing current therapies and for testing novel drugs and drug combinations against GBM. 45Page Gliobastoma multiforme (GBM) is an aggressive malignant form of brain tumour for which effective therapies are limited. Genetically engineered mouse models (GEMMs) harbouring mutations in components of the main signalling pathways that are altered in human GBM – including the receptor tyrosine kinase (RTK)–RAS– phosphoinositide-3-kinase (PI3K) pathway – are available. However, these GEMMs display a long latency to tumorigenesis and advanced tumour heterogeneity, which represents a challenge in preclinical drug testing. In this study, Zoë Weaver Ohler and colleagues developed an orthotopic and tractable mouse model of GBM by transplanting brain tumour cells derived from GBM-GEMMs into the brain  of syngeneic mice . This model develops GBM with features of the human disease, including high vascularisation and aggressive invasion of surrounding tissues, and thus was used to test the effects of two drugs that are currently in clinical trials for GBM and other solid tumours, namely BKM120 and PD0325901 . When tested