Panax ginseng C.A. Meyer, exerts multiple biological activities. However, the anti-tumour efficacy of Ro remains unclear because of its poor in vitro effects. In this study, we confirmed that Ro has no anti-tumour activity in vitro. We explored the anti-tumour activity of Ro in vivo in B16F10 tumour-bearing mice. The results revealed that Ro considerably suppressed tumour growth with no significant side effects on immune organs and body weight. Zingibroside R1, chikusetsusaponin IVa, and calenduloside E, three metabolites of Ro, were detected in the plasma of Ro-treated tumour-bearing mice and showed excellent anti-tumour effects as well as anti-angiogenic activity. The results suggest that the metabolites play important roles in the anti-tumour efficacy of Ro in vivo. Additionally, the haemolysis test demonstrated that Ro has good biocompatibility. Taken together, the findings of this study demonstrate that Ro markedly suppresses the tumour growth of B16F10-transplanted tumours in vivo, and its anti-tumour effects are based on the biological activity of its metabolites. The anti-tumour efficacy of these metabolites is due, at least in part, to its anti-angiogenic activity.Ginsenoside Ro (Ro), a major saponin derived and isolated from  Skin cancer is a common type of cancer with an increasing incidence rate and public health burden . As the Chemotherapy is one of the most effective approaches to cure malignant melanoma, but its toxicity and the development of drug resistance represents important limits in determining its efficacy . EnucleaNatural compounds derived from potential herbs were able to effectively interfere with tumour progression, inhibit angiogenesis, and block metastasis . Due to Panax ginseng C.A. Meyer) is traditionally used as an herbal medicine in Far Eastern countries and has gained popularity in Western countries in recent decades − in the negative all-scan MS spectrum and also contained an OA characteristic fragment ion m/z at 455 [M − H − 176]−. Simultaneously, fragment ions m/z 613 [M − H − 18]−, m/z 555 [M − H − 76]−, and m/z 509 [M − H − 122]− were produced by cleavage of the glycosidic ring, proving that the glycosidic bond was stable. The results indicate that the hexanoic acid is located at the C-3 position and is identified as calenduloside E (E) by the literature. The MS results show that the fragment ions of the abovementioned compounds are similar; thus, IVa, R1, and E are determined to be metabolites of Ro. R1 was found to be the most abundant metabolite in the plasma. The signal intensity of R1 was approximately two-fold that of Ro, 10-fold that of IVa, and 100-fold that of E. Glycosyl oleanolate and OA were not detected in the plasma . From day 11, the average tumour volume in R1-, IVa-, E-, and CTX-treated mice increased relatively slowly.The in vivo anti-tumour activities of R1, IVa, and E were evaluated in the same way as Ro. The anti-tumour effects of R1, IVa, and E on B16F10 tumour-bearing mice are summarised in To examine the effects of Ro and its metabolites on crucial functions in blood vessel formation, we investigated whether the compounds decreased the formation of tubes by human umbilical vein endothelial cells (HUVECs) in vitro. Our results showed that IVa, R1, and E markedly inhibited HUVEC tube formation. Tube formation was imaged, and the tube length was determined . Low conHaemolysis rate is an important parameter for evaluating blood compatibility, and less than 5% haemolysis is regarded as a nontoxic effect level . Nearly Panax ginseng) and American ginseng (Panax quinquefolius) are two species in ginseng genus [Ginseng is a popular herbal medicine worldwide, and its anti-cancer activity has been proven by numerous studies. Asian ginseng  routinely supplemented with penicillin and streptomycin. Both B16F10 cells and HUVECs were cultured at 37 °C in a humidified atmosphere containing 5% carbon dioxide (CO2). Male C57BL/6J mice (6–8 weeks old) and male Sprague Dawley rats (10 weeks old) were purchased from Vital River Laboratories (License No. SCXK (Jing) 2012-0001; Beijing, China). The animals were maintained in plastic cages with a 12 h light/dark cycle and given free access to food and water. All animals were handled in strict accordance with good animal practice according to the Animal Ethics Procedures and Guidelines of the People’s Republic of China, and the study was approved by The Animal Administration and Ethics Committee of the Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (Permit No. ISAPSAEC-2018-001).Fetal bovine serum (FBS) and Dulbecco’s Modified Eagle’s Medium (DMEM) were purchased from Gibco . MTT was purchased from Sigma . Ro, R1, IVa, and E were purchased from Chemfaces . The purities of all of the compounds were higher than 98%. B16F10 melanoma cell lines and HUVECs were purchased from the Type Culture Collection of the Chinese Academy of Sciences . The cells were cultured in DMEM containing 10% FBS (6 cells) was subcutaneously injected via the right axillary region of the C57BL/6J mice. The tumour-bearing mice were randomly divided into three groups (n = 6/group): model control group, positive control group, and Ro (25 mg/kg) administration group. In addition, a group of mice that did not receive tumour inoculation was used as the normal control. Normal and model mice were administered normal saline. The mice in the positive control group received CTX (20 mg/kg). The successive intraperitoneal injection of drugs into the mice from the day after tumour inoculation and the body weights were monitored every 2 days. After 15 days, all mice were sacrificed, and tumours were taken out and measured as previously described [An anti-tumour assay was conducted in a mouse xenograft model . B16F10 escribed . The thy4 cells/well) cells were seeded onto 96-well plates and incubated for 24 h in complete medium. After 24 h incubation, the cells were treated with various concentrations of Ro  for 24 h, and MTT  was then added to each well and incubated for an additional 4 h at 37 °C. The formazan crystals were dissolved in DMSO (150 μL), and the absorbance at 490 nm was measured using a microplate reader In this study, Ro was dissolved in dimethyl sulfoxide (DMSO) and diluted in DMEM and then filtered using a 0.22 μm membrane. The final concentration of DMSO in cell culture medium was 0.1%, and 0.1% DMSO-treated cells were used as controls. The effect of Ro on B16F10 cell growth in vitro was performed using the MTT assay . BrieflyIdentification of the metabolites of Ro was done using the same HPLC Trap MS system as previously described . BrieflyThe metabolites (standard substance) of Ro were dissolved in the same manner as Ro. Briefly, IVa, R1, and E were dissolved in dimethyl sulfoxide (DMSO), diluted in DMEM, and then filtered using a 0.22 μm membrane. The final concentration of DMSO in cell culture medium was 0.1%, and 0.1% DMSO-treated cells were used as controls. The effects of IVa, R1, and E on B16F10 cell growth were evaluated using the MTT assay as previously described. The cells were treated with various concentrations of IVa , R1 , and E  for 24 h. After incubation, MTT  was added and incubated for 4 h at 37 °C. Then the supernatants were carefully removed, and 150 μL DMSO was added to each well. After 10 min of incubation and vibration, the absorbance was read at a wavelength of 490 nm. IC50 values were calculated using Probit Analysis with SPSS 22.0 .n = 6/group): model control group, positive control group , R1 (25 mg/kg), IVa (25 mg/kg), and E (5 mg/kg) administration groups. In addition, a normal control group of mice did not receive tumour inoculation. Normal and model mice were administered normal saline. Drugs were intraperitoneally injected into the mice for 15 consecutive days. Tumour volumes were measured every 2 days, and tumour growth curves were plotted. At the end of the experiment, the mice were sacrificed, and the tumour weight and tumour growth inhibition rates were calculated.A xenograft experiment was performed using the same method as described in 4 cells/well) were seeded on the Matrigel and treated with various concentrations of Ro , R1 , IVa , and E . After incubation for 5 h, the formation of HUVEC tubular structures was captured using a microscope . The tube length was quantified using Image-Pro Plus 6.0 software.The tube formation assay was performed as previously described with some modifications . MatrigeTo evaluate the haemocompatibility of Ro, the haemolysis test was performed as previously described . Arteriap < 0.05 and extremely significant if p < 0.01.Statistical analyses were performed with SPSS 22.0 and GraphPad Prism 6.0 . All data were expressed as the mean ± standard deviation (SD). Data were analysed by ANOVA with Tukey’s multiple comparison test and Dunnet’s multiple comparison test. Differences were considered significant if The results of this study clearly demonstrate that Ro inhibits tumour growth in B16F10 tumour-bearing mice but has no effects on B16F10 cell growth in vitro. IVa, R1, and E, metabolites of Ro, had anti-tumour effects both in vitro and in vivo and also inhibited angiogenesis to some extent. Our findings provide substantial evidence that Ro might be beneficial for the therapeutic management of melanoma. These findings indicate that the metabolites of Ro may underlie its pharmacological anti-cancer mechanisms.


The fluid challenge (FC) is a well-established test of preload reserve. Only limited data exist in regard to the FC efficacy based on infusion time. Slow administration may be associated with lack of effect based on fluid redistribution and external conditions changes. On the contrary, fast administration may lead to brisk fluid overload and damage to the endothelium and endothelial glycocalyx (EG). The aim of this trial was to compare the FC infusion time on its hemodynamic effects and EG. (ii) Methods. Prospective randomized single-center trial of fast (5-10 minutes) versus slow (20-30 minutes) administration of 500ml balanced crystalloid FC in spinal surgery (cohort OR) and septic shock (cohort SEP) patients. Hemodynamic response was assessed using standard monitoring and blood flow measurements; damage to EG was assessed using the perfused boundary region (PBR) via intravital microscopy monitoring in the sublingual region within relevant time points ranging up to 120 minutes. (iii) Results. Overall, 66 FCs in 50 surgical and 16 septic patients were assessed. Fluid administration was associated with increase of PBR in general (1.9 (1.8-2.1) vs. 2.0 (1.8-2.2); p= 0.008). These changes were transient in OR cohort whereas they were long-lasting in septic fluid responders. The rate of fluid responsiveness after fast versus slow administration was comparable in global population (15 (47%) vs. 17 (50%); p=0.801) as well as in both cohorts. (iv) Conclusions. Fluid challenge administration was associated with increased PBR (and presumable EG volume changes) which normalized within the next 60 minutes in surgical patients but remained impeded in septic fluid responders. The fluid responsiveness rate after fast and slow FC was comparable, but fast administration tended to induce higher, though transient, response in blood pressure. Fluid resuscitation is considered standard of care in intensive care medicine and the operating room (OR), respectively. Over the years, adverse effects of fluid administration have been increasingly acknowledged ; therefoBased on the effectivity of mini-FC tests  the impaμm into the luminal surface of the EG by measuring the radial motion of RBC away from the central flow towards the endothelial cells. The more the EG is injured, the deeper the RBC penetrate into the glycocalyx and the higher the PBR is.Endothelial glycocalyx (EG) is a thin gel-like layer on the outer surface of endothelial cells within the human body. It consists of sugar-based macromolecules such as heparan sulfate or proteoglycan. This structure has been considered as a crucial regulator of endothelial functions such as endothelial permeability or interaction with circulating cells . It is sThe aim of this study was to assess the influence of fluid challenge infusion time on macrohemodynamic variables and PBR in surgical and septic patients. Our hypothesis was that faster fluid challenge leads to bigger macrohemodynamic effects but harms EG more than the slower one.This was a prospective open randomized trial performed at the Department of Anesthesiology and Intensive Care Medicine in Plzen  in two three-month periods between January and December 2016. The study was approved by the local ethical committee, registered under the ACTRN12618000385246, and financially supported by the Ministry of Health grant no. 15-31881A. Informed consent was obtained from all individual participants  included in the study.Patients undergoing scheduled operative intervention (cohort OR) or admitted to the ICU for sepsis/septic shock (cohort SEP) in the suspected need for fluid administration/response test based on clinical assessment were recruited into the trial.2O).The first cohort (OR) consisted of patients scheduled for major spinal surgery under general anesthesia of more than one-hour expected length. Inclusion criteria were age over 18 years, ASA physical status I-III, and signed informed consent. Patients with pathology in the oral cavity , previously diagnosed systemic microangiopathy, and atrial fibrillation were excluded from the trial. General anesthesia for the operative procedure was induced using propofol, sufentanil, and atracurium; sevoflurane in O2/Air mixture was used for maintenance. The patients were orotracheally intubated and proned after induction. Ringerfundin  at rate of 1ml/kg/hour was administered throughout the procedure. Standard monitoring of noninvasive blood pressure, pulse oximetry, and electrocardiography was commenced; Massimo rainbow plethysmograph with PVI assessment was used in addition to monitor fluid responsiveness. All patients were mechanically ventilated in volume-controlled mode  consisted of patients with sepsis or septic shock admitted to the intensive care within 48 hours from ICU admission . Patients younger than 18 years and those with intraoral bleeding and/or diathesis were excluded. Informed consent of the patients was obtained prior to inclusion. In case of patient's diminished consciousness either next of kin or independent physician was asked for consent; patient's agreement was obtained retrospectively if possible. All patients were initially fluid-resuscitated and monitored using the transpulmonary thermodilution  in addition to standard ICU monitoring. If needed vasoactive drugs  were used to reach generally accepted targets of global perfusion parameters . Analgesia, sedation, and/or mechanical ventilation were used as appropriate.https://sealedenvelope.com/) with predefined stratification (OR and SEP). A fluid challenge of 5 ml/kg predicted body weight of crystalloid  was used as a test of fluid response. Patients were randomly separated into two groups: fast administration  and slow . The study was designed as open so neither blinding of the operator nor outcome assessment was provided.Patients were randomized by the research staff using the sealed envelope block randomization scheme , T1 (immediately after FC), and T60 (60 minutes after FC) time points measurements were performed in both cohorts. In addition, T20 and T40 (20 and 40 minutes after FC) were made in OR cohort and T120 (120 minutes after FC) was performed in SEP patients.In case of sudden circulating blood volume change  or need for other fluid administration the monitoring was discontinued and following time points were omitted. Relevant cointerventions within the study period were screened . However, we have tried to restrict such interfering factors to the minimum by postponing them unless vitally important. The change of vasoactive medication in septic patients (SEP cohort) was allowed during the study period to maintain the blood pressure within predefined range (65-75 mmHg in patients without chronic hypertension and 70-80 in those with chronic hypertension).Primary objective was to assess the influence of balanced crystalloid fluid challenge infusion time on the PBR as a marker of endothelial glycocalyx thickness using the SDF imaging in the sublingual circulation.Secondary outcomes were to assess its effect on macrocirculation  and the temporary differences of the hemodynamic and PBR response in different subgroups .μm and the resulting number stands for an average of PBR that is corrected for the potential changes in the distribution of vessel diameters. The software identifies all available vessels and places 10 μm long vascular segments along them. Next, a sequence of 40 frames on this spot is recorded with approximately 300 segments in the field. Afterwards, the operator should reposition camera slightly allowing for recording of the next 40-frame sequence. Automated signal quality assessment is performed by the software itself displaying a direct user friendly feedback enabling gathering only valid data. The maximal data-sampling period is 5 minutes making the monitoring less prone to interobserver variability. However, the recording stops automatically when 3000 segments in focus and without movement are acquired; hence under normal conditions much shorter periods  are needed. Then the software selects segments with sufficient contrast with the background and counts the median RBC column width and its distribution from the intensity profile. From this intensity profile, the perfused diameter of the vessel is calculated by a linear regression analysis. The PBR stands for the distance between RBC column width and perfused diameter according to the equation: (perfused diameter – median RBC column width)/2.The perfused boundary region parameter was used to monitor the possible EG damage induced by FC. This parameter (PBR) was designated to determine the extent of penetration of the flowing red blood cells in capillary to its luminal border by calculating the radial motion of red blood cell away from central flow in capillary. In the situation of EG damage through various pathologic stimuli, this spreading closer to endothelial cells is more obvious and thus the PBR value becomes higher. An intravital real-time microscopy of sublingual circulation by specialized hand-held video microscope  was performed at each time point. Acquired data were processed with GlycoCheck software version 1.2.5.7211 . The software automatically measures PBR in vessels of diameter from 5 to 25 Besides the PBR, automated parameters based on two quality checks, which indirectly align to microvascular perfusion, were assessed in each time point. During first check the so-called “valid vascular segments” are reported (those with more than 60% contrast in vessel segments) making the parameter of valid vessel density. During a second check phase red blood cells (RBC) column is monitored allowing for the calculation of percentage of vascular segments with RBC present in all 40 frames of the monitoring session. Results of the monitoring are available within several minutes after the monitoring period had finished. Detailed description of automatic calculation of PBR, valid and total vascular density, and RBC filling parameters can be found elsewhere . ExcelleMacrohemodynamic changes were assessed using standard hemodynamic variables based on cohort-defined monitoring. In the OR cohort heart rate, noninvasive blood pressure, pulse pressure, and PVI parameters were used. A drop in PVI of 5% and more between T0 and T1 was measure of a positive fluid response.In the SEP cohort heart rate, invasive blood pressure , cardiac output/stroke volume values, stroke volume variation, and thermodilution derived global end-diastolic volume index (GEDI) were assessed. A stroke volume increase of 15% (T1 versus T0) was used to define positive fluid response.The study was designed as a pilot study, because no baseline data existed regarding both study outcomes . A sample of 50 patients in the cohort OR was deemed sufficient to ascertain a 10% difference in the PBR value with alpha error I =0.05 and study power = 0.9. The length of the study limited recruitment into the septic cohort and number of admitted septic patients therefore underwent no prior sample size calculation.http://www.medcalc.org; 2018) was used for statistical analysis.The usual descriptive statistics was used to compare patients between F and S groups; Kolmogorov-Smirnov test was used for assessing normality. Student's t-test (unpaired) or Mann-Whitney rank sum tests were used to compare intergroup differences; the time-based changes within groups were tested using RM ANOVA or RM ANOVA of Ranks (Friedman) appropriately. Chi square test was used to compare frequency distribution. p≤0.05 was deemed statistically significant. MedCalc Statistical Software version 18.2.1  or slow (group S-OR: 25 FCs) FC administration. In the SEP cohort in 16 patients, 16 fluid challenges were performed, randomized to fast (group F-SEP: 7 FCs) and slow (group S-SEP: 9 FCs) FC administration; the median time from sepsis onset  and intervention was 16 (7-33) hours. There were no dropouts; the flow of participants through the trial is displayed in e-The perfused boundary region was comparable at the baseline between F and S group (1.8 (1.72-2.05) vs. 1.89 (1.76-2.08); p= 0.176). The PBR increased after FC in general (1.88 (1.76-2.08) vs. 1.95 (1.79-2.20); p= 0.008) and in both groups in parallel (T1 in F group 1.91 (1.75-2.13) vs. 1.96 (1.85-2.26) in S; p=0.256). The PBR remained increased throughout the next course in both groups  vs. 2.02 (1.72-2.16) in S; p=0.576); see Based on the responsiveness criteria in global 32 FCs (49%) were assessed as positive: 24 (48%) in the OR and eight (50%) in the SEP cohort. No difference in the FC outcome was identified between fast and slow administration neither in global population nor in any of the cohorts .No differences in screened hemodynamic variables were observed at the baseline between F and S groups in any of the cohorts studied . HoweverIn septic patients, the PBR values were significantly higher (2.08 (1.90-2.22) in SEP vs. 1.81 (1.73-2.00) in OR cohort; p<0.001) at the baseline. In the S-OR subgroup there was an increase of the PBR after FC with later return to initial values . In the As mentioned previously in global FC response, there were no differences among any subgroup studied , nor at any other time point afterwards  vs. 2.10 (1.86 – 2.78); p=0.014), but remained stable in NR patients. This PBR increase occurred in fluid responders of both OR (1.76 (1.73-2.02) vs. 1.96 (1.79-2.26); p=0.016) and SEP cohort (1.96 (1.85-2.18) vs. 2.28 (2.04-2.52); p=0.039), but in SEP fluid responders the PBR not only increased against baseline value, but rose significantly even in comparison with fluid nonresponders (see μg/kg/min in T0 to 0.19 (0.05-0.32) in T1) and remained decreased until T120. No such change occurred in nonresponding patients. On the contrary, the central venous pressure value rose in nonresponding septic patients only (ESM The fluid nonresponders (NR) tended to have lower baseline value of the PVI in the OR cohort (10 % (6-16) vs. 19 % (13-22) in the FR; p= 0.001) and SVV (9 % (6-12) vs. 10 % (3-15) in NR; p=0.87). The initial values of MAP, PP, HR, SV, CI, GEDI, and ELWI were all comparable between fluid responders and nonresponders at the baseline; for full results, see ESM only ESM .In our trial, fluid administration in form of fluid challenge increased the PBR value independently of the infusion time. However, there may be a weak signal that septic fluid responders seem to be more affected. Secondly, the 5-10 minutes' or 20-30 minutes' infusion time of fluid challenge seems not to play an important role regarding rate of positive fluid response. However, a transient increase of mean arterial pressure and/or decrease in norepinephrine needs was more pronounced after fast administration.To ascertain the impact of different infusion time on the microcirculation we have used the perfused boundary region parameter. Based on previous observations the PBR may be linked to the endothelial glycocalyx thickness , 13 and On the contrary, in the septic patients the PBR pointed towards existing EG damage induced by sepsis and/or previous fluid boluses. Higher PBR values after FC were observed in septic fluid responders than nonresponders, but infusion time does not seem to play any role. Whether this PBR increase is due to recruitment of capillaries and hence local ischemia/reperfusion remains undetermined. The slightly lower density of valid microvessels and trend towards lower RBC filling support the hypothesis of capillary recruitment associated with hemodilution. Another important fact is that, unlike in OR patients in whom the PBR returned to preinfusion values within 60 minutes, in septic fluid responders the PBR remained increased for the next 2 hours. Therefore, another explanation could be that the increased systemic flow and precapillary pressure induces higher shear stress  to the aThe impact of fluids on EG has been studied previously. Mentioned studies by Chappell et al. , Powell Fluid challenge is a well-established test of preload reserve. Interestingly, the number of fluid responders and nonresponders is stable throughout different studies and patients' populations. The fact that rate of fluid challenge should affect its outcome has been postulated already by Weil and Vincent in the original TROL acronym (Type-Rate-Objectives-Limits of safety) . In geneThe longevity and delayed response to the FC were a secondary measure of our trial. In this regard, both short and prolonged infusions seem to have similar characteristics. In the fast infusion groups, a more pronounced pressure response was observed, but within the next 20-60 minutes, the blood pressure was equal in both groups. Unlike in the study by Aya et al.  the effeOur study has several important limitations, which need to be accounted for. Firstly, in the OR cohort fluid responsiveness was assessed based on clinically available parameter usually coupled with positive response to fluid administration (decrease in PVI). Use of advanced hemodynamic monitoring would possibly define the secondary outcome more precisely. The reason to use the readily available noninvasive monitoring tools was based on the ethical request not to increase the invasivity of the monitoring used and noninvasive hemodynamic monitor was not technically available at the time of the study. Therefore, we have used parameter, which is routinely available and possibly acceptable for definition of positive fluid response. In addition, the conditions in spinal surgery are rather specific  limiting the generalizability of our results into other populations . Secondly, the number of septic patients recruited into the study is low and could influence observed results. As mentioned in the methods section the inclusion of these patients was limited by the time of device availability and we have recruited the whole cohort of septic patients admitted to the ICU throughout the study period. Besides, the negative finding on the influence of fluid challenge infusion time goes in line with previous observations as reviewed by Toscani et al.  and MessIn conclusion, in our trial fluid challenge administration was associated with increased perfused boundary region  which normalized within the next 60 minutes in surgical patients but remained impeded in septic fluid responders.The fluid responsiveness rate after fast (5-10 minutes) and slow (20-30 minutes) fluid challenge administration was comparable in our patients. Fast administration tended to induce higher, but transient, response in blood pressure.


Social media enables the public sharing of information. With the recent emphasis on transparency and the open sharing of information between doctors and patients, the intersection of social media and healthcare is of particular interest. Twitter is currently the most popular form of social media used for healthcare communication; here, we examine the use of Twitter in medicine and specifically explore in what capacity using Twitter to share information on treatments and research has the potential to improve care. The sharing of information on Twitter can create a communicative and collaborative atmosphere for patients, physicians, and researchers and even improve quality of care. However, risks involved with using Twitter for healthcare discourse include high rates of misinformation, difficulties in verifying the credibility of sources, overwhelmingly high volumes of information available on Twitter, concerns about professionalism, and the opportunity cost of using physician time. Ultimately, the use of Twitter in healthcare can allow patients, healthcare professionals, and researchers to be more informed, but specific guidelines for appropriate use are necessary. Social media enables the public sharing of information between anyone with an account. While previously used primarily to connect public figures such as politicians, celebrities, and athletes with the general public, additional uses of social media have arisen. Calls to improve the alienating and inaccessible language of healthcare in order to improve patient–physician communication are not unique, and continue to plague medicine . Thus, iConflicting opinions have stirred controversy about if and how medical professionals should use social media platforms in their work. Skeptics of social media in healthcare cite the potential for misinformation, conflicting advice, and unprofessionalism as evidence that social media is not an appropriate medium on which to share healthcare information . Some arTo answer this question and analyze uses of social media in medicine, we first examine how medical professionals have used digital media in the past. Then, we compare Twitter’s features to prior media to investigate how Twitter is currently being used in medicine. From its current uses, we derive its limitations and potential for growth; finally, these limitations guide proposed solutions about how to effectively leverage Twitter in medicine. Ultimately, a review of the relevant literature demonstrates that the use of Twitter to share information about treatments and research among physicians has the potential to greatly improve care. However, when used inappropriately , Twitter’s privacy and misinformation concerns outweigh the benefit of accessibility.Previous uses of digital media provide necessary context for the current intersection of social media and medicine. The use of digital media in medicine is non-unique, as Dr. Gerald Weissman discusses in his book about medicine in the age of digitization. “Digital medicine” began in the early 2000s, immediately following the widespread popularization of cable television and the Internet . For exaDr. Mehmet Oz, a cardiothoracic surgeon at Columbia University, gained an enormous following by touting a new age of accessible medicine and advocating for alternative medicine, despite dubious scientific backing . Oz shatOf course, many asked why a reputable doctor who clearly understood appropriate medical practice would resort to recommending such treatments. The answer lies in digital media—for a television audience, “miracle weight loss pills” earned far more ratings than recommendations to eat healthier and exercise regularly ,7. WhileThe superficiality of digital media affects the information conveyed on the media itself. For instance, in order to be a successful and profitable television show, Dr. Oz compromised medical accuracy. Thus, misinformation plagues digital medicine, as solutions to health problems are not always simple and facile ,8. SuperDespite high rates of misinformation, the increased accessibility of medicine on digital media has the potential to improve patient care and change the perception of medicine as cryptic or esoteric. This accessibility is extremely desirable in medicine, as highly technical terminology can alienate patients and detract from their care ,9. Thus,Despite clear flaws, many researchers extol digital media as a promising tool to involve patients more in their care and remove barriers to understanding medical treatment . While tThe first reason why Twitter has increased in popularity in medicine is that Twitter allows medical professionals to reach a broad audience ranging from other physicians to trainees to patients ,7. AnyonMany medical professionals use Twitter for its potential to share and advance biomedical research. By allowing fellow researchers and physicians to connect and share research about new treatments, clinical problems that require further study, or interesting case studies, as seen in Reducing barriers to collaboration in medicine is extremely valuable, as frequent constructive collaboration  can greatly improve treatments and may range across disciplines into fields such as computer science and bioengineering . For resNot only can Twitter connect biomedical researchers, it also serves to make research advances more accessible for physicians. Connecting researchers and clinicians is extremely important and useful, as clinicians can use new information they discover from this closer contact with researchers to guide decision-making about patient treatments in an ever-evolving field. Moreover, this exchange of clinical problems and new research can spur research in impactful and unique fields more openly and quickly than other strategies for collaboration . Thus, tThrough its ability to connect millions of people with public tweets, Twitter has the potential to revolutionize public health efforts, including disseminating health updates, sharing information about diseases, or coordinating relief efforts . For exaA powerful example of the use of Twitter is that many of its benefits outlined above can potentially occur under a single post on the platform. For example, someone at a cardiology conference may respond to the tweet from Mayo Clinic about high blood pressure and discuss research on a new genetic correlation between high blood pressure and a specific gene. Another might respond by questioning the strength of the clinical outcomes of this study and other trials like it, prompting the sharing of papers. A practicing physician could respond with their experiences treating patients with hypertension. Another researcher might reply with a link to a healthcare conference where state-of-the art research on blood pressure management was presented. Moreover, a patient might ask these experts about the practicalities of dealing with a family member with hypertension. The diversity of expertise and backgrounds that can communicate on Twitter is unique, and this exchange of information can be extremely beneficial .Ultimately, the sharing of information on Twitter has the potential to create a communicative and collaborative atmosphere for patients, physicians, and researchers. In this way, physicians practicing daily are connected to the newest research, researchers can identify clinical problems to solve, and patients can understand their conditions better ,12,13. TWhile more accessible information on Twitter undoubtedly has the potential to benefit patient care, a major assumption made in this scenario is that all the information is accurate. Dr. Katherine Chretien and her research team at George Washington University studied the prevalence of misinformation in tweets about healthcare, and they found that about 20% contained inaccurate information . The higMoreover, no systematic process exists to check for misinformation on Twitter; instead, it relies on “crowdsourcing,” or voluntary contributions from medical professionals who try their best to correct inaccurate statements . Thus, iOne example of dangerous misinformation caused by non-experts sharing opinions without scientific backing is the celebrity anti-vaccination movement. Several celebrities, most notably Jenny McCarthy and Jim Carrey, have tweeted about how vaccines have been linked to autism, despite no medical basis in fact, as seen in As a celebrity comedian, Jim Carrey has a verified account, but has no formal expertise on the subject of vaccines. Twitter can be an “echo chamber of ideas,” representing shared opinion rather than balanced facts, due to the ease of quoting or retweeting messages . The antCelebrities rebuking vaccinations are egregious examples of non-experts commenting on medical phenomena, but the general issue of distinguishing representatives of commercial interests from unbiased physicians is as difficult and problematic . The matAnother issue with sharing information on Twitter for medicine is that Twitter can transmit such a high volume of information. The amount of information makes it nearly impossible to absorb and filter all relevant tweets . The samMoreover, lapses in professionalism are also serious potential problems with Twitter, as with other forms of social media. Previous studies have found high rates of unprofessional tweeting from accounts clearly identified as doctors ,15. UnprThe final potential harm of using Twitter in healthcare is the use of physician time. While making physicians and their knowledge more accessible on social media is valuable, these activities also take time out of the day for doctors. Moreover, over 80% of tweets from verified doctors are published during the workday, from 9 a.m. to 5 p.m.; this time on Twitter takes away from other potentially more important activities for daily patient care . PhysiciFor the sharing of general information on Twitter, the risks involved with using Twitter for healthcare discourse include high rates of misinformation, difficulties verifying the credibility of sources, overwhelmingly high volumes of information available on Twitter, concerns about professionalism, and the opportunity cost of using physician time. In order to compare the risks and benefits of the use of Twitter in medicine, this paper examines the current uses of Twitter in medicine to propose a solution to maximize benefits and minimize risks.With over 2000 healthcare providers on Twitter who tweet more than once per day and have at least 300 followers, Twitter is becoming a major part of modern medicine because of the benefits it can provide. Many tweets from medical accounts share general information for public health or new research about treatments or technology. For instance, in However, less-experienced physicians on Twitter have tweeted comments about interactions with patients, pictures of X-rays, and cropped images of notes from real patients. While some case studies can be instructive to a general audience, extreme precaution must be taken to remove identifying patient data from the tweets to prevent privacy violations. One study reported that out of a group of 500 doctors who had over 200 followers, more than 5% of tweets were violations of patient privacy . These bMoreover, Twitter accounts for doctors with fewer than 300 followers rarely had the disclaimer “Tweets are my opinions not medical advice”, which is important to inform the general public about the content of the tweets and prevent doctors from liabilities . Thus, iTwitter can be an excellent tool for sharing research and connecting physicians to experts in other fields. For instance, research conferences have extensively leveraged Twitter’s capabilities to generate interest and maximize impact . PhysiciOther clear applications of Twitter to medical research is the application of a multi-tiered approach of sentiment analysis, data-mining, and artificial intelligence to analyze tweets from the general population ,18. ThisExamining the current uses of Twitter in medicine has demonstrated that many doctors are using Twitter effectively to share information about research among their colleagues and collaborators and information about public health for the public. However, some doctors know much less about the appropriate uses of Twitter. This knowledge gap is problematic and suggests little formal education on social media practices amongst physicians.Medical professionals must constantly communicate with patients, peers, and researchers. As social media is becoming an integral part of communication, medical professionals of the twenty-first century must acquire new skills on social media. Concerns with misinformation, privacy, and unprofessionalism necessitate clear guidelines for physicians on Twitter.Despite this need for clear guidelines, the current guidelines from the American Medical Association (AMA) are vague, telling doctors to “use their common sense” ,21. The Thus, medical professionals must be formally trained on appropriate and effective social media use. This training is a necessity as social media becomes a bigger part of our daily lives and medicine. Similar initiatives have informed collegiate and professional athletes, who have now become major figures on social media ; formal Moreover, the AMA should enact new guidelines for the use of social media by medical professionals. These guidelines should emphasize that health professionals should maintain separate personal and professional accounts, avoid profanity, racist or sexist statements, or sexual references, respect the privacy and anonymity of patients, avoid promoting specific products or medication, and include clear statements of affiliations and conflicts of interest in Twitter account profiles ,16. HealWhile the proposed solution to educate medical professionals on social media etiquette during their training has potential to mitigate risks associated with physicians on social media, educating doctors should be an iterative and continuous process. Implementing any education program, which is better than the current complete lack of education, is a step in the right direction, but only a start. Moreover, the distinction between types of healthcare professionals, including doctors, physician assistants, nurses, and others, has not yet been addressed in the literature and requires further study for a more nuanced solution.Ultimately, Dr. Oz, WebMD, and Twitter all share the common goal of changing the perception of medicine from a black box to something more accessible—to allow patients to understand their conditions and make informed decisions. The use of Twitter in healthcare has the potential to allow patients to be more informed about their own health, but must balance accessibility with misinformation.


Three dimensional problems reflect more imperative understanding to real world issues in comparison to two dimensional problems. Keeping this fact in mind, a mathematical model is designed to deliberate the 3D magnetohydrodynamic couple stress nanofluid flow with joule heating and viscous dissipation effects past an exponential stretched surface. The analysis is performed keeping in mind the physical effects of Brownian motion and thermophoresis combined with convective heat condition. This paper also distinctly introduces a more realistic boundary constraint for nanoliquid flow model. For instance, zero mass flux condition has been instituted for the first time for 3D couple stress nanofluid model as far as the exponential stretched surface is concerned. Self-similar transformations are engaged to obtain a system of ordinary differential equations possessing high nonlinearity from the system of boundary layer partial differential equations. Analytic solution is constructed in the form of series using Homotopy Analysis Method (HAM). Numerically calculated values of Skin friction and local Nusselt number are also given with suitable analysis. Moreover, the influences of sundry parameters on velocity distribution, and heat and mass transfer rates are deliberated and depicted through relevant graphs. The results obtained clearly show that the Biot number and Hartmann number possess increasing effect on temperature distribution. To authenticate our obtained results, a comparison in limiting case is also given. The term “nanofluid” refers to the nanoparticles (having size less than 100 nm) suspended into the base fluid. Typical examples of nanoparticles include metals such as Copper, Aluminum and Silver, oxides e.g., Aluminum Oxide, carbides such as Silicon Carbides, nitrides like Silicon Nitride and Aluminum Nitride, and nonmetals such as graphite or carbon nanotubes. The customary fluids are ethylene glycol, water, and oil. The amalgamation of nanoparticles with the common fluid tremendously improves the thermal traits of the base fluid.1 were the pioneer to introduce the term nanofluid and the fact that several heat transfer physiognomies of the base fluids, such as thermal conductivity is enhanced by insertion of nanoparticles into it. Later, Wang and Arun2 deliberated that convective characteristics of base fluid are enhanced by addition of metallic and non-metallic particles into it. This was followed by an experimental study by Eastman3 who claimed that thermal conductivity of the ethylene glycol is improved by 40% once copper nanoparticles are inserted in it. Subsequently, Eastman4 also examined that the shape of nanoparticles has a pivotal role in increasing the thermal conductivity of base fluid. The decree of Eastman was verified by Murshed5 who studied that the amalgamation of water with spherical shaped nanoparticles (Titanium oxide) with sizes more than 40 nm, increases the thermal conductivity of the base fluid by 33%. The use of nanofluids is very common in cooling the transformers and nuclear reactors. In medical, magneto nanofluids are also being utilized in cancer treatment, hyperthermia and MRI (Magnetic Resonance Imaging). The use of nanofluids is also imperative in making the germs free surgical instruments and removal of tumors.Choi and Eastman6. In this case the dispersion of the nanoparticles in the base fluid is uniform and stable. Here, the impact of nanoparticles may be taken into consideration by deliberating the thermophysical characteristics of the nanofluids in the model equations. In the second case, named as two-phase flow, the association between liquid matrix and the nanoparticles is considered7. The two phase model was introduced by Buongiorno8, however, Tiwari and Das9 initiated the single phase model. Following these two proposed models, numerous researchers deliberated the thermal role of nanofluids to analyze the effective fluid characteristics19.In the literature, generally nanofluid flow can be modelled in two ways. Since the nanoparticles are smaller in size and can be mixed effortlessly in the base fluid so in the first case nanofluid is considered as a single phase flow20. Therefore, several mathematical models for studying non-Newtonian fluids have been suggested by researchers in the past.Investigation of non-Newtonian fluids is still a subject of curiosity for scientists and researchers because of their numerous applications in engineering and industry. Examples of non-Newtonian fluids may embrace shampoo, ketchup, polymer solutions, paper pulp and paints etc. Because of many complexities, non-Newtonian fluids cannot be expressed by a solitary constitutive relation in contrast to Newtonian fluidsi.e., the viscous fluid), and is comprises of couple stresses and body couples21. Examples of couple stress fluids may include animal and human blood, colloidal fluids, liquid crystals and liquids with long chain molecules. Basically, in these kind of fluids, the constitutive equations associate angular part of the velocity to the gradient of the angular velocity and the stress tensor’s skew symmetric part to the couple stress22. Erigen23 was the pioneer who used the term micropolar fluid for polar fluid; whereas dipolar fluids are recognized by their initiators Bleustein and Green24. The juncture of polar and dipolar fluids is phrased as couple stress fluids and was introduced by Stokes25. As the couple stress fluid’s stress tensor is not symmetric therefore Navier-Stokes equations are not adequate to model such fluids. Thus, the fluids with solid particles dangling in a viscid medium i.e., the synthetic fluids, the lubricants with small amount of polymer preservative and the blood may be treated as couple stress fluids26.Couple stress fluid model is one amongst various proposed viscoelastic fluid models that exhibits behavior of the non-Newtonian fluids. Couple stress fluid model is considered as generalization of classical fluid model  of three-dimensional couple stress fluid flow with Newtonian heating. Khan et al.28 examined numerical solution of time dependent magneto hydrodynamic couple stress fluid flow past a rotating disk. Hayat et al.29 deliberated analytic solution of three-dimensional magneto hydrodynamic couple stress nanofluid flow past a nonlinear stretched surface with convective heat and mass boundary conditions. Ramzan30 found series solutions of three-dimensional couple stress nanofluid flow with joule heating using HAM. Lately, Hayat et al.31 investigated series solution of three-dimensional magneto hydrodynamic couple stress nanofluid flow with heat generation/absorption under the effects of convective condition. Recently, Hayat et al.32 deliberated the 3D couple stress nanofluid flow in attendance of Cattaneo- Christov heat flux.On account of such important applications of couple stress fluid in various engineering fields, numerous researchers and authors have highlighted the various aspects of such fluids. Amongst these, Ramzan 41 is engaged to solve this system of ordinary differential equations. Graphical images depicting impacts of varied parameters on involved distributions with mandatory conversation are also given. An appraisal of the presented results to a previous study is also given to authenticate our results.From aforementioned literature review, it is found that flow of 3D magneto hydrodynamic couple stress nanofluid past an exponential stretched surface with convective heat and zero mass flux conditions is still a scarce. Effects of viscous dissipation and Joule heating are also deliberated to analyze of the flow problem. The system of partial differential equations acquired from boundary layer theory are converted to set of nonlinear differential equations using apposite transformations. Renowned Homotopy analysis method (HAM)U0, V0 are constants) are stretched velocities of the surface along x− and y− directions respectively. Impact of Joule heating and viscous dissipation are also considered. Couple stress nanofluid is electrically conducting with uniform magnetic field in a direction along z− axis  are velocities components along  directions respectively. Also, T, C, T∞ and C∞ represent the fluid’s temperature, the concentration, the ambient temperature and the ambient concentration respectively. Fluid flow is represented by the boundary layer equations as appended below:It is presumed that magnetic Reynolds number is small and owing to this assumption, the induced magnetic field is ignored when we compare it with the applied magnetic field. Also,  is engaged to obtain the series solutions for the system of nonlinear differential equations with allied boundary conditions. Over the years numerical techniques are developed but owing to obvious restrictions49. The initial guesses with respective linear operators required for the particular problem are given as under:Ai(i = 1 − 10) are the arbitrary constants.A comprehensive detail of this method with examples may be found atℏf, ℏg, ℏθ and ℏϕ. These parameters play a title role in controlling and regulating the convergence regions of resultant series solutions. To have the values of same parameters, ℏ− curves are obtained at 9th order of approximation. Figure ℏf ≤ −0.5, −1 ≤ ℏg ≤ −0.4, −1.0 ≤ ℏθ ≤ −0.5 and −1.15 ≤ ℏϕ ≤ −0.5. Table th order of approximations and it can also be presented as the counter check to ℏ− curves drawn in Fig. In this section we will define the series solutions’ convergence by via HAM. The HAM solutions encompass auxiliary parameters The goal of this portion is to portray the significant characteristics of arising parameters on velocity components, temperature, and concentration distributions, Skin friction and the Nusselt number.α on velocity components f′ and g′ along x− and y− axes respectively. It is noticed that an escalation in the values of α, f′ decreases however g′ shows an opposite behavior. This is because of the fact that the rate constant of velocity component along the y− axis is more dominant in comparison to the velocity component along the x− axis. Figures K on the velocity components f′ and g′ respectively. Both velocity components decrease with rise in the values of K. The values of K are directly linked with couple stress viscosity parameter n. Higher values of K means more viscosity which hinders the movement of the fluid and finally decrement in the velocity components is witnessed. Figure γ on temperature profile. From the curves of γ, it is revealed that temperature distribution upsurges for incremented values of γ. Actually, escalated heat transfer coefficient is perceived for growing estimates of γ which eventually rises the temperature of the fluid. It is also comprehended that temperature of the fluid rises more rapidly near the stretched surface for incremented values of γ. The effect of Hartmann number M on the temperature field is showed in Fig. M. Augmentation in the Lorentz force is observed because of augmented values of M; due to this phenomenon, resistance in the fluid motion is experienced which results in more collisions of molecules in the fluid and eventually upsurge in fluid’s temperature is witnessed. Figure Sc on the concentration distribution. A feeble mass diffusivity is witnessed for large values of Sc. This weak mass diffusivity will affect the mass concentration of the fluid and consequently decrease in the concentration field is witnessed. Figure Nt on concentration distribution. Mounting values of Nt push nanoparticles far away from the warm surface, which results in an enriched concentration distribution. In Fig. Nb on concentration field is portrayed. For higher values of Nb, reduction in concentration profile is witnessed. Actually, mounting values of Nb are the root cause to boost the random motion amongst nanoparticles and as a result decrease in concentration of the fluid is witnessed. The impact of Prandtl number Pr on the temperature field is depicted in Fig. Ec on the temperature distribution is illustrated in Fig. Ec. This is because of frictional drag that becomes the main source to raise heat energy in the fluid. Figures M, the Eckert number Ec and the Prandtl number Pr on Nusselt number −θ′(0). It is detected that Nusselt number is decreasing function of all three parameters. Nusselt number is a non-dimensional number that is used to gauge the heat transfer between a solid body and a moving fluid. The reason for decrease in value of Nusselt number is because of decline in the natural convection of nanofluids. Actually, the augmented Lorentz force due to the strong magnetic field weakens the natural convection for nanofluids.Figures x− and y− axes for varied values of ratio parameter α, couple stress parameter K and Hartmann number M and It is gathered that the Skin friction coefficients are enhanced for increasing values of α, K and M. Table γ, α, A and shows decreasing tendency for growing values of K, M, Pr, Ec and Sc. Table 50 and all obtained results are found in an tremendous concurrence. Table et al.51 in limiting case. An excellent concurrence is achieved when the results are compared.Tables For growing values of Brownian motion and thermophoresis parameters, the nanoparticle concentration distribution shows decreasing and increasing behavior respectively.α accounts for decrease in velocity component f′ and increase in the other velocity component g′.Effective enhancement of ratio of rates parameter The temperature distribution enhances versus increasing values of Biot number and Hartmann number.K, M, Pr, Ec and Sc, Nusselt number shows escalating behavior.For the values of The flow of couple stress nanofluid past an exponential stretched surface with effects of magneto hydrodynamic, viscous dissipation and Joule heating is examined here analytically. Impacts of convective heat and zero mass flux conditions are also deliberated. The system of nonlinear differential equations is solved using Homotopy analysis method. Influences of various parameters on velocity field, temperature field, concentration distribution, Skin friction coefficient and the local Nusselt number are depicted through graphical illustrations. The significant findings of the present problem are summarized as follows:


Pharmaceutical compounding is an essential component in pharmacy practice allowing pharmacists to provide dosage forms or strengths that are commercially unavailable. Medications compounded for patient-specific needs contribute to personalized medicine. Extemporaneous compounding provided by pharmacies overcomes the market shortage of these therapeutic products. The aim of this study is to investigate and characterize the prevalence, characteristics, and determinants of extemporaneous compounding in Jordanian pharmacies.This study was based on a cross-sectional questionnaire and included 431 randomly selected pharmacies in the twelve governorates of the country. Data were collected via face to face interviews of pharmacists who voluntarily and verbally responded to the questions.Results revealed that 223 (51.7%) of the surveyed pharmacies practiced extemporaneous compounding. The main reason for not providing extemporaneous compounding services was lack of prescription orders for compounded preparations (53.8%). The second reason was lack of the equipment and supplies necessary for compounding (24.4%). Extemporaneous compounding prescriptions were mainly issued by dermatologists (98.2%); dermatological indication was the most common of all extemporaneous compounded prescriptions. The main reason for requesting compounded medications was the lack of a commercially available product (87.9%). The vast majority of the compounded dosage forms were creams (99.6) and ointments (91.5), followed by solutions (23.3%). Only 5 (2.2%) of the studied compounding pharmacies prepared sterile products. The major sources for compounding protocols were the physician order (94.2%), and ‘in-house’ protocols (44.8%). However, the main resource for estimating compounded medications expiration date was information based on pharmacist’s experience (57.8%) and the physician’s order (53.4%).Extemporaneous compounding is a common element of pharmaceutical care. Topical preparations are the most commonly compounded products. Finding from this study suggest that there is a need for standardizing the compounded product formularies, product quality testing, and improving the consistency in estimation of an expiration date of compounded products. Extemporaneous compounding refers to the practice of the preparation of a therapeutic product by mixing and combining pharmaceuticals agents for an individual patient in response to an identified need . ExtempoNevertheless, extemporaneous compounding is still a relevant pharmaceutical service provided by many pharmacies worldwide –8. The cPharmaceutical Compounding – Nonsterile Preparations and <797> Pharmaceutical Compounding – Sterile Preparations [Application of quality standards in extemporaneous compounding is still a major concern for regulatory agencies since poor quality of compounding practices can result in life-threatening contamination or in products that don’t possess the required strength, quality, and purity . In the arations . Howeverarations . ExtempoData for this project were collected using a cross-sectional descriptive questionnaire. The questionnaire was constructed based on information collected from intense review of published relevant literature , 15, 16.Administration of this questionnaire was based on a personal interview with the pharmacist on duty; the data collector asked the pharmacist the questions and filled the questionnaire. Four senior pharmacy students performed the interviews with the participants. All interviewers were trained by the principal investigator (PI) and two of the co-investigators. The training focused on communication skills with the pharmacy staff and on correct administration of the questionnaire. Moreover, the questionnaire was supplemented with a protocol with instructions. The interviewers were instructed to contact the PI in case of any uncertainty to ensure consistency in administration of the questionnaire.The questionnaire was distributed to pharmacists from 431 randomly selected community and hospital pharmacies located in cities in the 12 governorates of Jordan. There were no exclusion criteria. The population frame was obtained as a list of all operating pharmacies  in the twelve governorates of Jordan. The list was provided by the Jordan Pharmacy Syndicate. Data were collected in February, 2018. Participating pharmacists were requested to sign an informed consent before responding to the questionnaire.p = 0.000).The data collection tool was evaluated by an expert in the field of pharmacy practice and piloting. A pilot test of the 26-item questionnaire was conducted in 30 pharmacies that were randomly-selected. The results from the pilot study were evaluated and used to modify the data collection tool before starting the main data collection period. Statistical confirmation of validity and reliability was achieved through the calculation of Cronbach’ Alpha value which was found to be 0.907 indicating consistency of the tool. Sampling adequacy was also confirmed using Principal Components Analysis (PCA) with Kaiser-Meyer-Olkin (KMO) equal to 0.841 and a significant Bartlett’s Test  described in Buurma et al.  and ZaidCategorical data were presented as frequency and percentages, while continuous data were presented as median and interquartile ranges.P-value of < 0.05 was considered significant. Data analysis was performed using SPSS® 23.0 .Bivariate analysis was used to test the differences among the variables that affect the compounding of extemporaneous drug preparations. Chi-square or Mann-Whitney tests were used to detect differences between different determinants. Logistic regression was used to evaluate the strength of association of factors that significantly determine the characteristics of compounding in the bivariate analysis. All hypothesis testing was two-sided. A The data collection team approached 444 community and hospital pharmacies. Invitation to participate in this study was accepted by 431 (97.1%) pharmacies. A total of 408 community pharmacies  and 23 Demographics and basic characteristics of the participating pharmacies are presented in Table Table p = 0.000). The number of pharmacists , the number of personnel  and the average number of daily prescriptions received by the pharmacy  were significantly associated with this service provision. While the type of pharmacy being hospital or community pharmacy and being part of a chain or not showed no association with compounding services provision.Factors that showed significant baseline differences between compounding and non-compounding pharmacies were entered into model testing using logistic regression to test for significant association with the decision of the pharmacy to provide compounding service. As shown in Table Table About half of pharmacies have mortars, pestles, spatula, and scales, and almost one third of pharmacies have funnels, flasks, beakers, measuring cylinders, and glass rods Table .The main source of references for compounding protocols were the physician’s order in 210 (94.2%) of the cases, and protocols developed by the pharmacy in 100 (44.8%) of the respondent pharmacies. The main source for estimation of the expiration date for compounded medications was based on pharmacist’s experience  and physician’s order . In 67 (30%) of the compounding pharmacies, expiration date was not provided for compounded medications but 217 (97.3%) of these pharmacies attach label to their compounded products. The expiration date included on the label was determined based on either in-house practice or physician’s order in 149 (66.8%) and 146 (65.5%) of the compounding pharmacies, respectively.In 377 (75.8%) of the compounding pharmacies, no compounding records were kept, and 34 (63%) of these records were hand-written. No pharmacy performed quality control tests of the compounded products.The current study addressed the prevalence, determinants, and characteristics of extemporaneous compounding and compounded products in both community and hospital pharmacies in Jordan. The present study is the first report in Jordan and one of few in the world that present the baseline data on extemporaneous compounding. Several important outcomes that emerged from this study can be used in the improvement of pharmacy practice.The high prevalence of the compounding practice in community pharmacies emphasizes the need of proper education and training of pharmacy students in extemporaneous compounding. There is also a clear need to incorporate extemporaneous compounding in professional development and continued education programs offered by the Jordanian Pharmacy Syndicate and the Jordanian Pharmacy Board. Results from this study also show the critical need for implementation of quality testing of compounded products and standardized regulations to ensure safe compounding practices.Data from this study show that 52% of Jordanian pharmacies perform compounding which is less than the percentage (add this percentage) reported in USA , 19, TheSeveral factors can play a role in the pharmacy’s decision to offer compounding services. These factors include the availability of the staff (both pharmacists and personnel) and the number of all prescriptions received and filled by the pharmacy. Pharmacies with a higher number of pharmacists reported making more compounded preparations. The time and efforts required to develop and manage extemporaneous compounding service are critical factors that influence the prevalence of compounding in Jordanian pharmacies. This issue has been addressed in Dutch community pharmacies by preparing a large part of compounded medications from semi-manufactured or almost finished products provided by specialized firms. Such products require minimal work to be finished at the pharmacy .As would be expected, the number of all prescriptions filled by the pharmacy correlates directly with the compounding services. However, some pharmacies with a long tradition in providing compounding services were observed to have a disproportionately higher number of compounding order to their overall number of prescriptions filled daily.Dermatologists were reported to be the prescribers of compounding orders by 98.2% of the compounding pharmacies in Jordan. They were ahead of other specialties by a large margin. This is in agreement with data from previously reported study on top indications for extemporaneously compounded products  and coulThe fact that community pharmacies were more involved extemporaneous compounding could be understood in the context that most of the compounded dosage forms are creams and ointments and the main prescriber specialty group was “Dermatologists”. Most health complaints addressed by dermatologists do not require hospitalization and prescriptions are often filled by community rather than hospital pharmacies.Pediatricians were the second highest specialists in terms of requesting compounded products with 18.4% of the compounding pharmacies reporting receiving orders for compounding from pediatricians. Buurma and colleagues reported that patients less than 12 years old received more extemporaneously prepared medications than other age groups .Solutions were the third most commonly compounded dosage form (23.3%) in Jordanian compounding pharmacies.Previously reported studies showed that patient-centered pharmaceutical care is the main reason for pharmacists to provide compounded medications , 6. PharAs shown in this study, the main reasons for requesting and providing compounding services is the unavailability of the required medications or a specific dosage form (87.9%) and the unavailability of the required dose (68.2%). An earlier study has linked the reasons for compounding with the specialty of the prescriber with dermatologists being reported to order combinations that are usually unavailable commercially and pediatricians requiring patients-tailored dosage strengths .The majority of pharmacies participating in this study stated lack of prescriptions for extemporaneously compounded products as a key reason for not providing compounding services. Zaid et al.  and McPhIn general, sterile compounding was not performed in pharmacies participating in this study. This can be explained by the fact that compounding of sterile products is expensive because it requires sterile environment, specific procedures and equipment. Improper preparation of sterile compounded preparations may easily lead to contaminated product .Buurma and colleagues reported that in 42% of the cases, pharmacies did not use a standardized or semi-standardized protocol . The curMoreover, the study uncovers the lack of documentation and quality assurance of the compounded product, although 24.2% of pharmacies keep records for their products and considerable number of pharmacists seeks patients’ feedback on their products. Despite of all of this, there is a need for agreed on protocols that cover procedures, labelling including expiry date, and quality control tests that should be followed and guaranteed during extemporaneous compounding to assure effectiveness and quality of the final product and improve the physicians as well as patients’ confidence in these products.The main limitation of this study is the difference in the number of community (408) and hospital pharmacies (23) included in the study. However, it is worth noting that we tried to include a similar proportion of community (18.1%) and hospital (21.7%) pharmacies of all those operating in Jordan. Another limitation is the fact that this study did not cover the compounding practice from the perspective of prescribers and patients. This includes the study of drivers for prescribing compounded products and the patients’ experience with the compounding services offered by pharmacies. We are attempting to cover this aspect in a future study.The data presented in this study was presented to and discussed with faculty members at the School of Pharmacy, University of Jordan in order to modify curriculum to better cover procedures, labelling including expiry date, and quality control tests that should be followed and guaranteed during extemporaneous compounding to assure effectiveness and quality of the final product and improve the physicians as well as patients’ confidence in these products. In addition, a plan was developed for offering a continuing education program to practicing pharmacists in collaboration with the Jordanian Pharmacists Syndicate in the area of best practices in extemporaneous compounding.Extemporaneous compounding is a widely spread pharmaceutical practice among community pharmacies in Jordan. Ointments and creams are the most commonly prescribed and compounded extemporaneous products. A higher number of pharmacists, pharmacy personnel and the total number of prescriptions were significantly associated with a higher number of extemporaneous products compounded. The lack of standardized procedures for preparing extemporaneous products, scientific basis for determination of expiration date of compounded products, and lack of quality control testing prompts an action.Additional file 1. Extemporaneous Compounding In Jordanian Pharmacies Survey .


Magnetic resonance imaging (MRI) is the method of choice for imaging meningiomas. Volumetric assessment of meningiomas is highly relevant for therapy planning and monitoring. We used a multiparametric deep-learning model (DLM) on routine MRI data including images from diverse referring institutions to investigate DLM performance in automated detection and segmentation of meningiomas in comparison to manual segmentations.n = 38) or grade II (n = 18). The DLM was trained on an independent dataset of 249 glioma cases and segmented different tumour classes as defined in the brain tumour image segmentation benchmark (BRATS benchmark). The DLM was based on the DeepMedic architecture. Results were compared to manual segmentations by two radiologists in a consensus reading in FLAIR and T1CE.We included 56 of 136 consecutive preoperative MRI datasets  of meningiomas that were treated surgically at the University Hospital Cologne and graded histologically as tumour grade I  for the total tumour volume (union of tumour volume in FLAIR and T1CE) and 0.78 ± 0.19  for contrast-enhancing tumour volume in T1CE.The DLM yielded accurate automated detection and segmentation of meningioma tissue despite diverse scanner data and thereby may improve and facilitate therapy planning as well as monitoring of this highly frequent tumour entity.• Deep learning allows for accurate meningioma detection and segmentation• Deep learning helps clinicians to assess patients with meningiomas• Meningioma monitoring and treatment planning can be improvedThe online version of this article (10.1007/s00330-018-5595-8) contains supplementary material, which is available to authorized users. Meningiomas are neoplasms originating from meningothelial cells and are among the most common intracranial neoplasms with an incidence of 0.9% in routine brain magnetic resonance imaging (MRI) –5. AlmosMRI is the key method for diagnosis and characterisation of meningiomas, resection planning, therapy decisions and monitoring of therapy , 7, 10. To the best of our knowledge, there are no studies regarding the fully automated detection and segmentation of meningiomas to date. As tumour progression of meningiomas is commonly slow, multifocal and occurring in different directions, an automated detection of meningiomas might facilitate and improve image reading. Regarding the manual volumetric assessment of meningiomas in MRI, it has been shown that three-dimensional assessments provide an increased sensitivity for the detection of tumour progression in comparison to two-dimensional assessments , 12. TheIn contrast, automated detection and segmentation of meningiomas in MRI may be performed as pre-processing before reading the images, possibly allowing for a more detailed analysis of tumour volumes and further multiparametric image analysis. Furthermore, automated tumour segmentation and evaluation may lead to an increased robustness and reliability due to reduced inter-reader bias . As the Automatic brain tumour segmentation algorithms should address several challenges to be reliable, such as anatomical variations, varying imaging data due to different MRI scanners as well as variations in scanner parameters. Further, pathologies such as brain tumours vary strongly in their presentation , 14. TheThe purpose of this study was to investigate the reliability of automated detection and segmentation of grade I and II meningiomas using a deep learning model on routine multiparametric MRI data from diverse scanners including referring institutions.n = 3), (2) severe leukoencephalopathy impairing the FLAIR tumour segmentation  and (3) strong artefacts due to patient movement (n = 2). Fifty-six patients fulfilled all criteria and were included in this study.This study was approved by the local institutional review board. One hundred and thirty-six patients that were referred to the University Hospital of Cologne from January 2012 to May 2016 for treatment of meningiomas were included in this retrospective study  Siemens MRI models: Avanto, Espree, Aera, Verio, Essenza , (2) Toshiba Titan  and (3) Philips MRI models: Panorama, Intera, Achieva, Ingenia  and on local scanners from the University Hospital of Cologne . MRI scan parameters are given in Supplementary Table SAll scans were conducted for clinical indications. The MRI acquisitions were performed on diverse scanners from referring institutions  was performed by two radiologists in a consensus reading using IntelliSpace Discovery . Contrast-enhancing tumour and FLAIR isointense to hyperintense tumour as well as surrounding hyperintense oedema were defined as tumour volume and segmented separately in T1CE and FLAIR images. Total tumour volume (TTV) was defined as the union of tumour volumes in T1CE and FLAIR, including solid contrast-enhancing tumour parts, surrounding oedema in FLAIR and if present tumour necrosis. T1CE tumour volume was defined as contrast-enhancing tumour volume in T1CE images.The DLM for automated detection and segmentation was trained on an independent dataset of 249 glioma cases. The DLM preforms voxel-wise classifications of four tumour classes  as defined in the BRATS benchmark .3 and (4) normalisation to zero-mean and standard deviation of one. The DLM was based on the DeepMedic architecture [MR images were pre-processed with established tools  before feeding into automatic segmentation. The processing pipeline included (1) bias field correction, (2) co-registration, (3) skull stripping, (4) resampling to isotropic resolution of 1 × 1 × 1 mmitecture  using a p < 0.05.Statistical analyses were conducted using JMP Software . Quantitative results are displayed as mean (± standard deviation). Wilcoxon signed rank test was used for the determination of statistical differences. Statistical significance was set to To evaluate automatic segmentation, the resulting tumour volumes were compared to the manual ground truth annotations. For TTV and T1CE TV, segmentations were compared with respect to volume and voxel-wise accuracy. As before, the accuracy was computed as overlap of ground truth segmentation S1 and model segmentation S2 using the Dice coefficient (similarity index) :\documenn = 6), convexity (n = 24), sphenoid wing (n = 9), olfactory groove (n = 4), suprasellar (n = 2), posterior fossa (n = 10) and with attachment to the sinus (n = 1).The 56 adult patients included 28 women and 28 men with a mean age of 59.1 ± 13.7 years . Thirty-eight patients had a grade I meningioma and 18 patients a grade II meningioma, including meningiomas of the falx  with a rather small tumour size of 12.7 cmp > 0.05). Further, Dice coefficients did not differ significantly between grade I and II meningiomas. For TTV, the mean Dice coefficient was 0.80 ± 0.11 for grade I and 0.83 ± 0.07 for grade II meningiomas. Mean Dice coefficient for T1CE tumour volume was 0.76 ± 0.21 for grade I and 0.83 ± 0.11 for grade II meningiomas.Manual segmentation and automated deep-learning-based segmentation correlated well regarding TTV and contrast enhancing tumour volume. The mean Dice coefficient for TTV was 0.81 ± 0.10  and 0.78 ± 0.19 for T1CE tumour volume . There was no significant difference between Dice coefficients of TTV and T1CE TV  either for TTV or T1CE. In three patients Dice coefficients in both TTV and T1CE were 0.90 or better. A patient with a meningioma grade II in the left frontal lobe with surrounding oedema showed best automated segmentation with Dice coefficients of 0.92 for TTV and 0.95 for T1CE TV Fig. .Fig. 3A In some patients automated segmentation did not perform appropriately and resulted in Dice coefficients below 0.70. This was mostly the case either for TTV or T1CE tumour volume. Dice coefficients below 0.70 were obtained in three cases for TTV and nine cases for T1CE TV. Only in one patient with a small paramedian meningioma grade I at the os sphenoidale without surrounding oedema both TTV (0.52) and T1CE tumour volume (0.58) showed Dice coefficients below 0.70 Fig. .Fig. 4A In the 16 meningiomas that were attached to the skull base, automated segmentation appeared to perform slightly worse than for meningiomas situated at the convexity of the skull, however without significance of differences. Mean Dice coefficients for TTV were 0.78 ± 0.12 for meningiomas at the skull base and 0.82 ± 0.08 for meningiomas situated at the convexity of the skull. For T1CE tumour volume mean Dice coefficients were 0.73 ± 0.23 at the skull base and 0.81 ± 0.15 at the convexity of the skull.This study investigated automated detection and segmentation of meningiomas by DLM. The method proved to allow for accurate detection and segmentation, even though diverse MR images from different scanners, including data from referring institutions (66% of the available images) were included in this study. Detection accuracy was high (>98%). Automated segmentation correlated well with manual segmentations. Overlap measured by Dice coefficients was high for TTV and for T1CE TV . These results are comparable with other recently published studies in brain lesion segmentation using deep learning , 28–31 aThe accurate automated detection of a cerebral tumour, as presented in our study, is clinically relevant as it allows for a preselection of lesions and patients of priority and as a control mechanism for the radiologist as a computer-assisted device , 36–39. The applied DLM was trained on glioma imaging data. Despite different appearances of the two tumour entities, detection and segmentation accuracies were high. Gliomas consist of contrast-enhancing tumour parts, necrosis and surrounding oedema and are quite varied. In contrast, meningiomas present as solid contrast-enhancing tumours with surrounding oedema and necrosis is less common. Meningiomas tend to show less complex tumour structures than, for example, glioblastomas and it could therefore be argued that classification accuracies should be higher. But there are several challenging aspects that make segmentation of meningiomas also difficult: (1) surrounding oedema in FLAIR may result in complex tumour structures, as can be seen in Fig. This study has several limitations that need to be considered beyond the retrospective study design. Since the study tests the segmentation of known meningiomas, the study does not test the accuracy for the detection of meningiomas in general. Also, it was not tested how far the DLM would segment false-positive tumour volume in normal brain MRI. Further, the presented segmentation accuracies between automated and manual segmentations might still be too preliminary for clinical applications and should be evaluated in future studies. The relatively small amount of cases may not reflect all types and sizes of meningiomas. The available image data were quite diverse as they included examinations from referring institutions. Further, gliomas were used as training data for the DLM; however, the study aimed to evaluate to what extent automated detection and segmentation was possible despite difference in training and despite heterogenic imaging data, as would appear in clinical routine. The study did not aim to present a DLM specifically designed for meningioma segmentation. Nevertheless, we plan to adapt the applied DLM with the manual meningioma segmentations as training data to yield improved results in future studies.Automated detection and segmentation of meningiomas based on a DLM were accurate and reliable. Precise and standardised TV definition allows for a more sensitive detection of tumour growth and thereby may improve monitoring and treatment of this highly frequent tumour entity. Further, automated detection by machine learning could function as a useful tool for pre-assessing and preselection as well as a control mechanism for radiologists.ESM 1(DOCX 21 kb)


Compared with clinically functioning pituitary adenoma (FPA), clinically non-functioning pituitary adenoma (NFPA) lacks of detectable hypersecreting serum hormones and related symptoms which make it difficult to predict the prognosis and monitoring for postoperative tumour regrowth. We aim to investigate whether the expression of selected tumour-related proteins and clinical features could be used as tumour markers to effectively predict the regrowth of NFPA.Tumour samples were collected from 295 patients with NFPA from Beijing Tiantan Hospital. The expression levels of 41 tumour-associated proteins were assessed using tissue microarray analyses. Clinical characteristics were analysed via univariate and multivariate logistic regression analyses. Logistic regression algorithm was applied to build a prediction model based on the expression levels of selected proteins and clinical signatures, which was then assessed in the testing set.Three proteins and two clinical signatures were confirmed to be significantly related to the regrowth of NFPA, including cyclin-dependent kinase inhibitor 2A (CDKN2A/p16), WNT inhibitory factor 1 (WIF1), tumour growth factor beta (TGF-β), age and tumour volume. A prediction model was generated on the training set, which achieved a fivefold predictive accuracy of 81.2%. The prediction ability was validated on the testing set with an accuracy of 83.9%. The area under the receiver operating characteristic curves (AUC) for the signatures were 0.895 and 0.881 in the training and testing sets, respectively.The prediction model could effectively predict the regrowth of NFPA, which may facilitate the prognostic evaluation and guide early interventions.The online version of this article (10.1186/s12967-019-1915-2) contains supplementary material, which is available to authorized users. Pituitary adenoma (PA) constitutes approximately 15% of all intracranial neoplasm , 3. SurgFew systematic reports have discussed the prediction of the regrowth possibility of NFPA using statistical prediction models. In this study, we identified 41 key proteins whose expression were related to tumorigenesis and progression of pituitary adenoma. We then established a regrowth prediction model with two clinical signatures and three tumour-associated proteins whose expression levels were varied in NFPA. The main purpose of our study was to determine whether we could build a prediction model and validate its authenticity. Our study may facilitate the prognostic evaluation and early intervention to patients with NFPA.We retrospectively collected regrowth and non-regrowth tissue from 295 patients diagnosed with NFPA at Beijing Tiantan Hospital from April 2006 to September 2014. All patients were performed enhanced head MRI scan before and after surgery in order to assess tumour volume, Knosp classification and tumour resection grade. The minimum follow-up time was 36 months, and the average follow-up time was 86.5 months (range 36–137 months). Regrowth of NFPA was defined as a tumour maximum diameter increases from any direction on MRI of more than 2 mm from the day of surgery to follow-up endpoint with or without the reappearance of visual disturbance, headache or hypopituitarism.NFPA samples were stored and fixed in 10% neutral-buffered formalin immediately upon removal from the sellar region and then embedded in paraffin. Specimen slides stained with hematoxylin and eosin (H&E) were viewed by two different pathologists, who marked the tumour tissues on the samples.Two 2.0-mm diameter samples were removed then transferred to a recipient paraffin block to construct TMAs using a Tissue Array MiniCore 3 . Samples (4-µm thick) were obtained from each TMA with Leica Rotary Microtome RM2135 . Immunohistochemical staining was performed on Leica BOND III automated system. All samples were pretreated in a 65 °C oven for 1.5 h. Staining was performed with dewaxing and epitope retrieval. Samples were blocked with peroxide solution for 7 min. Selected antibodies  that were valuable  including the previous 14 proteins ], Dopamine receptor DBased on the 14 candidate protein signatures from the intersection of significant proteins in the differential analyses and survival analyses, a logistic regression analysis was used to screen the most likely candidate factors for tumour regrowth . Age, Knosp grade, tumour volume and tumour resection rate were found to be correlated with regrowth (P < 0.05).We preliminarily selected sex, age , tumour volume , tumour resection rate  and Knosp grade  as candidate clinical predictors for the prediction of tumour regrowth. All of the selected clinical characteristics were categorical variables. The clinical factors that were statistically significantly associated with the regrowth of NFPA are shown in Table P < 0.01) and tumour volume (P = 0.01) were independent risk factors of regrowth /(1 + exp(Y)). In our classification model, the cut-off score was set at 0.5. When the discriminant score P was calculated to be less than 0.5, the patient was classified as a non-regrowth case, the case was predicted to be a regrowth.During the training phase, a fivefold cross-validation accuracy was used to assess the unbiased performance of the logistic regression-based classifier in distinguishing regrowth and non-regrowth patients. For the training set of 186 fivefold cross-validation cases, the combined signature provided an overall accuracy of 81.2% (151 of 186), in which 36 of 61 regrowth cases and 115 of 125 non-regrowth cases were correctly predicted Fig. a. The fiP < 0.001, Fig. P < 0.001, Fig. The ROC analyses were used to assess the sensitivity and specificity of the regrowth prediction. Our classification model based on the combination of clinical and protein signatures showed a good sensitivity and specificity for regrowth prediction with an AUC of 0.895 in the training set , thyroid-stimulating hormone (TSH), growth hormone (GH) and prolactin (PRL) . The serIn an attempt to identify proteins that allow us to establish a reliable NFPA regrowth prediction model, we started by screening the key papers of pituitary adenoma to identify 41 tumour related proteins. We then narrowed the set to 14 proteins with differential protein expression and Kaplan–Meier analyses. The final three protein signatures including p16, WIF1 and TGF-β were validated via logistic regression analyses with the p values less than 0.05. They were adopted to build the prediction model in which low expression levels were related to regrowth in our analyses. As far as their biological functions are concerned, low expression level of p16 and WIF1 is observed in pituitary tumorigenesis and is necessary for tumour progression, the methylation of their promoters indicates a poor prognosis –11. The Previous researchers have taken attempt to predict regrowth with clinical features, but they have not reached a consensus in this respect. Tumour residue has always been considered as a risk factor for regrowth because either trans-sphenoidal surgery or open surgery has difficulties in removing tumour invading cavernous sinus and most patients faced with regrowth in around 5 years , 14. HowKnosp grade is a pivotal factor in clinical treatment because of its instruction to surgical resection. However, its significance in tumour regrowth is quite controvertible –17. Our The potential of age as a risk factor for tumour regrowth deserves some consideration. Several studies have reported that younger age to be strongly correlated with regrowth either in relation to residue or as an independent risk factor , 18, 19.In recent years, new genetic markers researches including cell-free nucleic acids or long noncoding RNA have been increasingly reported in a variety of tumour, suggesting a promising new class of molecular markers for tumour diagnosis and prognostic evaluation –23. HoweTo our knowledge, our study is the first to establish a promising statistical model to predict the regrowth of NFPA with clinical and protein signatures. This work provides a novel insight into prognostic evaluation and may help patients to benefit from accurate early intervention.Additional file 1: Table S1. Antibody information involved in the research.Additional file 2: Table S2. P values of 41 tumour related proteins in differential and Kaplan–Meier analyses.