Purpose: Netarsudil, an inhibitor of Rho kinase and a norepinephrine transporter, has been shown to lower elevated intraocular pressure (IOP) in controlled studies of patients with open-angle glaucoma and ocular hypertension, and in healthy volunteers. The mechanism of this ocular hypotensive effect in humans is unknown.Methods: The objective of this study was to evaluate the effect of netarsudil 0.02% on aqueous humor dynamics (AHD) parameters. In this double-masked, vehicle-controlled, paired-eye comparison study, 11 healthy volunteers received topical netarsudil ophthalmic solution 0.02% or its vehicle once daily for 7 days (morning dosing). The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes.Results: In netarsudil-treated eyes, diurnal outflow facility increased from 0.27 ± 0.10 μL/min/mmHg to 0.33 ± 0.11 μL/min/mmHg  after 7 days of treatment. In placebo-treated eyes, diurnal outflow facility did not significantly change (P = 0.94). The difference between netarsudil and placebo eyes in diurnal change of outflow facility was 0.08 μL/min/mmHg (P < 0.001). Diurnal episcleral venous pressure (EVP) in netarsudil-treated eyes decreased from 7.9 ± 1.2 mmHg to 7.2 ± 1.8 . Diurnal EVP was not significantly different between netarsudil- and placebo-treated eyes. There was a trend toward decreasing aqueous humor flow rate . No treatment changes were seen in uveoscleral outflow rate.Conclusions: Once-daily dosing of netarsudil ophthalmic solution 0.02% lowered IOP through increasing trabecular outflow facility and reducing EVP. This suggests a combination of mechanisms that affect both the proximal and distal outflow pathways. Goldmann expressed the relationship between these variables as a simple equation,11 which was later modified to account for the presence of the uveoscleral outflow pathway (the modified Goldmann equation):Aqueous humor is produced by the ciliary body, passes through the pupil into the anterior chamber, and exits through both trabecular and uveoscleral pathways.Q is the aqueous humor production rate, C is outflow facility, and U is uveoscleral outflow rate. Measurements of AHD variables have been used to explore the action of pharmacological agents that reduce IOP. For example, measurement of aqueous humor flow rate demonstrated the suppression of aqueous humor production by timolol to lower IOP.13 Also, calculation of uveoscleral outflow rate from the modified Goldmann equation has been used to demonstrate an increase in uveoscleral outflow rate as a mechanism for IOP reduction in response to prostaglandin analogs.15where For this study, we evaluated the effects of topically applied netarsudil ophthalmic solution 0.02% on IOP, outflow facility, EVP, aqueous humor flow, and uveoscleral outflow in healthy volunteers.16 Also, women of childbearing potential were excluded if they had a positive urine pregnancy test. The study adhered to the principles of the Declaration of Helsinki and was reviewed and approved by the Institutional Review Board of Mayo Clinic. All subjects gave consent to participate after discussion of risks and benefits of the study.This study was designed as a double-masked, vehicle-controlled, paired-eye comparison trial. Study participants included healthy adult volunteers with IOP between 14 and 21 mmHg inclusive in each eye and best-corrected visual acuity (BCVA) in each eye of 20/50 (LogMAR +0.4) or better. Individuals were excluded if they had chronic or acute ophthalmic disease, previous intraocular or refractive surgery, and recent ocular trauma or infection. Individuals with refractive errors greater than −4.00 D or +2.00 D were excluded due to possible effects on measurement of outflow facility using tonography.During a screening examination, heart rate and blood pressure were measured and both eyes were examined by slit-lamp biomicroscopy, including gonioscopy and dilated ophthalmoscopy. IOP was measured by Goldmann applanation tonometry in both eyes. Three-dimensional images of the anterior chamber were recorded by using Scheimpflug photography . BCVA was recorded and individuals were evaluated for their ability to instill eye drops.17 at 09:00, 11:00, and 13:00 h. No other ocular measurements were performed during this time due to the possible effects of topical anesthetics and preservatives on corneal permeability.18 After fluorophotometry was completed, IOP, EVP, and outflow facility were measured using the techniques described below. These measurements were repeated at 15:00 h.Baseline AHD evaluation was scheduled for Day 1 of the study, and enrolled participants instilled 3–8 drops of 2% fluorescein solution (prepared by the Mayo Clinic Research Pharmacy) in each eye approximately 8 h before the start of measurements. Participants arrived at the clinic at 08:00 h, and heart rate, blood pressure, and any ocular symptoms were recorded. Fluorescein concentrations in the anterior chamber and cornea were measured by fluorophotometry19 morning instillation, as used in previous earlier stage trials,21 was selected for this mechanism study to optimize measurements of AHD during normal working hours. Each participant received 2 bottles of study medication for home use, coded as “right” or “left” eye, but were otherwise externally identical. On the night preceding the Day 8 (posttreatment) examination, participants instilled 2% fluorescein drops as they did in the baseline examination. On the morning of Day 8, participants instilled their 7th dose of study medication in each eye at 06:00 h. Participants returned to the clinic for a repetition of the measurements performed on the baseline day, with the addition of biomicroscopy. Conjunctival hyperemia was scored as 0 (none) to 3 (severe)19The eyes of each participant were then randomized to receive netarsudil ophthalmic solution 0.02% in one eye and its vehicle in the fellow eye  each morning for 7 days. Note that while netarsudil was dosed at night in Phase 2b and Phase 3 trials,IOP was measured by pneumatonometry . A mean of 3 measurements was used at each time point.22 The probe with a 5.5-g weight was held perpendicularly against the anesthetized cornea of the supine subject for 4 min. A second-order polynomial was fitted to pressures recorded by the tonography unit, and outflow facility was directly calculated using Excel spreadsheets  based on Grant's formula23 and standard tables introduced by Friedenwald.25Outflow facility was measured by using a custom digital Schiøtz tonography unit.26Aqueous humor flow rate was calculated by measuring the clearance rate of fluorescein from the anterior chamber and cornea. The concentration of fluorescein was measured by using a scanning ocular fluorophotometer.28 A clear silicone inflatable bulb was placed over an episcleral vein, and then inflated at a constant rate. Collapse of the vein was recorded by a video camera. The chamber pressure was recorded and synchronized with the video stream. Brightness profiles across a selected vessel were calculated using custom image analysis software. Peak vessel brightness decreased as increasing pressure in the bulb collapsed the vein. Venous pressure was assumed to be the applied pressure that initiated venous collapse.28EVP was measured by automated episcleral venomanometry by using a custom-built device and software.Uveoscleral outflow rate was calculated by using a priori an 80% chance of finding a minimum difference of 1.6 mmHg , assuming a mean baseline EVP of 6.5 mmHg and standard deviation of 1.5 mmHg, based on previous studies in healthy participants.28 Observations throughout the day were averaged for “diurnal.”The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes. The sample size was selected to have t-tests with 2-sided 90% confidence intervals (CIs). In addition, the mean changes in AHD measures were compared between netarsudil and placebo using paired t-tests with 2-sided 90% CIs. Probability was estimated by using PC-SAS version 9.3 or higher . Statistical significance was defined as a one-tailed P-value of 0.05 or lower, with no correction for multiplicity.For AHD parameters, the mean values at baseline were compared with the mean values post-treatment using paired In this paired comparison study conducted between May 2015 and January 2016, from 35 individuals screened, 11 participants were randomized and treated and 10 (90.9%) of them completed the study. Among the individuals screened, but not randomized, 12 did not meet the IOP criteria, 3 were on ocular medications, 2 had suspicious discs, 2 had a history of other eye diseases, 1 was unable to tolerate the AHD measurements, and 4 withdrew consent after screening, but before randomization. One randomized participant discontinued the study early and withdrew consent because of an adverse event .The study population was 90.9% female (10/11), with a mean age of 38.6 ± 13.8 years (range 21–56 years). The majority of participants were white  and not Hispanic . Iris color was similarly distributed among brown, blue, and hazel, with one participant with green irides. The eye receiving netarsudil ophthalmic solution 0.02% was the left eye for 6 participants and the right eye for 5 participants.A summary of the AHD findings are presented in Observed values: At baseline, mean IOP in the eyes randomized to netarsudil and placebo were similar: 17.4 ± 2.9 and 17.2 ± 2.2 mmHg, respectively, at 13:00 h and 16.6 ± 2.4 and 16.1 ± 1.6 mmHg, respectively, at 15:00 h. Baseline mean diurnal IOP (average of IOP at 13:00 and 15:00) was 17.0 ± 2.5 and 16.7 ± 1.8 mmHg, respectively. After 7 days of dosing with netarsudil, with the last dose at 06:00 h on Day 8, mean IOP decreased to 12.8 ± 2.7 mmHg and 12.0 ± 1.9 mmHg at 13:00 h (7 h after dosing) and 15:00 h (9 h after dosing), respectively. Mean diurnal IOP in netarsudil-treated eyes decreased to 12.4 ± 2.2 mmHg. In placebo-treated eyes, mean IOP decreased to 16.4 ± 2.6 mmHg and 15.5 ± 1.8 mmHg, respectively. Mean diurnal IOP in placebo-treated eyes decreased to 16.0 ± 2.1 mmHg.P < 0.0001), and the mean diurnal IOP was 3.5 mmHg lower (P < 0.0001) than in placebo-treated eyes. Mean IOP on Day 8 was 4.6 mmHg lower than baseline at 13:00 and 15:00 h (P < 0.0001) in netarsudil-treated eyes. Reductions in mean IOP of less than 1 mmHg were recorded in placebo-treated eyes at 13:00 and 15:00 h. However, the mean IOP decrease from baseline in the netarsudil-treated eyes was greater than in the placebo-treated eyes by 3.8 mmHg and 3.9 mmHg at 13:00 and 15:00 h, respectively (P < 0.0001).Treatment effects: On Day 8 (the 7th day of treatment), mean IOP in netarsudil-treated eyes was 3.6 mmHg and 3.5 mmHg lower than in placebo-treated eyes at 13:00 and 15:00 h, respectively  and 0.08 μL/min/mmHg (P = 0.001) higher than in placebo-treated eyes at 13:00 and 15:00 h, respectively, and the mean diurnal outflow facility was 0.06 μL/min/mmHg higher (P = 0.004) than in placebo-treated eyes. The mean increase in outflow facility on Day 8 compared with baseline for netarsudil-treated eyes was 0.03 ± 0.11 μL/min/mmHg (P = 0.2) and 0.07 ± 0.10 μL/min/mmHg (P = 0.049) at 13:00 and 15:00 h, respectively, and mean diurnal change from baseline outflow facility was 0.05 ± 0.07 μL/min/mmHg (P = 0.02). For placebo-treated eyes, there was no statistically significant change in outflow facility from baseline at 13:00 and 15:00 h , or diurnally . The change in outflow facility from baseline in the netarsudil-treated eyes was significantly greater than the change in the placebo-treated eyes at 13:00 and 15:00 h , and diurnally .Treatment effects: On Day 8, the mean outflow facility in netarsudil-treated eyes was 0.04 μL/min/mmHg , or mean diurnal EVP . However, EVP in netarsudil-treated eyes on Day 8 was decreased significantly compared to baseline at 13:00 h  and diurnally , with a trend toward a decrease at 15:00 h . There was no statistically significant change in EVP in placebo-treated eyes compared to baseline at 13:00 h, 15:00 h, or diurnally . The difference in change from baseline EVP between netarsudil- and placebo-treated eyes was −0.5 mmHg (P = 0.06) and −0.2 mmHg (P = 0.3) at 13:00 and 15:00 h, respectively, and the difference in mean diurnal change from baseline EVP was −0.3 mmHg (P = 0.08).Treatment effects: After 7 days of treatment (Day 8), there was no statistically significant difference between netarsudil- and placebo-treated eyes in mean EVP at 13:00 and 15:00 h . On Day 8, there was a trend toward a decrease in aqueous humor flow rate relative to baseline in netarsudil-treated eyes , with no trend in placebo-treated eyes . There was a trend toward a difference in change from baseline aqueous humor flow rate between netarsudil- and placebo-treated eyes .Treatment effects: There was no significant difference in aqueous humor flow rate between netarsudil- and placebo-treated eyes on Day 8, after 7 days of treatment  and 0.4 μL/min (P = 0.1) at 13:00 and 15:00 h, respectively, and the difference in mean diurnal uveoscleral outflow was 0.5 μL/min (P = 0.07). Although there was a statistically significant difference between netarsudil- and placebo-treated eyes at 13:00 h on Day 8, it should be noted that calculated mean uveoscleral outflow was higher in the eyes assigned to netarsudil treatment at baseline. There was no significant difference in calculated uveoscleral outflow for netarsudil or placebo on Day 8 relative to respective baseline values. Changes from baseline in calculated mean uveoscleral outflow for netarsudil were 0.5 ± 1.0 μL/min (P = 0.08) and 0.4 ± 1.5 μL/min (P = 0.2) at 13:00 and 15:00 h, respectively, and mean diurnal change from calculated baseline uveoscleral outflow was 0.4 ± 1.1 μL/min (P = 0.2). There was no significant change from baseline in calculated mean uveoscleral outflow for placebo at 13:00 h , 15:00 h , or diurnally . Similarly, there was no significant difference in calculated change from baseline uveoscleral outflow between netarsudil- and placebo-treated eyes at 13:00 h , 15:00 h , or diurnally .Treatment effects: The difference between netarsudil- and placebo-treated eyes in calculated mean uveoscleral outflow rate was 0.5 μL/min  and one participant reported mild eye pruritus in the netarsudil-treated eye (assessed as likely unrelated to netarsudil use). No adverse events were reported in the vehicle-treated eye. There were no changes in visual acuity, heart rate, or blood pressure.30 this study represents the first measurement of netarsudil effects on AHD in living humans. The methods required to measure these variables in human subjects are technically challenging, and are necessarily noninvasive. In contrast, some of the methods used to measure AHD in animals are invasive  and cannot be used in humans.31The objective of this study was to evaluate the effects of netarsudil ophthalmic solution 0.02% on AHD. While this question has been studied in rabbits, mice, non-human primates, and human donor eyes,21 The ocular hypotensive effect of netarsudil measured in this study was similar to that observed in a previous study in healthy volunteers following 8 days of once-daily dosing,21 and therefore confirms the ability of netarsudil to produce large reductions in IOP in participants with normal baseline IOP.In this study, netarsudil decreased IOP by 4.6 mmHg from baseline (∼27%). In eyes receiving the vehicle, there was a small reduction in IOP (0.7 mmHg). Given that this was a paired-eye study, a small contralateral effect of the drug cannot be ruled out, although this seems unlikely given that systemic exposure to netarsudil is not measurable after topical ocular dosing.5 and the ability of netarsudil,6 as well a number of other Rho kinase inhibitors,29 to increase outflow facility in non-human primates. However, based upon the Goldmann equation, a 20% increase in outflow facility accounts for less than half of the measured decrease in IOP produced by netarsudil, if all other parameters remained unchanged. Other changes in dynamic variables must account for the remaining change in IOP.The aqueous humor dynamic variables measured in this study suggest that an increase in outflow facility was the most important parameter to reduce IOP in response to netarsudil. In netarsudil-treated eyes, outflow facility increased by approximately 20% both from baseline and compared to the contralateral placebo-treated eyes. This result is consistent with the ability of the netarsudil primary metabolite, AR-13503, to increase outflow facility in perfused enucleated human eyes,7 The larger effect seen in rabbits could reflect a species difference, and it was noted in that study of Dutch belted rabbits that the baseline IOP (33.2 ± 8.3 mmHg) and EVP (16.3 ± 3.4 mmHg) were much higher than in New Zealand White rabbits . It is also possible that the difference in effect could be attributed to differences in the method of measurement. Cannulation of the episcleral veins in rabbits enables a more direct measurement of pressure, as well as a continuous tracing of the pressure profile. However, this technique would require removal of the overlying conjunctiva and penetration of the vessel with a glass cannula. These procedures could potentially affect absorption of netarsudil into the episcleral vasculature. Concerning the mechanism for EVP reduction, it is not clear if the effect on EVP is simply caused by vessel dilation, since dilation of the arteriovenous anastomoses in the episcleral vasculature could increase blood flow to the episcleral veins and offset the pressure reduction expected from episcleral vein dilation.34 Regardless, these results suggest an effect of netarsudil on the distal portion of the conventional outflow pathway.Measurement of EVP by using an objective noninvasive technique showed that netarsudil reduced EVP by about 10% from baseline. However, EVP was not different between netarsudil- and placebo-treated eyes. This may have been due to higher variability in measurement of EVP in this study than anticipated (up to SD = 1.81 in some groups vs. 1.5 mmHg expected), resulting in the study having lower power than estimated. In a previous study by Kiel and Kopczynski, topical netarsudil was shown to reduce EVP in normotensive rabbits by approximately 35% from baseline.P = 0.08), this study was not powered to detect a change in flow rate of this magnitude. However, the numerical decrease in aqueous humor flow rate of about 15% relative to baseline was consistent with a previous study in normotensive monkeys, which reported 23% decrease in flow rate from baseline in eyes treated with topical netarsudil.6 As with the measurement of EVP, the larger effect seen in the animal model could reflect a species difference or a difference in methodology. Of note, that study used a higher concentration of netarsudil (0.04% vs. 0.02% in our study), and 2 drops (instead of a single drop) were given in each eye. Nevertheless, further research is required to clarify the effect of netarsudil on aqueous humor flow rate in humans.Measurements of aqueous humor flow rate by fluorophotometry showed a trend toward a decrease in flow rate in netarsudil-treated eyes compared to baseline. While this trend was not statistically significant , but none of the other changes approached statistical significance. Given the variability in this parameter, and the small number of subjects in this study, any apparent change in uveoscleral outflow rate should be interpreted with caution.Uveoscleral outflow rate was not directly measured in this study, but was instead calculated from the modified Goldmann equation and the measured values for IOP, outflow facility, EVP, and aqueous humor flow rate. Unfortunately, direct measurement of uveoscleral outflow rate in humans requires perfusion with radioactive tracers and subsequent enucleation, a technique that has only been performed in a small group of patients with diseased eyes scheduled for enucleation.13 The 2 parameters that demonstrated statistically significant changes from baseline, outflow facility, and EVP could explain the observed changes in IOP. However, trends suggesting a reduction in aqueous humor flow rate and an increase in uveoscleral outflow rate require further research.Overall, there appear to be multiple mechanisms by which netarsudil lowers IOP. No single parameter is able to explain the changes in IOP even when extrapolating to the limits of the 95% confidence intervals for the AHD parameters. This contrasts with other agents, such as topical β-adrenoceptor antagonists, which are known to lower IOP through a single mechanism, an approximately 50% reduction of aqueous humor production.21There were no substantial safety issues with netarsudil in this study, other than the previously reported finding of conjunctival hyperemia, which was mostly mild and transient.In conclusion, in this study of healthy volunteers, once-daily dosing of netarsudil ophthalmic solution 0.02% lowered IOP through multiple mechanisms of action, including increased trabecular outflow facility and decreased EVP. This appears to be a unique combination of mechanisms that impact both the proximal and distal portions of the conventional outflow pathway. The roles of aqueous humor suppression and uveoscleral outflow enhancement require further investigation.


In patients with septic shock, the administration of fluids during initial hemodynamic resuscitation remains a major therapeutic challenge. We are faced with many open questions regarding the type, dose and timing of intravenous fluid administration. There are only four major indications for intravenous fluid administration: aside from resuscitation, intravenous fluids have many other uses including maintenance and replacement of total body water and electrolytes, as carriers for medications and for parenteral nutrition. In this paradigm-shifting review, we discuss different fluid management strategies including early adequate goal-directed fluid management, late conservative fluid management and late goal-directed fluid removal. In addition, we expand on the concept of the “four D’s” of fluid therapy, namely drug, dosing, duration and de-escalation. During the treatment of patients with septic shock, four phases of fluid therapy should be considered in order to provide answers to four basic questions. These four phases are the resuscitation phase, the optimization phase, the stabilization phase and the evacuation phase. The four questions are “When to start intravenous fluids?”, “When to stop intravenous fluids?”, “When to start de-resuscitation or active fluid removal?” and finally “When to stop de-resuscitation?” In analogy to the way we handle antibiotics in critically ill patients, it is time for fluid stewardship. In patients with septic shock, hemodynamic stabilization using intravenous fluids remains a major therapeutic challenge as numerous questions remain regarding the type, dose and timing of fluid administration. In these patients, fluids play an important role beyond hemodynamic stabilization and resuscitation. Intravenous fluids should be prescribed as any other drug we give to our patients: we should take into account the indications and contraindications for different types of fluids –8. We shIn this review, we will expand on the concept of the “four D’s” of fluid therapy . We will also focus on the recent concept defining four different phases in the time course of septic shock . Each phase requires a different therapeutic attitude regarding fluid administration. Taking into account both of these concepts in combination with other suggested ideas may promote more rational fluid administration aimed at avoiding both too little and too much. In analogy to the way we handle antibiotic usage in the critically ill, it is now time for fluid stewardship.Treating a patient with septic shock inevitably results in some degree of salt and water overload. First and foremost, this is the result of the initial fluid resuscitation with the aim of restoring intravascular volume, increasing cardiac output, augmenting oxygen delivery and improving tissue oxygenation. Salt and water overload can also result from the administration of large volumes of fluid as drug diluents, artificial nutrition and maintenance fluids. The capillary leak that is inherent to sepsis promotes the extravasation of large amounts of fluid, inducing relative central hypovolemia that often requires further fluid administration, despite interstitial oedema. Capillary leak represents the maladaptive, often excessive, and undesirable loss of fluid and electrolytes with or without protein into the interstitium that generates anasarca and end-organ oedema causing organ dysfunction and eventually failure . Fluid oAs often described in paediatric populations, the percentage of fluid accumulation is calculated by dividing the cumulative fluid balance in litres by the patient’s baseline body weight and multiplying by 100%. Fluid overload at any stage is defined by a cut-off value of 10% of fluid accumulation, as this is associated with worse outcomes , 76, 88.Studies demonstrate an association between fluid overload, illustrated by the increase in the cumulative fluid balance, with worse patient centred outcomes  in critiTherefore, current treatment of septic shock should include every effort to reduce the cumulative fluid balance. We must always bear in mind that fluids are drugs and oedema is akin to a drug overdose. Their characteristics, indications and contraindications should be carefully considered when choosing their type, their dose, the timing of their administration and the timing for their removal. In parallel, a reasoned fluid strategy requires that we do not consider septic shock as a single “one size fits all” disease, but rather that it is made of different phases, each implying a different therapeutic attitude .When prescribing fluids in patients with septic shock, we must take into account their composition and their pharmocodynamic and pharmacokinetic properties. In practice, we should consider the “four D’s” of fluid therapy: drug, dosing, duration and de-escalation Table  5]. Man. Man5]. We should consider the different compounds: crystalloids versus colloids, synthetic versus blood derived, balanced versus unbalanced, intravenous versus oral. The osmolality, tonicity, pH, electrolyte composition  and levels of other metabolically active compounds  are all equally important. Clinical factors  must all be taken into account when choosing the type and amount of fluid for a given patient at a given time. Moreover, the type of fluid is different depending on the reason why they are administered. There are only four indications for fluid administration, namely resuscitation, maintenance, replacement and nutrition, or a combination.Resuscitation fluids are given to correct an intravascular volume deficit in the case of absolute or relative hypovolemia. In theory, the choice between colloids and crystalloids should take into account the revised Starling equation and the glycocalyx model of transvascular fluid exchange . When caglobal increased permeability syndrome and ongoing fluid accumulation [Some patients will not transgress to the “flow” phase spontaneously and will remain in a persistent state of mulation . The glomulation .hydroxyethyl starches are contraindicated in case of septic shock, burns, patients with acute or chronic kidney injury or in case of oliguria not responsive to fluids (within 6 h) [http://www.ema.europa.eu).Because of their potential risk, hin 6 h) . In otheebb phase, which refers to the phase when the patient shows hyperdynamic shock with decreased systemic vascular resistance due to vasodilation, increased capillary permeability, and severe absolute or relative intravascular hypovolemia. The Surviving Sepsis Campaign guidelines mandate the administration of IV fluids at a dose of 30 mL/kg given within the first 3 h, as a possible life-saving procedure in this phase, although there is no randomized controlled trial to support this statement [flow phase refers to the phase after initial stabilization where the patient will mobilize the excess fluid spontaneously. A classic example is when a patient enters a polyuric phase recovering from acute kidney injury. In this post-shock phase, the metabolic turnover is increased, the innate immune system is activated, and a hepatic acute-phase response is induced. This hypercatabolic metabolic state is characterized by an increase in oxygen consumption and energy expenditure [Septic shock starts with an tatement . The floenditure .albumin as a resuscitation fluid in patients with hypoalbuminemia [Glucose should never be used in resuscitation fluid. Surprisingly, normal saline, which does not contain potassium, will result in a higher increase in potassium levels in patients with renal impairment compared to a balanced solution (lactated Ringer’s) containing 5 mmol/L of potassium, owing to concomitant metabolic acidosis due to a decreased strong ion difference (SID) [It is justified to use uminemia , 19. Gluce (SID) , 21.balanced solutions may avoid these complications. Recent evidence shows the association between fluid-induced chloride loading/hyperchloremia and worse outcomes, probably due to an impact on renal function [(Ab)normal saline as resuscitation fluid should not be administered in large amounts as it carries the risk of hypernatremic hyperchloremic metabolic acidosis, acute kidney injury and death. The use of function , 23. In function . Neverthfunction . Similarfunction , althougfunction . Recentlfunction , 27. In function . Howeverdistribution and/or elimination and excretion will be slowed in case of shock, hypotension, sedation or general anaesthesia [infusion continues and even increases to 100% when the arterial pressure has dropped. Elimination is very slow during surgery and amounts to only 10% of that recorded in conscious volunteers. Capillary refill further reduces the need for crystalloid fluid when bleeding occurs. These four factors (distribution–elimination–infusion–capillary refill) limit the need for large volumes of crystalloid fluid during surgery [The context-sensitive half-time of crystalloids and colloids may change and vary over time depending on the patient’s condition Fig. . In factesthesia , 30. ThiMaintenance fluids are given, specifically, to cover the patient’s daily basal requirements of water, glucose and electrolytes. As such, they are intended to cover daily needs. The basic daily needs are water, in an amount of 25–30 mL/kg of body weight, 1 mmol/kg potassium, 1–1.5 mmol/kg sodium per day and glucose or dextrose 5 or 10% 1.4–1.6 g/kg (to avoid starvation ketosis) .Some specific maintenance solutions are commercially available, but they are far from ideal. There is a lot of debate whether isotonic or hypotonic maintenance solutions should be used. Data in children showed that hypotonic solutions carry the risk of hyponatremia and neurologic complications , 33. HowReplacement fluids are administered to correct fluid deficits that cannot be compensated by oral intake. Such fluid deficits have a number of potential origins, like drains or stomata, fistulas, hyperthermia, open wounds, polyuria  .Data on replacement fluids are also scarce. Several recent guidelines advise matching the amount and composition of fluid and electrolytes as closely as possible to the fluid that is being or has been lost , 36. An Often overlooked, it is about time to consider parenteral nutrition as another source of intravenous fluids that may contribute to fluid overload. Likewise, nutritional therapy in the critically ill should be seen as “medication” helping the healing process. As such, we might consider also the four D’s of nutritional therapy in analogy to how we deal with antibiotics and fluids : drug , crystalloids early (post-operative hypovolemia), albumin late (sepsis). Similarly, maintenance fluids are often a combination of enteral and parenteral nutrition, other glucose-containing solutions, saline and/or balanced crystalloids to dissolve medications.The longer the delay in fluid administration, the more microcirculatory hypoperfusion and subsequent organ damage related to ischaemia–reperfusion injury. In patients with sepsis , Murphy As Paracelsus nicely stated: “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous” Like other drugs, it is the dose of fluids that make them poisonous. As stated before, the risk of excessive fluid overload is well established.Pharmacokinetics describes how the body affects a drug resulting in a particular plasma and effect site concentration [Similar to other drugs, choosing the right dose implies that we take into account the pharmacokinetics and pharmacodynamics of intravenous fluids Table . Pharmacntration . Pharmacntration , 43.TablVolume kinetics is an adaptation of pharmacokinetic theory that makes it possible to analyse and simulate the distribution and elimination of infusion fluids . ApplyinPharmacodynamics relates the drug concentrations to its specific effect. For fluids, the Frank–Starling relationship between cardiac output and cardiac preload is the equivalent of the dose effect curve for standard medications. Because of the shape of the Frank–Starling relationship, the response of cardiac output to the fluid-induced increase in cardiac preload is not constant [http://articles.latimes.com/2007/jan/14/local/me-water14). The difference between toxicity and efficacy is dependent upon the particular patient and the specific condition of that patient, although the amount of fluids administered by a physician should fall into the predetermined therapeutic window. Unanswered questions remain: what is an effective dose of IV fluids? What is the exact desired therapeutic effect? What is the therapeutic window? In some patients, volume expansion increases the mean systemic filling pressure (the backward pressure of venous return), but it increases the right atrial pressure (the forward pressure of venous return) to the same extent, such that venous return and, hence, cardiac output do not increase [constant . The effincrease . Hence, increase . The proincrease .threshold of 15% is most often used for this definition, as it is the least significant change of measurements of the techniques that are often used to estimate cardiac output [Fluid responsiveness indicates a condition in which a patient will respond to fluid administration by a significant increase in stroke volume and/or cardiac output or their surrogates. A c output , 91. Phyc output .The adverse effects of fluids must also be considered in their pharmacodynamics. Depending on the degree of vascular permeability, the oedema resulting from fluid administration is highly variable. At the maximum, disruption of the capillary barrier leads to global increased permeability syndrome (GIPS). This pharmacodynamic aspect is also very important in patients with acute respiratory distress syndrome (ARDS), as the effect of a given amount of fluid on the lung function basically depends on the pulmonary vascular permeability . TherefoAs we will discuss below, the final step in fluid therapy is to consider withholding or withdrawing resuscitation fluids when they are no longer required , 14, 15.Like for antibiotics Table , the durNot only are the characteristics of fluids important, but also the strategy for their administration. This strategy fundamentally changes along with the time course of septic shock. Recently a three-hit, or even four-hit model of septic shock was suggested trying to answer four basic questions, in which we can recognize four distinct dynamic phases of fluid therapy : resuscifirst hit which can be sepsis, but also burns, pancreatitis or trauma, the patient will enter the “ebb” phase of shock. This life-threatening phase of severe circulatory shock can occur within minutes and is characterized by a strong vasodilation leading to a low mean arterial pressure and microcirculatory impairment , while s et al. , 55. A rs et al. . In addis et al. –59. Whats et al. .In fact, rather than infusing a predefined given amount of fluid, the goal should be individualized for every patient, based on the evaluation of the need for fluids and on the patient’s premorbid conditions , 61–64. At the very initial phase of septic shock, answering the question is easy: fluid administration will significantly increase cardiac output in almost all cases. Nevertheless, after the first boluses of fluid, the likelihood of preload unresponsiveness is high. Therefore, at this stage, fluid administration should be conditioned to the positivity of indices and tests predicting fluid responsiveness. However, it must be noted that the state of responsiveness can only be determined a posteriori (after the intervention with administration of fluid bolus) and when a hemodynamic monitoring device is in place to estimate or calculate cardiac output. Therefore, we advocate the use of specific tests to increase the a priori probability and likelihood for a favourable event/outcome, as fluid administration should be limited to responders.A fluid bolus is the rapid infusion of fluids over a short period of time. In clinical practice, a fluid bolus is usually given to correct hypovolemia, hypotension, inadequate blood flow or impaired microcirculatory perfusion. The volume of fluid bolus is heterogeneous among clinicians , 89, typSeveral of these tests are available today . InsteadThis is a process that consists of predicting before fluid administration whether or not subsequent fluid administration will increase cardiac output. It avoids unnecessary fluid administration and contributes to reducing the cumulative fluid balance. It also allows one to undertake fluid removal as it informs that such removal will not result in a hemodynamic impairment . PredictA fluid challenge is a dynamic test to assess fluid responsiveness by giving a fluid bolus and simultaneously monitoring the hemodynamic effect (e.g. the evolution of barometric or volumetric preload indices). A fluid challenge is therefore also a fluid bolus, which means that it tests the response to treatment by administering the treatment itself up to the level where the treatment has no longer a response. This is why repeated fluid challenges may potentially lead to fluid overload. Recently, it has been shown that in clinical practice there is a marked variability in how fluid challenge tests are performed .second hit occurs within hours and refers to ischaemia and reperfusion , evolving over the next few days Table . It is dFluid therapy is now only needed for ongoing maintenance in the setting of normal fluid losses  and replacement fluids if the patient is experiencing ongoing losses because of unresolved pathologic conditions , 76. SinDaily fluid balance is the sum of all fluid intakes and outputs over 24 h, and the cumulative fluid balance is the sum of daily fluid balances over a set period of time , 87. IntMaintenance fluids should be used only to cover daily needs, and their prescription should take these other sources of fluids and electrolytes into account. Therefore, when a patient already receives daily needs of water, glucose and electrolytes via other means , specific intravenous maintenance fluids should be stopped.third hit, usually resulting from global increased permeability syndrome with ongoing fluid accumulation due to capillary leak [late goal-directed fluid removal and late conservative fluid management.After the second hit, the patient may either further recover, entering the “flow” phase with spontaneous evacuation of the excess fluids that have been administrated previously, or, as is the case in many critically ill patients, the patient remains in a “no-flow” state followed by a ary leak , 79. In ary leak  and finaary leak . It specLate goal-directed fluid removal involves aggressive and active fluid removal using diuretics and renal replacement therapy with net ultrafiltration. It is characterized by the discontinuation of invasive therapies and a transition to a negative fluid balance [Late conservative fluid management describes a moderate fluid management strategy following the initial treatment in order to avoid (or reverse) fluid overload. Recent studies showed that two consecutive days of negative fluid balance within the first week of the intensive care unit stay is a strong and independent predictor of survival [ balance . Late cosurvival .In this de-resuscitation phase, we try to find an answer to the third and fourth question: “When to start fluid removal?” and “When to stop fluid removal?” in order to find the balance between the benefits (reduction in second and third space fluid accumulation and tissue oedema) and risk (hypoperfusion) of fluid removal. To answer these questions, testing preload responsiveness may still be useful. Indeed, if no preload responsiveness is detected, it is reasonable to assume that fluid removal will not induce a reduction in cardiac output . On the Obviously, the risk at this phase is to be too aggressive with fluid removal and to induce hypovolemia, which may trigger a “fourth hit” for hemodynamic deterioration and hypoperfusion Fig. . If fluihttp://www.hra.nhs.uk/news/research-summaries/radar-icu/).This four-phase approach should be better characterized by some epidemiological studies. Its prognostic impact might be significant, because it may lead to a reduction in the cumulative fluid balance, which by itself is clearly associated with poor prognosis Fig. . Similarindications for fluid administration in the critically ill: resuscitation, maintenance, replacement and nutrition . In this review, a conceptual framework is presented looking at fluids as drugs by taking into account the four D’s  and the four phases of fluid therapy within the ROSE concept . The four hits model is presented herein. This will provide answers to the four basic questions surrounding fluid therapy: (1) When to start IV fluids? (2) When to stop fluid administration? (3) When to start fluid removal and finally (4) When to stop fluid removal? In analogy to the way we deal with antibiotics in critically ill patients, it is time for fluid stewardship.There are only four major


Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection. We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-angiogenic and pro-tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the micro-occlusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2α in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-associated tumorigenesis and its treatment. Summary: Induction of pulmonary microthrombosis by three distinct methods enhances HIF-a expression and tumour formation; increases in tumorigenesis that are induced by these thrombotic insults occur in a time- and mode-dependent manner. There is extensive evidence that cancer is a thrombotic disease . SignifiThrombotic events in cancer include thrombosis and thromboembolisms, which may be caused by a range of factors, including tumour-induced changes in plasma coagulants, inflammation (and the consequent activation of the endothelium leading to increased adhesion), along with vessel obstruction, whether by tumour-derived cell debris or circulating tumour cells . As the The primary aim of this study was to develop a mouse model of thrombosis-associated metastasis in the pulmonary vasculature, and to determine how microvascular occlusion affects pulmonary tumour formation. We show here that pulmonary microthrombosis enhances tumour formation, and that it does so in a manner that is dependent on the time at which such insult is induced with respect to the introduction of tumour cells. The model systems presented in this study provide an experimental means of investigating thrombosis-associated tumour spread and its potential treatment.During tumorigenesis, microthrombi can arise in a number of ways, such as from microvascular occlusion by tumour cell aggregates, or fibrin formation as a result of tumour-increased clotting mechanisms . To inveApproximately 1000 microbeads were injected intravenously, a number that did not cause any discernible respiratory distress. The microbeads that seeded in the pulmonary microvasculature could be visualized by fluorescence A, and ∼8Fig. S1A). Interestingly, HIF1α- and HIF2α-positive staining was not confined to the sites of micro-occlusion, as we found increased signal for these transcription factors in regions of the pulmonary microvasculature  that were not immediately adjacent to microbeads , suggesting a relay signal to surrounding tissues, potentially to circumvent or correct local vascular obstruction.When pulmonary expression of both HIFα isoforms was enhanced compared to the vehicle controls (i.e. at day 1 post-treatment), regions of the pulmonary microvasculature that contained microbeads stained positively for HIF1α, HIF2α, and a macrophage cell marker, Mac2, on contiguous tissue sections (Table S2), likely because the obstruction is in very small regions and sampling the whole organ inevitably dilutes the signal produced at the site of occlusion. However, the levels of several tumorigenic factors detected in the circulation at day 1 post-microbead injection were significantly higher than those found in the circulation of vehicle control animals. All of these factors, i.e. insulin-like growth factor binding protein (IGFBP) 1, interleukin (IL) 1α, IL1β, and thymidine phosphorylase   of these factors in whole lung homogenates at day 1, none of these differences reached statistical significance (D-ECGF)] A-D are, D-ECGF)] . This fiTo ascertain the period of time in which any pro-metastatic effect of pulmonary microvascular occlusion on tumorigenesis could occur (relative to tumour cell seeding), microbeads were introduced 1 or 5 days before, at the same time, or 1 or 5 days after tumour cell injection into the tail vein. As can be seen in Fig. S2A), and collagen content remained similar across all treatments . Microbead-induced increases in tumour formation (i.e. those observed when beads were given after LLC injection) were accompanied by concomitant increases in both pulmonary HIF1α and pulmonary HIF2α expression . Interestingly, we found that there were more microbeads in the tumours of mice receiving beads the day after tumour cells, when compared with those receiving beads before or concomitantly with the tumour cells D, while pression A,B. In tpression B.Fig. 4To determine whether the greatest increases in tumour burden could be driven by increases in circulating tumorigenic factors, the same panel of 53 tumorigenic factors described above were measured in the circulation of tumour-bearing microbead- and vehicle-treated mice on day 14 post-LLCs (endpoint). In microbead-treated mice versus vehicle controls, there were increases in the circulating levels of delta-like ligand protein (DLL) 4, fibroblast growth factor (FGF) 7, fractalkine, IGFBP10, IL10, and TP A-F, all in vitro and also had an approximate diameter of 15 µm . There were no significant effects of this form of micro-occlusion on tumorigenesis when the fibrin microthrombi injections occurred one day prior to, or at the same time as, administration of the tumour cells. However, and similarly to what was shown in the microbeads model, introduction of fibrin microthrombi 1 day after the tumour cells more than doubled the number of tumour foci detectable in the lungs, and this was accompanied by an overall doubling in the area of the lung filled by tumour mass .During the optimization stages of this study, we also examined the effect of two other thrombotic agents on tumorigenesis. First, we substituted the microbeads with approximately 1000 fibrin microthrombi per mouse. These fibrin fragments were generated from fibrinogen activated of 15 µm . They alFig. S3D,E). These qualitative differences indicate that, although different types of thrombotic insults can enhance tumour formation in the lung, the nature of the agents can directly impact outcome; these discrepancies are likely in part due to the expected variability in populations of dead cells and fibrin fragments, including differential persistence in the vasculature and differential inflammatory potential.Second, we evaluated the effect of introducing non-viable (heat-killed) tumour cells in place of the microbeads. In this case, the pro-tumorigenic impact occurred exclusively when dead and live tumour cells were injected simultaneously  cells were cultured in Dulbecco's modified eagle medium with 10% fetal bovine serum and 1% penicillin/streptavidin  at 21% oxygen and 37°C. Studies were performed on C57BL/6J mice  under the Animals (Scientific Procedures) Act, 1986.n=5/group), fluorescent polystyrene microbeads were injected via the tail vein . For studies on pulmonary tumour formation (n=5/group), polystyrene microbeads , or saline vehicle (100 μl) were injected via the tail vein 1 or 5 day(s) before, at the same time, and 1 or 5 day(s) after tail vein injection of viable LLCs . During optimization stages of the protocol, fibrin microthrombi  or heat-killed tumour cells  were used as obstructive agents instead of polystyrene microbeads. Fibrin microthrombi were generated and fluorescently labelled with Texas Red  as described . Microthrombi numbers were assessed by counting fibrin-positive (red) deposits in the microvascular lumen of MSB-stained lung tissue as described . Occlusin=5/group) and in the circulation of tumour-bearing mice at day 14 post-LLCs (n=4-5/group) by protein array according to manufacturers' instructions . Serum and lung samples were also prepared according to the manufacturers' instructions of the array.A panel of 53 tumorigenic growth factors and cytokines were measured in the circulation and lungs of vehicle- and microbead-treated mice at day 1 post-microbeads (n=221) . In breast tumours, levels of protease-activated receptor 1 and 2 were quantified by immunostaining and image analysis as described  . Pancreaescribed , and plaescribed . In breat-test. ANOVA with Bonferroni post-test was used to test differences between multiple groups. Correlations were assessed using Spearman's correlation. Significance was assumed at P<0.05 in all analyses . Data are expressed as means±standard error.Pairwise comparisons were analyzed by the unpaired two-tailed Student


The authors regret that an incorrect grant number appeared in the Acknowledgements. The correct funding statement should read as follows:National Science Foundation grants DMR-1307138 and DMR-1507830, and through the John and Claire Bertucci Foundation.We gratefully acknowledge funding for this work through The authors would like to apologise for any inconvenience caused.


Candida lusitaniae Fungemia”, which appeared in Volume 96, Issue 45 of Medicine, Dr. Puvanalingam Ayyadurai's first name appeared incorrectly as Puvvalingam.In the article, “Uncommon cause of fungemia in a patient with renal cell cancer: A case report of


AimSocial media (SoMe) platforms have become leading methods of communication and dissemination of scientific information in the medical community. They allow for immediate discussion and widespread engagement around important topics. It has been hypothesized that the activity on Twitter positively correlates with highly cited articles. The purpose of this study was to analyze the prevalence and activity of Trauma and Orthopaedic Surgery journals on Twitter, with the hypothesis that impact factor is positively associated with Twitter usage.MethodsThe top 50 Trauma and Orthopaedic Surgery journals, ranked by 2016 Impact Factor were analyzed. The Twitter profiles of each journal or affiliated society were identified. Other SoMe platforms used were also recorded. Twitonomy software  was used to analyze the Twitter profiles over a one-year period. Twitter Klout Scores were recorded for each journal to approximate the SoMe influence. Altmetric Scores  were also recorded. Statistical analysis was carried out to identify correlations between journal Impact Factors, SoMe activity, Twitter Klout Scores and Altmetric Scores. ResultsTwenty-two journals (44%) had dedicated Twitter profiles. Fourteen journals (28%) were associated with societies that had profiles and 14 journals (28%) had no Twitter presence. The mean Impact Factor overall was 2.16 +/- 0.14 . The journals with dedicated Twitter profiles had higher Impact Factors than those without . A greater number of Twitter followers were associated with higher Impact Factors . Journals with higher Twitter Klout Scores had higher Impact Factors . Altmetric Score was positively associated with Impact Factor . Journals with higher numbers of retweets  had higher Altmetric Scores .ConclusionTrauma and Orthopaedic Surgery journals with dedicated Twitter profiles have higher Impact Factors than those without. Altmetrics is likely to play a significant role in the literature evaluation going forward along with the traditional metrics. The engagement with Twitter by Trauma and Orthopaedic surgeons should be encouraged. Social media (SoMe) is a network of web-based and technological tools that aid the creation, sharing, and dissemination of information and ideas between individuals and communities online . The useTwitter is one of the world’s largest social media platforms. Founded 11 years ago, it is a microblogging site that provides information, opinions, and commentary about “what is happening in the world and what people are talking about right now” . TwitterIt has been hypothesized that activity on Twitter positively correlates with highly cited articles . WhetherDespite this, the data are still not available to determine if and how social media is used by Trauma and Orthopaedic Surgery journals and whether or not its use influences the Impact Factors of these journals. The purpose of this study is to analyze the use of Twitter by the leading Trauma and Orthopaedic Surgery journals, with the hypothesis that a journal’s Impact Factor is positively associated with a journal’s use of Twitter.A search was conducted of InCites Journal Citation Reports 2016 (Thomson Reuters) on June 26, 2017, using “orthopedics and trauma” as the journal category filter. Non-orthopaedic, non-trauma related and non-English-language journals were excluded from the study. The remaining top 50 journals were ranked by Impact Factor and subsequently analyzed. The presence of each journal on Twitter was identified as having a dedicated journal specific Twitter profile, having an affiliated society Twitter profile or having no Twitter presence. Using InCites Journal Citation Reports, the year that each journal joined Twitter was recorded, as well as the journal’s Impact Factor that same year. The mean Impact Factor overall and of each category of journal Twitter presence was calculated. Whether or not journals experienced an increase in Impact Factor since joining Twitter was investigated. The use of other social media platforms was also recorded .twitonomy.com on June 26, 2017. Twitonomy is an online application that links with Twitter to collate and process data related to user profiles. It has been used previously in Urology and Vascular Surgery research [The Twitter profile of each journal was individually analyzed using Twitonomy software  www. research -11. The Each Trauma and Orthopaedic journal Twitter profile was analyzed over a one-year period using Twitonomy software, from January 2016 to December 2016. The data collated included the total number of tweets, total number of retweets, number of followers, number of times the journal username is mentioned, replies to followers, as well as the year the journal created its Twitter profile. For journals with dedicated Twitter profiles, the change in Impact Factor between 2015 and 2016 was recorded. Clinical Biomechanics (@jclinbiomech) was excluded from this analysis as it joined Twitter in 2016 and thus had no measurable change in the Impact Factor.www.klout.com) was measured via their Twitter profile on 16 June 2017. A Klout Score is generated by aggregating a large set of online reactions centered around the activity stimulated by a user or profile, such as clicks, likes, comments, reshares and purchase behavior [To further assess SoMe influence, each journal’s Klout Score . Altmetric collates data from multiple sources; bookmarks via reference managers like Mendeley; mentions, clicks and views on social media networks like Facebook and Twitter; citations via online information sites, such as Wikipedia. Each of the top 50 Trauma and Orthopaedic journals was searched on Altmetric and the datasets were downloaded as spreadsheets. The Altmetric Score  was recorded for each journal. The presence of an association between the length of time a journal had been active on Twitter and the total number of mentions the journal had accumulated across the online and SoMe stratosphere was investigated.Another parameter of SoMe influence investigated was that of alternative metrics via the online analysis software Altmetric  version 24 .Overall, 72% of the journals were represented on Twitter, either by a dedicated Twitter profile or Twitter profiles of societies affiliated with the journals. Twenty-two journals (44%) had dedicated Twitter profiles. Of the remaining 28 journals with no dedicated Twitter profiles, 14 (28%) were associated with affiliated societies that had Twitter profiles, and 14 (28%) journals did not have a presence on Twitter. Of the journals with dedicated Twitter profiles, 21 out of 22 (95.5%) provided direct links to the journal website on their Twitter accounts.Nineteen of the 22 (86.4%) journals with dedicated Twitter profiles had profiles on Facebook, 10 (45.5%) had profiles on Linkedin and six (27.3%) had Youtube profiles. As for the 14 journals with no presence on Twitter, two (14.3%) had a SoMe profile other than Twitter. The journals with a dedicated Twitter account were more likely to have a presence on other social media platforms, compared to journals with no Twitter account (p <0.001).Association between Impact Factor, Twitter, and Twitter profile activityThe mean Impact Factor of all journals was 2.35 +/- 0.15 . The Impact Factors of journals with dedicated Twitter profiles were higher than those without . No statistically significant difference was found between the Impact Factors of the journals with affiliated society Twitter profiles and no Twitter presence (P=0.07).Since the time of joining Twitter, 16 out of the 21 journals (76%) with dedicated Twitter profiles experienced an increase in the Impact Factor. Clinical Biomechanics (@jclinbiomech) was excluded from this analysis, as it joined Twitter in 2016 and thus had no measurable change in Impact Factor. There was no correlation between the number of years a journal had been active on Twitter and its Impact Factor. The mean change in the Impact Factor since joining Twitter was an increase of 0.35 +/- 0.09 . The mean change in Impact Factor from 2015 to 2016 across all journals was an increase of 0.17 +/- 0.51 . Journals with dedicated profiles and journals with no Twitter presence displayed no significant difference in Impact Factor change between 2015 and 2016 .Association between Impact Factor, Klout Score, and Alternative metricsThe top-ranked journal by 2016 Impact Factor and the top journal by Twitter Klout Score was The American Journal of Sports Medicine. The number one journal by Altmetric Score was Spine . Journals with higher numbers of followers had higher Twitter Klout Scores . Of the journals with dedicated Twitter profiles, the mean number of Twitter followers was 8923 +/- 2342 . The number of followers a journal had did not influence its Impact Factor . The number of years a journal had been active on Twitter had no association with Twitter Klout Score. The mean number of tweets per day was 1.31 +/- 0.28 . The number of tweets per day that a journal produced on Twitter had no correlation with its Impact Factor or with its Twitter Klout Score. The mean number of tweets retweeted was 237.7 +/- 51.4 . The number of tweets retweeted had no influence on Impact Factor but was associated with having a higher Klout Score .The mean Altmetric Score for journals with a dedicated Twitter profile was 8942, compared to 1791 for journals with no Twitter presence (P= <0.001). The mean Altmetric Score for journals with dedicated versus affiliated society Twitter profiles was 8942 and 3711, respectively (p=0.011). No significant difference was seen in Altmetric Scores between journals with affiliated Twitter profiles compared to those with no Twitter presence. A statistically significant correlation was found between journal Altmetric Scores and Impact Factors in 2016 , and in 2015 . Having a higher Klout Score was not associated with a higher Altmetric Score, nor was having a higher number of Twitter followers. Journals with higher numbers of tweets were found to have higher Altmetric Scores. Having a higher number of retweets, each retweet being a virtual citation in the Twittersphere was also associated with higher Altmetric Scores .This study demonstrates a high level of engagement of Trauma and Orthopaedic Surgery journals with SoMe, with Twitter being the most prevalent SoMe platform in use. Of the leading Trauma and Orthopaedic journals, 72% are represented on Twitter by dedicated Twitter profiles or Twitter profiles of affiliated societies, 66% have Facebook profiles, 44% are represented on Linkedin and 18% have YouTube profiles. For this reason, Twitter was chosen as the SoMe platform most appropriate for analysis in this study. Twitter has been shown to be used not only for professional purposes by board-certified Orthopaedic surgeons and residents but also by members of the public as a means of interaction with their physician and Orthopaedic Surgery as a specialty .Since its development in the 1960’s, Impact Factor has been used as a quantitative measure of journal quality. Essentially, how important a journal is to its end users is equaled to the number and frequency of citations it receives in the scientific literature . HoweverGiven the limited amount of time physicians spend reading scientific journals, SoMe platforms like Twitter help to distill vast quantities of the literature down to key articles and content to view . In addiOur study found that journals with dedicated Twitter profiles have higher Impact Factors. This is similar to what was shown in a recent study by Kelly, et al. that analyzed Twitter usage among Radiology journals . It may When an individual produces content on SoMe by way of a post, Tweet, or comment, other users may see this content and perform actions in response to it. The fact that they were prompted to do so implies that the original post influenced them in some manner. Klout Score was developed around this hypothesis , 17. TheThe Klout scoring system is a complicated algorithm that is not published and cannot be reproduced according to its creators . It is lAltmetric Scores amalgamate web-based data to evaluate the impact of scholarly material online via alternative metrics, such as mentions, clicks, views on social media, Wikipedia citations, downloads, and many other parameters of digital interaction. Our study found that Altmetric Score is positively associated with Impact Factor regardless of whether a journal has a dedicated Twitter profile, affiliated profile or no Twitter presence at all. Journals with dedicated Twitter profiles have significantly higher Altmetric Scores overall. Furthermore, Twitter Klout Score had no correlation with Altmetric Score. This demonstrates that the influence of Altmetric Score on Impact Factor goes deeper than SoMe use alone. Altmetric Scores were found to be high irrespective of the number of followers or Tweets a journal produced. We noted that it is the appeal and relevance of a journal’s online content that drives up its online reach, as it increases the likelihood of interaction, sharing, and dissemination. Unlike Twitter Klout Score, the number of Tweets and followers had no association with higher Altmetric Scores.Butler, et al. proposed that alternative metrics are likely to play a significant role in literature evaluation going forward alongside traditional metrics . HoweverUndoubtedly SoMe provides many positive opportunities for engagement and interaction with medical literature and facilitates its wider dissemination. However, whilst journal content is subject to strict peer review prior to publication, no such rules or constraints exist on SoMe. At the click of a button, information can be posted online for public consumption, whether it is based in fact or not, creating a forum that is open to bias, ego, and abuse. For this reason, users need to act in a mature and responsible manner when interacting with SoMe content. Guidelines have been developed to advise medical professionals on appropriate behavior online .We acknowledge that a limiting factor of this study is the small sample size analyzed. We looked at the Twitter profiles of Trauma and Orthopaedic Surgery journals alone. A broader exploration of these trends across different specialties, and perhaps across more than one SoMe platform, is warranted. We also identified a variation in the levels of journal Twitter activity; some journals produced significantly more output than others on the SoMe site. Furthermore, looking at Twitter and SoMe activity alone is unlikely to give a true representation of the interaction with a journal online, as not everyone uses SoMe , 22. ThiIn this study, the use of Twitter and SoMe platforms by leading Trauma and Orthopaedic Surgery journals was investigated. The activity on Twitter and the prevalence of its use among these journals was of key interest. It was found that a positive correlation exists between Impact Factor and the use of Twitter by Trauma and Orthopaedic Surgery journals. It is evident that the use of Twitter and other SoMe platforms provides a means of rapid dissemination of the scientific information, publications, and real-time updates. It also serves to promote international and cross-border engagement, collaboration and interaction around seminal Trauma and Orthopaedic Surgery topics. The engagement with Twitter by Trauma and Orthopaedic Surgeons, and indeed other medical professionals, is to be encouraged as a means of keeping up to date with current literature.


We present a case of 16-year-old male, who was referred from private centre for dyspnoea, fatigue, and orthopnea. The chest radiograph revealed complete opacification of left chest which was confirmed by computed tomography as a large left mediastinal mass measuring 14 × 15 × 18 cm. The diagnostic needle core biopsy revealed mixed germ cell tumour with possible combination of embryonal carcinoma, yolk sac, and teratoma. After 4 cycles of neoadjuvant BEP regime, there was initial response of tumour markers but not tumour bulk. Instead of classic median sternotomy or clamshell incision, posterolateral approach with piecemeal manner was chosen. Histology confirmed mixed germ cell tumour with residual teratomatous component without yolk sac or embryonal carcinoma component. Weighing 3.5 kg, it is one of the largest mediastinal germ cell tumours ever reported. We describe this rare and gigantic intrathoracic tumour and discuss the spectrum of surgical approach and treatment of this exceptional tumour.  Germ cell tumours are embryologically derived from reproductive cells, and they originate mostly from the gonads. However, in 5% of the cases, they are extragonadal in origin . The mosThe presentations vary ranging from accidental findings on routine radiography to life-threatening respiratory and cardiovascular compromise. Huge intrathoracic mass poses a dramatic challenge for operating surgeons and anaesthetists in terms of the management strategies. According to a surgeon's point of view, the nature of mass suggests the possible surgical difficulties with regard to the approach and accessibility. A huge intrathoracic mass may compress the contralateral lung during positioning which may obstruct the venous return to the heart and thus poses a challenge to the attending anaesthetist.We present a case of gigantic intrathoracic germ cell tumour which was resected successfully via a piecemeal surgical approach. The anatomical basis of this huge tumour and the treatment modalities are discussed.A previously well 16-year-old male was referred from a private hospital to our tertiary medical centre with acute history of dyspnoea, fatigue, and orthopnea. He denied history of fever, pleuritic chest pain, dysphagia, and loss of weight. Clinically, there was stony dullness on the left chest wall. No abnormalities were detected in other systemic examinations.Chest radiograph showed a generalized haziness of left chest . ComputeHe was given standard neoadjuvant chemotherapy consisting of bleomycin, etoposide, and cisplatin-based chemotherapy (BEP) regime for 4 cycles. Tumour markers after chemotherapy improved remarkably with AFP of 17 ng/mL and LDH of 477 iu/L. Unfortunately, beta human chorionic gonadotropin (beta-HCG) was not assessed during the course of chemotherapy. Despite biochemical improvement, there was no tumour reduction upon reassessment of CT scan.He was decided for tumour debulking to reduce the tumour load. Patient was put on general anesthesia with double lumen ventilation. A standard left posterolateral skin incision was made. In order to achieve minimal incision, the tumour was dissected via piecemeal manner . IntraopPostoperative recovery was uneventful. Assisted ventilation was withdrawn 12 hours after operation. The tumour weighed 3.5 kg. Histopathologic evaluation revealed mixed germ cell tumour with residual teratomatous component. There was no yolk sac or embryonal carcinoma component seen. However, the lung tissue was firmly adhered to the tumour but no obvious tissue infiltration. He was discharged after one week following hospitalization without any postoperative complication. Currently, he is under oncology follow-up for further management.Germ cell tumours are embryologically derived from reproductive cells. In majority, they are originated from gonadal organs. It is unusual to find germ cell tumours which are extragonadal in origin, whereby it accounts for 5% of the cases . The mosThe clinical features vary differently from accidental findings on routine radiography to life-threatening respiratory and cardiovascular compromise. Symptoms arising from such huge tumours are due to compressive effect on the surrounding organs which include cough, shortness of breath, failure symptoms, and chest pain or due to tumour rupture such as pleural effusion and pericardial effusion , 7. The Preoperative biopsy is indicated in this case in order to guide our treatment strategy. The role of clinical assessment is highly limited. Hence, radiological finding to determine the tumour origin and location in the mediastinum is crucial. Fine needle core biopsy is accepted as the standard procedure for confirmatory histological diagnosis . It shouTumour markers are frequently elevated in germ cell tumours, namely, LDH, AFP, and beta-HCG . Tumour Almost 70% of the nonseminomatous germ cell tumours contain more than two germ cell components, so they are termed as mixed germ cell tumours . The maiIn the era of minimally invasive surgery, small mediastinal tumours have been surgically removed via laparoscopic procedure, but large masses are best managed using median sternotomy approach . A clamsAccording to the observed reason, we have decided to perform alternative method which could provide more benefit to the patient. Using standard posterolateral incision, access was obtained. The patient was placed in lateral decubitus position with padding to the elbows and knees. The lower hand was put straight on arm board and the upper hand was rotated in a forward direction and allowed to hang over the operating table. This position allowed free rotation of the scapula. The inferior angles of the scapula, spinal, and axillary borders were identified. The incision was made from a point located 3 inches from midspine vertebral line to the anterior axillary line, passing below the tip of the scapula. The incision was made and deepened until fascia overlying the latissimus dorsi and trapezius muscles. Latissimus dorsi was transected sparing the trapezius muscle. The serratus anterior was retracted anteriorly to get access to the rib cage. Selection of the appropriate intercostal space was guided by counting the ribs whereby the hand slipped below the scapula and was gently pushed upwards to the apex. en bloc dissection. Complete excision of the mass was challenging as hugeness of the tumour compressing on the left lung. Besides, it caused difficulty to differentiate between tumour tissue and lung parenchyma; hence decision to perform pneumonectomy was decided. The surgery was performed with a double lumen endotracheal tube in place. Adequate deflation of the underlying lung was in order to facilitate exposure of the surgical field and to avoid risking of the contralateral lung. Such method is favourable as it enhances patient's recovery postoperatively besides having perfect cosmetic results. Complications of surgery include bleeding, pyothorax, and phrenic nerve injury.The 6th intercostal space was identified and the pleural space was entered after division of the intercostal muscles with the electrocautery probe. The dissection was near to the lower rib of the interspace to avoid injury to the neurovascular bundle. A large rib spreader was inserted and opened slowly and progressively to minimize the risk of rib fracture. The tumour was dissected via piecemeal manner rather thanPrimary mediastinal nonseminomatous germ cell tumours are considered as poor risk status and guarded prognosis with a 5-year survival rate of 48% , 14. CheEven if the patient initially presented with acute respiratory distress, we had decided to offer him BEP regime in view of age factor and good performance status. The usage of bleomycin can lead to progressive pulmonary fibrosis. In certain centre, 4 cycles of VIP  regime are used for those who may not tolerate bleomycin. Unfortunately, ifosfamide is not available in our centre. Since he has a potential respiratory complication, intraoperative lung care was carried out aggressively. High concentration of supplemental oxygen was avoided because of the potential harmful effects after neoadjuvant treatment with bleomycin .Other prognostic factors include nonpulmonary visceral metastases and presence of high tumour markers  . BesidesPrimary mediastinal nonseminomatous germ cell tumours are rare in origin. Following chemotherapy, despite regression of the tumour biochemically and histologically, the size remains the same and requires surgical intervention. The present case was a humble attempt to highlight the extragonadal location of the germ cell tumour, its clinical features, and treatment which may be beneficial for academicians and clinicians.


The EGVI also revealed stronger associations between the index value and functional outcomes for some studies. The EGVI successfully addresses shortcomings in the GVI calculation that affected magnitude and directional specificity of the index. We have confirmed the validity of prior published work that used the original GVI, while also demonstrating even stronger results when these prior data were re-analyzed with the EGVI. We recommend that future research should use the EGVI as a composite measure of gait variability.Prior research has established the Gait Variability Index (GVI) as a composite measure of gait variability, based on spatiotemporal parameters, that is associated with functional outcomes. However, under certain circumstances the magnitude and directional specificity of the GVI is adversely affected by shortcomings in the calculation method. Here we present an enhanced gait variability index (EGVI) that addresses those shortcomings and improves the utility of the measure. The EGVI was further enhanced by removing some input spatiotemporal variables that captured overlapping/redundant information. The EGVI was used to reanalyze data from four previously published studies that used the original GVI. After removing data affected by the GVI’s prior shortcomings, the association between EGVI and GVI values was stronger for the pooled dataset (r The Gait Variability Index, GVI , is a gepn’  tends to become increasingly more negative when the distance d⍺,HP is very small . Next, the z-score is calculated, i.e. the number of SDs separating the raw score of an individual from the raw score of the reference group. As the reference mean and SD of the raw GVI are respectively 1.61 and 0.91, the z-score also increases artificially. For example, if an individual α is very close to the reference with a distance d⍺,HP of 0.01, then ln (0.01) will be -4.61. Once the z-score is computed, the individual will be at 6.84 SDs from the reference, as shown below:When the absolute distance “, the new distance will be 1.01 and so ln (1.01) = 0.01.To avoid artificially high z-scores, for the computation of the EGVI, we added +1 to the computed distance The absolute difference in gait variability between an individual and the reference group, whether positive or negative, will produce a single GVI value. It is important for the EGVI to be able to differentiate these two situations.Therefore, we considered that the EGVI is 100 if the raw GVI for the individual is comprised within . EGVI = 100 indicates that the person has a similar level of variability as the reference (neither too little nor too much). Each 10-point difference corresponds to a separation of one SD from the reference, indicating that the variability of the individual is greater than (EGVI >100) or lower (EGVI <100) than the amount of variability observed in normal gait.The GVI is the mean of the left and right side GVI computed from spatiotemporal parameters related to one side (left or right limb). To enhance the capability of the EGVI in differentiating variability between legs, some optimizations were performed. Of the 9 previous variables, 5 were retained. The retained spatiotemporal variables in the EGVI are step length (cm), step time (s), stance time (s), single support time (s), and stride velocity (cm/s). Stride length and stride time were considered redundant in relation to step length and step time. Also, they were removed because they include simultaneous information from left and right sides. We also removed swing time since it is the same as the contralateral single support time.Once all optimizations were performed, data from four previous publications using the original version of the GVI was extracted to compute the EGVI scores, and the results were compared.When GVI<100, the gait variability is increased or decreased compared to the reference and GVI≥100 indicates a normal amount of gait variability. The EGVI differentiates low and high variability, and EGVI<100 indicates low variability, EGVI = 100 similar amount of variability as the reference group, EGVI>100 high variability.To compare unbiased values of the GVI scores to the EGVI, data that corresponded to GVI>100 (magnitude problem), or GVI<100 and EGVI<100  were removed before calculating the coefficients of determination. Previously published data for individuals with Friedreich ataxia (FRDA dataset) , older a2 between GVI and EGVI was 0.87. When the data affected by the shortcomings of the GVI were removed, the total data set reduced to 320 participants and the r2 between GVI and EGVI increased to 0.95.2 between GVI and EGVI for this data set was 0.98 . The r2 between GVI and EGVI was 0.88 and increased to 0.91 once the affected data were removed  who had GVI higher than 100 due to a smaller distance  removed .2 between GVI and EGVI was 0.88 (the r2 was 0.67 when affected data were included).11 individuals had GVI scores >100 reflecting the magnitude problem , with a2 between the GVI and the EGVI was 0.96, while the r2 was 0.70 when all data were considered.The GVI and EGVI values for the PD cohort are summarized in Table A4. Out of the 100 subjects, 53 were identified as having increased gait variability with a mean overall EGVI of 114.2 (9.4) and 116.3 (9.1) for the most affected side only. Further, 12 individuals were identified as having lower gait variability than the reference mean, with a EGVI of 96.3 (2.8)  and 94.7 (3.5) (most affected). No significant differences were found between EGVI scores for H&Y 2 and 3.The correlation between the EGVI and the MiniBESTest and TUG improved as compared to the GVI, however, they were still low to moderate (see Table A5). Lastly, Table A6 shows the comparative result of the ROC analysis, showing the ability of the GVI and the EGVI to discriminate mild from moderate disease severity in PD. The results show low discriminatory ability in both indices.The GVI has served as a quantifiable conglomerate index of gait variability and has been validated in healthy controls and those with impaired mobility. However, some issues remain with the GVI; artificially high scores  and the lack of ability to distinguish high and low variability . The purpose of this study was to propose an improved version of the GVI, the enhanced gait variability index. We hypothesized that the EGVI would solve the magnitude problem and lack of direction specificity without compromising the final outcome measure. The results of our study were in agreement with our hypothesis. When analyzing previously published datasets, the results were similar and, when problematic data where present, they were better using the EGVI.In populations with higher variability than heathy adults (like in FRDA or TD datasets), the GVI is not affected by either of the issues of magnitude or lack of direction specificity because the subjects are all more variable than the healthy controls. Specifically, the FRDA data set included individuals with Friedreich’s ataxia, a condition where motor control is severely compromised, and it is expected that individuals with Friedrich’s ataxia have higher gait variability. Similarly, typically developing children are expected to have gait patterns that are different from adults. Therefore, the results for the FRDA and TD datasets did not change from previously published data and in addition, the correlation between the existing version of the GVI and the EGVI was high. Nonetheless, the additional improvements added to the EGVI enables standardized reporting in these datasets and likely better differentiation.The issues with the original version of the GVI, in turn, are more apparent when individuals within a population have an amount of variability close to the healthy population, as in the OA and PD datasets, or are even less variable. The OA dataset included older adults (aged 65 years and older) across a range of mobility limitations, from low to high functioning. Therefore, it can be expected that this dataset included some individuals with variability similar to the healthy reference population, leading to uninterpretable GVI above 100, that turn into 100 when EGVI is used . In addition, specifying direction with the EGVI allowed for identification of those older adults with lower variability than the reference group. A minimum level is required to ensure ability to regulate step-to-step variations  and a loThe calculated EGVI values for the PD data set demonstrates how the method differentiates between those individuals with higher, lower and normal gait variability  were deleted to enhance the identification of inter-limb variability. Interrelated spatiotemporal parameters  were also deleted to avoid redundancy. This reduction in number of spatiotemporal parameters included in the calculation of the EGVI did not affect the outcome.Our study had some limitations. It is plausible that the sensitivity in the calculation of the EGVI may have been improved using coefficients from a specific population. However, we validated the EGVI on varied datasets. Future work should establish the reliability of the EGVI and further test the ability of this enhanced version to discriminate inter-limb variability.Clinical evaluation of gait typically focuses on visible impairments such as slow speed and asymmetry. Mounting evidence suggests that gait variability is a relevant outcome measure reflecting gait and mobility deficits that may be otherwise masked by average measures . ImportaThe calculations for the GVI had shortcomings under certain circumstances, which we have resolved with this enhanced gait variability index (EGVI). We have confirmed the validity of prior published work that used the original GVI, while also demonstrating even stronger results when these prior data were re-analyzed with the EGVI. We recommend that future research should use the EGVI as a composite measure of gait variability.S1 AppendixTable A1. Pearson’s correlations with the GVI and the EGVI. Table A2. Spearman’s correlations with the GVI and the EGVI. Table A3. Spearman’s correlations with the GVI and the EGVI. Table A4. EGVI in individuals with Parkinson’s Disease (means and standard deviations). Table A5. Associations between dynamic balance and mobility and the GVI and the EGVI. Table A6. ROC analysis: Area Under the Curve for GVI and EGVI(high). Figure A1. Means and 95% CI for EGVI according to the ‘‘Posture and Gait Disturbances” ICARS sub-score. Figure A2. Means and 95% CI of EGVI for each age group. The position of the data on the x-axis corresponds to the mean age of the subjects for the considered group . Figure A3. Sensitivity and specificity of the overall EGVI(high) (A) and the most affected side EGVI(high) (B). The EGVI for those with higher gait variability than the reference mean is included in the analysis (n = 53).(DOCX)Click here for additional data file.