SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice. SDHA likely pathogenic or pathogenic germline variants  are identified in up to 10% of patients with phaeochromocytoma and paraganglioma (PPGL) and can account for up to 50% of SDH-deficient wild-type gastrointestinal stromal tumours (wtGISTs) or up to 30% of wtGIST.SDHA (henceforth referred to as SDHA PGV carriers) present with an apparently sporadic tumour without relevant family history, and most PGVs are inherited from a parent who has not presented with any clinical features.SDHA PGV carriers and 56 non-index SDHA PGV carriers, highlighted that the tumour penetrance is low in non-index SDHA PGV carriers, with penetrance at age 70 years estimated to be 10%.SDHA PGV carriers was estimated as 39% at 40 years of age in a prospective study of a population-based registry of patients with PPGL, there was a significant difference in index patients  versus SDHA carrier relatives .SDHA PGVs in EXAC data and patients with PGL and in a cohort of SDHA PGV carriers (~0.1%–4.9%).SDHA NM_004168.4: c.91C>T p.(Arg31*) accounts for a large proportion of known carriers and also occurs at frequency of 0.04% (53/128 900) in non-Finnish Europeans .SDHA c.91C>T p.(Arg31*) has a different penetrance to any other SDHA PGVs and variant specific management is not advocated by other groups.A large study of patients with paraganglioma (PGL) from the Netherlands, including 30 index SDHA PGV carriers will not manifest SDHA-related tumours, thus calling into question the clinical utility of surveillance in this low-risk group, probands with SDHA-related tumours and confirmed SDHA PGVs typically present at young ages , a surveillance protocol for SDHA PGV carriers was agreed consisting of annual clinical review and biochemistry with abdominal imaging and MRI neck, thorax, abdomen and pelvis at baseline, followed by 3–5 yearly imaging, based on published recommendations and expert opinion.At the UKCGG (UK Cancer Genetics Group) Consensus meeting in Cambridge in Spring 2019 .SDHA PGVs may potentially contribute to a wider phenotypic tumour spectrum, current evidence for further clear associations beyond the tumours defined in For these recommendations, it was agreed to define clear ‘on-target’ SDHA c.91C>T p.(Arg31*), provided other causes have been excluded or there is appropriate immunohistochemical evidence .In most situations within current UK clinical practice, germline SDHA PGVs may also be identified in off-tumour settings, that is, in individuals with tumours not listed in However, with increasing use of large germline cancer predisposition gene panels, large somatic solid tumour panels and paired whole-genome sequencing (WGS), SDHA PGV is identified during tumour analysis, the likelihood of it being of germline origin is high in both on-tumour (associated tumour types) and off-tumour (non-associated tumour types) settings. Where an SDHA pathogenic variant has been identified in tumour tissue, germline testing has been recommended by the European Society of Medical Oncology Precision Medicine Working Group.SDHA PGV in an individual with a non-SDHA-associated tumour could be considered a secondary or incidental finding. ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing, which are supported and followed within UK practice, suggest that these findings are not reported.When an SDHA PGV is identified in an individual with cancer but in an off-tumour setting, for example, through WGS or extended gene panel testing, that the PGV is reported but coupled with a recommendation that SDH immunohistochemistry (IHC) is performed and the finding considered to be a non-actionable secondary finding unless there is immunohistochemical evidence of SDHB/SDHA protein loss or a family history of SDHA-associated tumours .The working group felt that due to the low penetrance of  members . Should SDHA PGV may be identified. ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing, which are supported and followed within UK practice, suggest that these findings are not reported.In some situations where an individual has had germline genetic testing for another indication but does not have a personal history of cancer, an SDHA PGV carrier with an SDHA-associated tumour, with respect to the primary tumour, we would recommend at the very least annual clinical examination to include blood pressure assessment and biochemistry to include plasma metanephrines, combined with imaging of the original tumour region  if complete resection was achieved. Ongoing follow-up, surveillance and discharge for their original diagnosis should be determined by multidisciplinary team decision depending on the clinical details and consideration of relevant published guidelines for the follow-up of PPGL.For an SDHA PGV. However, metachronous tumours have been reported, in single case reports and in 4 out of 21 index cases in a study from the Netherlands.There are minimal data on the occurrence of a second tumour in individuals with an With regards to ongoing surveillance for metachronous tumours, based on UKCGG Consensus guidelines,The UKCGG guidelines did not make recommendations for pituitary surveillance. This is in part due to the low penetrance for pituitary adenoma, but also the relatively high rate of incidental detection of non-functional microadenoma, estimated to be 10% or greater in a healthy population.SDHA in non-probands is likely to be low: 10%–13% lifetime risk in two studies.SDHA-associated tumour may be low. However, patients can present with aggressive and metastatic disease which may be avoided by early detection. The lifetime penetrance in non-proband family members is also higher than in penetrance estimates from comparing SDHA allele frequencies in affected individuals and population controls, ~2%.A limited number of small studies have demonstrated that the penetrance of The survey of UK Geneticists and Endocrinologists suggested that at present while there is recognition that the cancer risk for non-proband family members may be low, it was felt that the data in this area are limited and there was concern about not discussing predictive testing with family members. There was agreement that while there are limited data available, predictive testing and surveillance should be discussed within the context of our current knowledge, but that this should be reviewed as and when new data on penetrance and effectiveness of surveillance are available.SDHA PGV has been identified in an individual with an SDHA-associated tumour  from age 10.Radiological surveillance every 3–5 years of neck, thorax, abdomen and pelvis, preferably with MRI from age 15. Where possible, imaging is best performed in centres with experience of surveillance for PPGL. Ultrasound is not recommended.SDHA PGV carriers affected with SDHA-associated tumours section).Routine pituitary imaging is not recommended (see also Recommendation 4: surveillance for These recommendations are in line with recently published international consensus guidelines for SDHx PGV carriers, who also advise that by the age of 70 years, if individuals are well with no tumours, the interval of imaging can be increased to 5 yearly until age 80 and then stopped if well.SDHA PGVs. Therefore, there is a critical need for systematic prospective data collection to address this and the outcomes of surveillance.It was recognised that there is currently limited knowledge regarding the full phenotype and penetrance of tumours in individuals with It was also recognised that there has been inconsistency in practice across the country, and it is hoped that these recommendations will help to address this. To improve patient understanding, development of a national patient leaflet is planned to both highlight the uncertainty regarding true cancer risk for this patient group, the pros and cons of predictive testing and surveillance and education on symptoms.Given the uncertainties and lack of data highlighted in this report, the working group recommend that:SDHA PGVs identified with SDHA-associated and SDHA non-associated tumours and consider if specific genetic or environmental factors alter the penetrance in SDHA carriers.Prospective research studies and/or service evaluations are undertaken to define of the natural history of individuals with SDHA PGV carrier probands and non-probands are carefully documented and evaluated.The outcomes and clinical utility of surveillance in Novel means of early detection are sought to reduce burden on radiology departments.The opinions and preferences of patient groups are canvassed.


The temocillin AUC in ascitic fluid was 46% of the plasma AUC. Plasma unbound concentrations were best described by a two-compartment model, and an additional compartment was added to describe unbound concentration in ascitic fluid, with renal clearance as a covariate. Dosing simulations showed that 90% PTA was achieved in the plasma with the current dosing regimen for MIC ≤ 16 mg/L (EUCAST susceptibility breakpoint) but not in the ascitic fluid if renal clearance was ≥40 mL/min. Hypothetical dosing with a higher (a) loading dose or (b) infused dose allowed to reach target concentrations in ascitic fluid (a) more rapidly or (b) sustainably, but these simulations need to be evaluated in the clinics for safety and efficacy. Temocillin is active against Gram-negative bacteria, including many extended-spectrum β-lactamase (ESBL)-producing Enterobacterales. We studied its pharmacokinetics in plasma and ascitic fluid after intravenous administration of a loading dose of 2 g over 30 min, followed by continuous infusion of 6 g/24 h, to 19 critically-ill patients with septic shock associated with complicated intra-abdominal infection. We established a pharmacokinetic model describing unbound temocillin concentrations in plasma and ascitic fluid and performed Monte-Carlo simulations to evaluate the probability of target attainment (PTA) of unbound concentrations (100%  Intra-abdominal infections (IAI) in critically-ill patients are associated with high morbidity and mortality, making their treatment highly challenging . ChangesAdvanced generation β-lactams are often first-line therapies for critically-ill patients based on their broad-spectrum, low toxicity, and high activity on Gram-negative bacteria , which rTemocillin (6-methoxy-ticarcillin) is a β-lactam antibiotic active, among others, against Enterobacterales ,15. The ƒT > MIC) [For β-lactam antibiotics, the PK/PD parameter driving efficacy consists of the time interval during which the unbound concentrations remain above the MIC against the target microorganisms (T > MIC) , but theT > MIC) . For higT > MIC) ,28,29. IT > MIC) ,31 plasmT > MIC) ,32 to a T > MIC) . A previT > MIC) . Yet, inT > MIC) . More spHowever, there are so far no data regarding the penetration of temocillin in the ascitic fluid. In other fluids, temocillin penetration usually reaches values ranging from 8–15%  to 50–7fT > MIC) was then estimated for MICs of 8 or 16 mg/L  and relDemographic and biological data are presented in Escherichia coli (n = 20) and Klebsiella spp. (n = 10) were the most frequent  and the unbound  concentrations as well as between the unbound plasma AUC of and the total AUC in ascitic fluid   .PK modelling was performed using the data from the 114 plasma and ascitic fluid unbound concentrations. We limited our modeling to the study of the unbound concentrations, which are considered responsible for antimicrobial activity. The structure of the final covariate model is presented in CRurinary/39.9) where CLi is the population estimate of temocillin clearance from the central compartment, and CL is the individual estimate of temocillin clearance from the central compartment) for a given patient and was linearly related to urinary creatinine clearance (CLCRurinary) . Model diagnostics and selection criteria are presented in The plasma unbound concentration of temocillin was best described by a two-compartment model, as previously published , and an urinary) . CLCRuri2 values between 0 and 0.24). No linear relationship was observed between weight, age, plasma proteins, or albumin and CL30, neither between CL30 and Vd, Cli, or CLs (R2 with Error = (SD + L2)0.5, where L (lambda factor) is the process noise associated with the observations. The final Lambda (L) error factor was set at 2.26 for the residual unexplained source of variability. Residual error or uncertainty associated with the assay was best described by first-order polynomial functions: SD = 0.1 + 0.1Y, where SD is the standard deviation of measured temocillin concentrations (Y), for both plasma and ascitic fluid. The population PK parameter estimates for the final model are presented in For the error model, each observation was weighted by 1/Errorp = 0.714; Shapiro–Wilk test, p = 0.514; Kolmogorov-Smirnov test, p = 0.096 for plasma temocillin and D’Agostino test, p = 0.371; Shapiro–Wilk test, p = 0.041; Kolmogorov-Smirnov test, p = 0.797 for ascitic fluid temocillin). The visual predictive check plots, which highlight the performance, robustness, and acceptable agreement between the predicted and observed unbound concentrations of temocillin in plasma and ascitic fluid over the dosing interval, are presented in Visual inspection of the residual plots is shown in fT > target MIC of unbound temocillin in plasma and in ascitic fluid for different simulated dosing regimens of temocillin in representative patients with septic shock and IAI (with a CLCRUrinary of 39.9 mL/min) are illustrated in The PTA for achieving 100% CRurinary was associated with a reduced PTA in ascitic fluid, but with no major impact in plasma  and (3)) and for MICs < 4 mg/L when the loading dose was increased to 4 g (regimen (2)) a. Duringn plasma . This study is the first to describe the pharmacokinetics of temocillin administered by continuous infusion in plasma and ascitic fluid from patients with septic shock associated with IAI and ascitic fluid effusion. Our main conclusion is that an infusion of 6 g/24 h after a loading dose of 2 g allows for maintaining the unbound temocillin concentration in the plasma above a MIC of 16 mg/L 100% of the time whereas, in the ascitic fluid, this regimen seems to be adequate only for patients with altered renal function. In addition, a series of observations with clinical implications have been made. First, the direct examination of individual pharmacokinetic profiles reveals high variability in the total and unbound concentrations reached both in the plasma and in the ascitic fluid, not only between patients but also over time in a given individual patient, in spite of the fact they all received the same dose by continuous infusion. This variability was also found in the population PK model constructed from these data. The PK profile of unbound temocillin was best described by a two-compartment model with an additional distribution/elimination compartment corresponding to ascitic fluid. The inter-individual variation was greater than 50% for inter-compartmental clearances as well as for the volume of distribution of the ascitic fluid compartment. This variation was expected and is in the line of previous observations with continuous infusion of temocillin or other antibiotics in critically-ill patients. It might be explained by the variability and instability of the patient’s pathophysiological and biochemical characteristics over time ,45. For Second, temocillin adequately penetrates the ascitic fluid, with an ascitic fluid/plasma AUCs ratio of 46%; this is slightly lower than that previously reported for ceftazidime (67%) or ceftriaxone (63%) in patients with cirrhosis or peritoneal carcinoma but normal renal function  or for tWhen comparing this penetration in ascitic fluid with that reported in a series of other body fluids  was excellent when given as a continuous infusion (CI) of 6 g/24 h after a loading dose of 2 g; regimen (1)), leading to a PTA ≥ 88% considering a pharmacodynamic target of unbound concentration above a MIC ≤ 16 mg/L 100% of the time. This target was, however, not reached over the first 24 h, or during the first 12 h even if doubling the loading dose (regimen (2)). This could be problematic, as an early effective treatment increases the chance of clinical success [CRurinary, but would also generate sustained total plasma concentrations higher than the current peak level measured after discontinuous infusion, requiring prior in-depth safety assessment. Of note, a large proportion (72%) of the isolates had MICs ≤ 8 mg/L, allowing them to reach the pharmacodynamic target with the regimen (1) for CLCRurinary < 90 mL/min. In this context, it is interesting to note that microbial eradication was obtained in 84% of the patients. Monte Carlo simulations showed that exposure to temocillin in the ascitic fluid of a representative patient (CL regimen ), leadin success ,56,57. TIn contrast, in the plasma, unbound concentrations, which are higher than those measured in ascitic fluid, allow reaching the pharmacodynamic target for MIC ≤ 16 mg/L with the conventional dosing regimen (1), whatever the renal function of the patient, as observed in a previous cohort of critically-ill patients . ImportaWe acknowledge some limitations of this work. The number of included patients remained limited but was still sufficient to establish a valid population PK model and run robust Monte-Carlo simulations. However, the study protocol did not anticipate dose adjustments based on PK data and we were not able to test our recommendations. Moreover, the study was not powered enough to evaluate the treatment’s clinical efficacy and to correlate it with PK/PD markers. Nevertheless, our data might help in guiding the design of further studies by taking these limitations into account.CRUrinary. The currently used regimen  allows to achieve adequate PTA for isolates with MICs below the EUCAST resistance breakpoint of 16 mg/L in plasma, and in the ascitic fluid of patients with CLCRUrinary < 40 mL/min. Dose adjustments are proposed but would need to be clinically evaluated, especially regarding the safety of this dose escalation. Indeed, only limited data in healthy volunteers are available so far with increased dosing regimens. They failed to detect safety issues after 8 days of treatment with 4 g twice daily [At this stage, we can however already conclude that the clearance and the PTA of unbound temocillin in critically-ill patients with intra-abdominal infection are mainly dependent on CLce daily . This doCliniques universitaires St-Luc . The inclusion criteria were patients with septic shock, >18 years old, diagnosed with an IAI caused by a pathogen expected to be susceptible to temocillin. The exclusion criteria were patients allergic to any penicillin, including temocillin, pregnant or lactating women; or patients having participated in another experimental study with the same drug during the 4 preceding weeks.This prospective, monocentric, open-label, and non-randomized pharmacokinetic study enrolled adult patients with septic shock associated with intra-abdominal infection (IAI) hospitalized in the intensive care unit of the Crurinary, C-reactive protein, total protein and albumin levels in plasma and ascitic fluid, hepatic enzymes serum levels . A Child-Pugh score [The following parameters were recorded in all patients: demographic data , treatment duration, isolated pathogens, severity scores (acute sepsis-related organ failure assessment (SOFA) , and Acugh score  and Modegh score  were calg for 15 min at 4 °C. All fresh ascitic fluid samples (10 mL) were collected via the drainage system in a tube , simultaneously with each blood sample when possible. All plasma and ascitic fluid samples were stored at −80 °C until analysis. All patients were treated with temocillin according to the following scheme: a loading dose (2 g) was administered over 30 min in 50 mL of water for injection, followed by a continuous infusion (6 g/24 h in 48 mL of water for injection infused at a rate of 2 mL/h). Temocillin was given as monotherapy for documented infections caused by susceptible pathogens. Additional antibiotics were given for Gram-positive bacteria as needed. Blood and fresh ascitic fluid samples were drawn between 0.5 to 96 h after the start of the treatment . All bloTemocillin was obtained from EUMEDICA S.A., Manage, Belgium, as the branded product (NEGABAN) approved for parenteral human use in Belgium, the UK, and France. Ticarcillin disodium  was acquired from Sigma-Aldrich Corp., St. Louis, MO, USA; HPLC-grade methanol and acetonitrile, from J.T. Baker, Deventer, The Netherlands; formic acid and ammonium acetate, from Merck KGaA, Darmstadt, Germany. Ultrapure water was from a MEDICA-R 7/15 water purification system  or a Milli-Q Academic apparatus . Total and unbound (free) temocillin plasma and ascitic fluid concentrations were measured by an HPLC-MS/MS method, previously validated for assay in serum, plasma, and ascitic fluid ,63,64 us®, and E-test®) of the Cliniques universitaires Saint-Luc.Microorganisms were identified and MIC determined using automated routine systems available at the clinical microbiology laboratory ; PE (%) = 100 × , and PR (%) = 100 × , respectively.Plasma and ascitic fluid total and unbound temocillin concentrations were plotted against time and the area under the concentration-time curve (AUC) was determined . Unbound®, version 1.5.1 package for R  [2 with Error = (SD + L2)0.5 and Error = SD × G, where L (lambda factor) and G (gamma factor) are process noises associated with the observations. In addition, the error associated with the analytical assay was modelled as a second-degree polynomial function (SD = C0 + C1Y + C2Y2 + C3Y3), where SD is the standard deviation of measured temocillin concentrations (Y), and C0, C1, C2, and C3 are coefficients calculated from assay validation data supplied by the analytical method of the dosage of temocillin in plasma and ascitic fluid, or independently estimated by Pmetrics®.Modeling was performed only for unbound concentrations because these are those considered microbiologically active. We used experimentally measured unbound concentrations and did not calculate them based on total concentrations, which would be rather complex because total and unbound concentrations are not linearly related due to the saturable, concentration-dependent character of temocillin protein binding. Unbound temocillin in plasma and ascitic fluid were co-modeled using the non-parametric adaptive grid (NPAG) algorithm within the PmetricsCA, USA) . One-, a® using univariate associations between the tested covariate and individual median Bayesian estimates of PK parameters such as volume of distribution of the central compartment (Vc) and clearance (CL). Covariates selected for screening included age, weight, height, body mass index, C-reactive protein, urinary creatinine clearance, plasma, and ascitic fluid albumin level, SOFA, and APACHE II scores. After the selection of significant covariates in univariate analysis, a covariate model was built using stepwise forward inclusion followed by backward elimination if necessary. At each step of inclusion, the model with the greatest reduction in the -2LL and/or improved goodness-of-fit plots was retained.Demographic and biologically plausible covariates were screened in Pmetricsp < 0.05).Model diagnostics included goodness-of-fit of the observed versus predicted plots, minimization of bias and imprecision, shrinkage, the precision of PK parameter estimates, Akaike information criterion (AIC), and satisfactory visual predictive checks (VPC), and consideration and the −2log-likelihood ratio test (-2LL). The -2LL ratio test was chosen for the selection between two hierarchical models. The difference in -2LL of 2 hierarchical models follows approximately a χ2 distribution so that a decrease of 3.84 in the -2LL was considered statistically significant , with a resistance breakpoint set at MIC >16 mg/L [fT > target MIC of temocillin in plasma and ascitic fluid throughout the treatment. An a priori probability of target attainment (PTA) of ≥90% was considered optimal [Monte-Carlo dosing simulations (n = 1000) were performed for temocillin regimens of (1) 2 g loading dose infused 30 min followed by continuous infusion of 6 g/24 h; (2) 4 g loading dose over 30 min followed by continuous infusion of 6 g/24 h; (3) 2 g loading dose over 30 min followed by continuous infusion of 8 g/24 h. Dosing simulations were performed from 0 to 12 h, 12 to 24 h, and 24 to 96 h. The pharmacodynamic target recommended by EUCAST for temocillin is to maintain unbound concentrations above the MIC 35–41% of the time . The used parametric or non-parametric tests are indicated in the text, based on the preliminary determination of the normality of the distribution by the Shapiro–Wilk test. In all cases, the results were considered statistically significant when the


Inappropriate prescription of intravenous fluid therapy is highly prevalent in hospitals, with up to 1 in 5 patients suffering from preventable, additional morbidity. Since trainee physicians are frequently responsible for prescribing intravenous fluids, it is possible that common medical student resources do not sufficiently cover the topic. There is a paucity of recent literature on this issue, which this study was designed to address.Two original evaluation tools were created by the authors to evaluate reference books, official guidelines, and online reference sources commonly used by medical students in the United States of America, Australia, and the United Kingdom on their coverage of foundational and clinically relevant principles of intravenous fluid prescription. The choice of student resources was guided by a literature search and personal experience. A total of 10 resources was assessed.Resources were generally deficit in their coverage of basic intravenous fluid topics. The total points each topic accumulated ranged from 0.5 (5%) to 7.5 (75%), with the median score being 4.5 (45%), on a scale from 0 to 10 points.Popular medical student resources poorly cover intravenous fluid therapy topics. This may be contributing to inadequate fluid prescribing practices.The online version contains supplementary material available at 10.1186/s12909-022-03433-4. Fluid infusion therapy is ubiquitous in the inpatient setting, with over 200 million liters of saline prescribed annually in the United States of America (US) alone . SuboptiThe responsibility of prescribing fluid therapy often rests with trainee physicians, such as interns and residents. This is despite the wide disparities in competency displayed by junior medical staff with regards to appropriate IV fluid prescribing and documentation practices . A 2018 One could argue that intravenous fluid prescribing is a practical skill to be learnt ‘on the job’. However, clinicians and researchers are increasingly describing fluids as ‘drugs’, with their own set of quantifiable efficacies and toxicities . MoreoveAnother issue with trainee physicians learning IV fluid therapy prescribing on the job is that no medical intervention is without conveying a certain level of risk to the patient. Medical schools often reach significant depth with their basic science education of commonly prescribed drugs, and the interactions these drugs may have on overarching physiologic systems. IV fluids are deceptively complex, and can influence electrolyte balances, haemodynamic parameters, acid–base balance, and all organ systems. The difference between optimal IV fluid therapy and devastating outcome may hinge on a single dynamic, such as rate of infusion in the case of acute pulmonary edema or pontine osmotic demyelinating syndrome. , 9 Yet, This study aims to assess whether current medical student learning resources are insufficient in their coverage of foundational IV fluid knowledge. If so, this could at least partially account for the knowledge deficiencies some junior residents have with IV fluid prescribing practice. Recognizing the centrality of context in medical education, we synchronize our evaluative approach with the increasing normalization and pervasiveness of self-directed learning by assessing the medical school learning resources most used by clinical medical students from the US, United Kingdom, and Australia, as reported in the literature and through the personal experiences of the authors. This is instead of evaluating authoritative medical textbooks or resources recommended by medical school for learning, which may not be appropriately representative of actual resource use patterns .Prior to commencing the survey, the authors created two original evaluation tools for assessing student resources. An extensive list of potential topics was first created by the authors following a review of the literature on the topic, which were then selected for inclusion based on their clinical relevance for a medical intern. Relevance was determined through consultation with senior physicians, interns, medical students, and the clinical experience of the authors, who both have a special interest on the subject. Both tools are checklists consisting of common concepts related to fluid prescription practices, with Tool 1 covering basic knowledge and Tool 2 covering clinical knowledge. Resources were scored based on whether they covered everything in the checklist (1 point), some of it (0.5 points) or none of it (0 points). The maximum possible points each topic on Tool 1 and Tool 2 could score was 10 points.(1): Fluid balance: normal input; normal output; (2): Fluid balance: causes of altered output in a clinical setting; (3): Fluid status physical findings: hypervolemia, hypovolemia; (4): Electrolyte maintenance input for: Na, Cl, K; (5): Cannulas: basic indications for gaining central vs peripheral access; (6): 0.9% NaCl: electrolyte content, tonicity, osmolarity; (7): Ringer’s lactate: electrolyte content, tonicity, osmolarity; (8): 0.45% NaCl: electrolyte content, tonicity, osmolarity; (9): D5W: electrolyte content, tonicity, osmolarity; (10): Albumin: content, tonicity, osmolarity; (11): Semi-synthetic colloids: content, tonicity, osmolarity; (12): Risks of hypertonic IV fluids ; (13): Risks of hypotonic IV fluids .(1): ‘Bolus’ IV fluid: indications, choice of fluid, volume, rate, when to stop; (2): Maintenance IV fluid when NPO: indications, choice of fluid, volume, rate, when to stop; (3): Fluid restriction: indications, volume, timing, supplementation, when to stop; (4): Fluid resuscitation in the setting of blood loss: choice of fluid, volume, rate, when to stop; (5): Fluid resuscitation in the setting of GI loss: choice of fluid, volume, rate, when to stop; (6): IV fluid challenge: indications, choice of fluid, volume, rate, when to stop; (7): Use of crystalloids and blood products in the setting of shock.Following this, the authors conducted a literature search for recent, high-quality evaluations of clinical year medical students and their self-reported primary study resources. Data was extracted from four studies –14, whicThe resources were then independently evaluated by one author. To assess the reliability of scoring, a second blinded author independently assessed a resource that was selected through a random generator. The two scorings were then compared, and Spearman’s rank correlation coefficient was subsequently calculated.p = 0.001).The scoring comparison between the two independent evaluators yielded a Spearman coefficient of Rank concordance of 0.9425  to 7.5 (75%), with the median score being 4.5 (45%). As there were 10 resources, and the possible evaluation scores were 0, 0.5, and 1 point, the total possible points each topic could achieve was 10. Evaluation Tool 1 was the checklist used to evaluate basic knowledge, while Evaluation Tool 2 evaluated clinical knowledge. Finally, Group 3 is the combination of points topics from both tools accumulated. Table There is comparable representation of practical content and knowledge base content across resources, with the pooled median score of the resources of each country being 4.5 (45%) for knowledge-based topics, and 5.5 (55%) for practical topics. As seen by the percentage scoring, the depth of coverage is globally deficient.Notably, the highest performing medical student book, Toronto Notes, scored only 12.5/20 (62.5%). This is concerning, as at least one medical student book from each country that is regarded as an unofficial ‘gold standard’ from each country was included in the resources selected for analysis.Surprisingly, only one of the three guidelines provided comprehensive coverage of topics, with a total score of 19 (95%), whereas the other two guidelines only scored 11.5 (57.5%) and 13 (65%), which is inferior to the commercial AMBOSS online medical student reference resource, which scored 15 (75%) . This is likely because its widespread use has fallen out of favor due to concerns with increasing mortality rate, though there are still a few specific indications that support its use. A comparison of indications for peripheral and central cannulas also only scored 2 points. This was surprising as this topic was considered fundamental for the intravenous delivery of any product. All the abovementioned topics are clinically relevant and commonly encountered in general medicine and surgical wards.Since all the non-guideline resources parallel local medical student examination standards, their content provides a reasonable barometer for the depth and likelihood of any given topic’s appearance in live examination format. We therefore deduce from this that the current appearance of IV fluid therapy in exams is likely limited in breadth and depth. Therefore, we call for increasing IV fluid therapy representation for the trainees’ and patients’ benefit. This could trigger a significant change of the topic in non-guideline medical student resources. The newly evolved medical education landscape may then better transition the medical student into their role as a physician in training, as they will be better equipped with the basic knowledge to manage some of the most common prescriptions in hospital. Beyond that, IV fluid therapy related patient complications may potentially decrease.Our international approach in surveying the IV fluid therapy medical education landscape increases suspicion that neglect of this topic may be globally pervasive rather than isolated to a particular geographic region. Indeed, there is evidence that IV fluid prescription is sub-optimally performed in countries without a mainly English-speaking population, with one Iranian study of 450 inpatients who received IV fluids reporting a prescribing error rate of 1.3% per patient.  Further The primary limitation of this study is that it did not account for content directly derived from medical school curricula, which is likely to be heterogenous in content and quality .For each country, one top resource was selected from each following categories: reference book, online guidelines, and online reference source. However, the culture of learning may be different between countries, with physical textbooks being preferred by UK students for certain clinical studies, whereas online resources may be more popular for US students . TherefoIV fluids are among the most frequently prescribed products in hospitals. Inappropriate IV fluid prescription practices are common and contribute to substantial, costly, and preventable patient morbidity and mortality. The most frequently used medical student resources in the United States, United Kingdom, and Australia do not adequately cover fundamental topics related to IV fluid prescribing. There is no evidence to suggest that this deficiency is restricted to these three countries. The authors suggest that a possible contributing reason may be due to underemphasis of IV fluid prescribing in examination settings. This in turn can lessen the resolve of resource creators to detail the topic in further detail, as the top resources in all three countries tend to be highly succinct and focused on material most likely to appear in examinations. Further studies on IV fluid prescription practices and medical student resources on the topic in other countries can help determine the degree to which this issue extends to on a global scale.Additional file 1.


Competitive grant funding is a well-established mechanism for generating activity and interventions in the field of chronic disease prevention. Yet grant competitions may be burdensome for organizations, and money may not be enough to bring about lasting change in communities. In this study, we explore the dynamics of awarding and receiving money in the context of a state-level government grant competition to support community organizations and promote community-driven action for health and well-being in Tasmania, Australia. Drawing on reflections of successful grant recipients and real-time observation of grant decision-making, we consider the role and value of grant competitions both for individual organizations and for generating broader change processes. We found that grant competitions operated according to an ‘icing-on-the-cake’ approach to funding, whereby money was provided for extra activities and new initiatives. In this way, the grant competition was valuable not only for stimulating new programme activities but also to effect broader organizational change, such as developing planning capacity, igniting new directions and pushing organizations towards ‘health’-focused activities. But for smaller organizations, grant funding was often stretched to support core work (i.e. cake rather than icing). Grants targeting specific focus areas could be a drain on resources if they diverted staff time away from core activities. We suggest an alternative approach to funding in which grants are able to be more responsive to the needs of community organizations and the support they require, as well as to desired outcomes. We describe the policy response to the results to date. The field of health promotion has a long history of using competitive grant funding to foster community-based health promotion programme delivery. Different types of organizations may award grant funding including government, philanthropic foundations and industry. Government funds are typically targeted to generate activity around one or more national or state policy priority areas  as an attempt to increase the population-level ‘dose’ of prevention  with a focus on building community connections. The fund provided roughly AU$2 million in both 2019 and 2020.Organizations had to apply for funding through single funding round each year, advertised 6 weeks ahead of the application deadline. Grant recipients were selected from those that applied on the basis of recommendations by a Review Panel made up of representatives from the Department of Health, Department of Education, Department of Communities Tasmania and Primary Health Tasmania. Meeting over 2 full days, the Review Panel assessed more than 100 applicants each funding round. Proposed projects were weighed against one another based on their individual merit, as well as considerations of the ‘mix’ of grants, that is, how funded projects complement one another and reach across different regions of the state. Applications were appraised against criteria including evidence base, the diversity or number of participants, access for priority communities, collaboration with other organizations and community partners, evaluation plans, and value for money. Projects were also required to demonstrate sustainability and had to describe how they would continue to provide benefits to communities beyond the lifetime of the grant.This research is part of a broader study of funding processes in chronic disease prevention in Tasmania, conducted as part of a collaborative chronic disease prevention research partnership involving university-based academics and policy-makers (n = 11) and local government organizations (n = 5). Half of the participants had received small grants up to $50 000 and half had received large grants up to $200 000. From May to August 2020, we conducted semi-structured interviews with participants for 60–90 minutes. Plans for face-to-face interviews were suspended due to nationwide COVID-19 lockdowns and interstate border closures, and all interviews were recorded over Zoom and transcribed verbatim. Interviews began with open-ended discussions about how grant programmes had changed during lockdown, which we report elsewhere in detail . There were nine people in the 2020 meetings . All members of the review panels provided written consent. One of the authors (KG) adopted a role consistent with that of a ‘para-ethnographer’  providinAll transcripts were anonymized and coded in NVivo 12  by one oSuccessful grant recipients (GRs) spoke specifically about their recent experience and reflected generally about grant competitions as funding models. Many had long experience with grant competitions, observing that funding had become more competitive. Although the term ‘grants’ was sometimes used to refer to longer term recurrent funding arrangements (3 or more years), in the examples below, the term is used only in reference to short-term funding (2 years or less). We present the results first using the reflections of the GRs. We then introduce insights from the panel discussion, where we witnessed to-and-fro and real-time ‘agonizing’ on some of the same issues as the GRs.GRs described multiple ways grant competitions were of value for their organizations. For organizations that had secured recurrent funding from other government funds, this grants programme was a way to experiment with new initiatives that took them beyond their usual activities:Our one-off projects, I always put them to the side. They’re the extra. They’re the icing on the cake… Our [grant from funding body], that’s 15,000. Again, that’s icing on the cake. It’s for extra.One GR described her organization as ‘at that awkward adolescent phase of our grant management’ and thought they should apply for more grants because of the boost it would provide to the organization’s strategic development:The more we apply for grants, the better the momentum builds, and we’re just kind of at the cusp of that right now… it would then be easier to do more.In this way, the value of grants appeared to be contingent on the stage of an organization’s maturation. Another GR described how relationships built up over many years gave them an edge in grant competitions. People knew the GR could successfully run programmes and partnerships were crucial for future grant success.For a GR in a local government organization, grants could push the organization beyond their traditional focus towards a ‘health’ approach:The money is linked to that but it’s not all about the money… It’s much more about that sense of feeling enabled, encouraged, pushed to particularly follow a focus.Some GRs described how grants could build capacity for programme planning. One GR recalled a previous experience with a different grant competition, where they were funded to do ‘preapplication work’ such as developing the programme idea and partnerships:That [funding] was valuable because it enabled us to find really strong partners, and to really develop the plan properly, rather than just going with okay, here’s a million dollars available on grants, let’s just come up with something quickly and put it in.Another organization, a well-established leader in their field, no longer needed grants to deliver their services. They planned to use their grant to build the case for expanded core funding:We did the pilot, we built some evidence around the effectiveness of the pilot. Now, we’re able to do a larger scale piece of work. We’re hoping that, again, this continues to build the foundation of why this is so important, in the hope that we can make a case that this could get ongoing funding from government.This illustrates the importance of thinking through how grant money is distributed in relation to what is already happening within an organization as well as the resources that are necessary to plan for a new programme of work with a community.A number of GRs described the importance of being strategic in their approach to grant applications. One GR saw grants as an opportunity to fill a knowledge gap:I often use a different technique to leverage money, and that is to look at a particular issue and say, “Oh, I wish I better understood that particular problem.” I wonder if I can get $10,000 to do a little research post and then we’ve got the answer to that problem.The grants programme allowed another GR to pursue an evidence-based programme where they felt necessary services were lacking:We would go online and see what was being funded, and not necessarily agree with what was being funded. Then I think part of it was also just being fed up like, “What do we use to apply for this? We’re the best situated to deliver this.”Though sometimes, even with long-running programmes demonstrated to work, GRs described how continued avenues for funding were not always forthcoming. In continually having to look for grants to fund successful programmes, one GR explained how they felt compelled to reinvent successful programmes so they could continue to attract money from grant competitions.For GRs working within small organizations, grant competitions could be ‘a double-edged sword’. As numerous GRs made clear, getting the grant money was only one step in effecting change:Sometimes getting told you’re successful is scary… thinking, ‘Do we have the resources to make it successful for our community?’ I mean, at the end of the day, spending the money and having the grant is great, but it needs to make a difference in your community.Additional resources—particularly staff time—were needed:Having extra funding doesn’t mean that you’re going to get extra programs or better programs… because people have got to have the capacity to be able to run them.As one GR described, ‘we have so few resources to help do anything other than our direct work’. So programmes funded through grants competitions could really stretch resources.For organizations that had no recurrent funding, the continuous search for grant money was not only taxing, it was critical for service provision:Any programs… or events that we want to run, or host, or facilitate, we actually have to find the funding for them… without the funding, we wouldn’t be having [the program]To make funding applications competitive, one GR described keeping programme budgets very lean, minimizing requests for overhead costs. But this meant grants could be ‘a drain’ on small organizations. By contrast, larger organizations, including local government, usually had secure staffing arrangements and a larger workforce, so grant applications could just include ‘the bare bones of what you need to deliver’ programmes.Many GRs emphasized the importance of a targeted approach to grant competitions, because there was a danger in taking on too much. One GR recalled how their organization had once applied for more grants than they could reasonably manage:The team had put in for all these grants thinking they might get three and then they got eight… There was definitely some sense of that was way too much to do. We winged it, we should never do that again.As well as illustrating the difficulties of managing too many grant-funded programmes, this shows how the lack of predictability around funding through grant competitions means that even with a targeted approach, grant-funded activities are difficult to plan around.It was often the case that funding did not provide the resources GRs felt were most needed. For those in smaller organizations, staffing issues were brought up over and over during interviews. Many lamented that there were not more large grants available to fund staff:Sometimes [grant applications] are not worth writing because they don’t give you what you need. I mean, I’d love to have a whole other person. But if the grant’s only 70,000 or 80,000 I’m not applying for it because it’s not enough money. And I don’t want a part person, I want a whole person.Another GR spoke about how great it was when they got funding for staff instead of relying purely on volunteers—but also made clear this was very rare. Their organization had calculated the value of their volunteers as far exceeding AU$1 million. Yet they felt too much was expected of volunteers:There’s too much emphasis with funding bodies on everything has to be volunteered. You need to be able to recompense people something sometime… there’s a lot of money contributed in kind. And they do great work, it’s not like they’re sitting around taking up time, they’re actually contributing.The Review Panel meetings offer an additional perspective on the grant competition as a mechanism to leverage resources in organizations within the wider prevention system. Proposals are assessed based on the potential of individual applications as well as what each application represents in terms of the overall pool of applicants. While the assessment process is shaped by predetermined eligibility criteria, panel discussions reveal how panel members try to ascertain which applicants will be the best ‘fit’ for the grant competition purpose. Applications that requested funding for ongoing operational costs or ongoing salaries were not eligible. Those requesting funds for staffing had to explain how this would leave lasting skills and knowledge within the community.new activities or if they already received funding for proposed services (making them ineligible).Panel discussions were supplemented by background work before and after the panel meetings. Findings from the research team’s analyses of the 2019 review panel meetings and GR interviews were provided to the 2020 research panel members prompting discussions around the benefits of funding for network/relationship building, how to balance applications from smaller and larger organizations and contemplating the meaning of ‘sustainability’ in the context of short-term grants. Background work was also necessary for panel members to keep abreast of other funding sources that align with or augment the activities proposed by applicants. One of the tasks facing the panel was, therefore, to discern whether the application was requesting funds for Panel members were wary of funding programmes that seemed to ‘prop up’ organizations or where ongoing funding would be needed to support a particular programme. They deliberated over whether applicants were requesting funds for core activities, and often questioned whether or not the applicant organization ought to be ‘doing this already’. A ‘positive’ proposal could be knocked out by suggestions that proposed activities should be part of an applicant organization’s ‘core business’.But determining what ought to be ‘core’ for an applicant organization was not always straightforward, particularly with smaller organizations. When the panel discussed whether a local council should be funded for a community event, for example, the panel was divided. One panel member felt councils should be running events as a matter of course, rather than through grants. However, another panel member pointed out that small councils did not necessarily have funding to deliver on health and well-being initiatives. In this sense, the concept of ‘core’ activities was considered against whether smaller organizations could carry the infrastructure/overhead costs of a new programme, and also whether ‘health’ was an existing part of an organization’s mission.Requests for staff wages were often a red flag for the panel, raising questions about the sustainability of the programme beyond the 2-year grant period. One application received initial favourable assessments based on good connections with relevant experts and effective engagement with high-risk groups. But when a panel member pointed out the budget relied heavily on staff wages, it was decided the proposed programme needed ongoing funding rather than a one-off grant. The issue of where such ongoing funds could potentially come from was not broached in this discussion.As panel members considered each application, they often grappled with the meaning and purpose of grants as a whole. A striking example was a discussion regarding an application to build kitchen equipment. The panel members wondered together whether this was appropriate for this grant competition, as it was not intended for infrastructure. It was raised that a kitchen could serve as ‘a vehicle’ for all kinds of important community connections. However, some felt the organization already had good engagement and community activities were already happening. The panel noted the application depended on funding from two other sources, both of which were listed as ‘pending’ and appeared not to be confirmed. For the panel, it was therefore ‘a risk’ to grant funding:I think we’re going to have to say, ‘No,’ because what if those [other funding applications] ones don’t come off? Then they can’t put icing on the cake if the cake’s not there.Here we see how the ‘icing on the cake’ metaphor, also used by GRs, conveys how panel members are looking for applicant organizations to have minimum resource structures in place before they can reasonably allocate extra funding through the grant competition See We note that our interviews were only held with successful grant recipients. However, many participants discussed their experiences being unsuccessful in other grant competitions. It is not unusual to interview grant receivers, but by using interview material alongside the deliberations of grant funding panels, this study provides a unique, real-time account of the merits of individual grants, as well as the larger context and dynamics in which decisions were being made. Having the ‘giver’ and ‘receiver’ data sets side by side enabled us to see how GRs and panel members often mirrored each other. For example, where GRs felt grants could be a drain on the resources of small organizations due to trimming the budget to keep down overhead costs, panel members were similarly wary of seemingly undercooked budgets that could indicate that an applicant organization was inexperienced or being overly ambitious.We saw how funding could benefit organizations and we saw what else was needed to bring about broader change in communities. Many GRs acknowledged that getting a grant was valuable but making a difference in communities required much more than money. Significant ‘pre-application’ resources were required to plan a new programme of work. GRs from small organizations felt disadvantaged where they needed to factor in staff or overheads in their budgets, whereas larger organizations had the capacity to leave these ‘core’ costs out. Others have observed that competitive processes impede the ability of smaller organizations to respond to emerging social issues .GRs described how grant funding enabled organizational development. As one GR explained, ‘it’s not all about the money’ but rather that money could ignite a symbolic shift for organizations through directing priorities towards a health and well-being agenda. Grants could also help build the organizational momentum and facilitate future grant success. This happened through building critical partnerships, or through creating relationships with funders, building ‘inside’ knowledge or building a reputation as a trusted, reliable organization. For some organizations, funding allowed for the development of novel ideas or new knowledge based on learnings from practice. Generating practice-based evidence was an important stepping stone for organizations wanting to scale new services in the community. However, these gains can potentially create a ‘privileged class of grant seeker’ as the application process favours those with social capital such as social networks and established legitimacy in the field , p. 220.ought to work: by granting funds (icing) to organizations to enhance core work (cake) that they already do. This icing-cake model implies a clear delineation between core activities/resources of an organization and extras that would ideally be funded by grants programmes. For well-established organizations who have secured recurrent core funding to deliver prevention services, this model can work well to stimulate new programmes of work and experiment with new ideas. And yet the findings also reveal a gap between this ideal icing-cake model of grants competitions and what many organizations require to undertake long-term processes of change in communities. This gap is illustrated as GRs describe the challenges of getting funding for what they really need and the pressures of trying to carry out funded programmes of work with inadequate paid staffing roles. The gap is further evidenced by struggles of panel members as they assess applications that offer promise, but are not well served by short-term funding arrangements and the constraints that are typical of a categorical grant competition.Both GRs and funders spoke of ‘icing’ and ‘cake’. The icing-on-the-cake metaphor is often understood to mean taking something that is good (cake) and making it even better (icing). We saw how the icing-on-the-cake metaphor provided a way for GRs and panel members to express an ideal-typical scenario for how the grants competition What the icing-cake metaphor really signals is a lack of balance in the overall mix of funding mechanisms for health promotion. There is a lack of fit in terms of what many organizations require and the larger system of funding support for local health promotion practice. The challenges described by organizations could not simply be solved by coming up with a better idea or improved application. Similarly, the review panel was faced with navigating questions about sustainability of grant proposals that required support for ‘core’ activities that were ineligible under the terms of the competition.Many of the key elements of community capacity cannot be provided directly through external funding mechanisms. Instead, they must be built and maintained over time by community workers and volunteers. External funds are still helpful in developing the necessary soft infrastructure  but the funds must be provided in ways that accommodate the flexibility and varied timelines that capacity building requires  and collective control of money to foster empowerment of communities as a route to addressing health inequalities . In addition, we suggest considering a move towards a more explicit community-centred grant funding model which allows state-wide topics to be addressed while catering to a diversity of community abilities. As well as aiming to encourage activities and services that move communities further ahead in terms of well-being, community-centred grants would aim to progress local capacity according to the stage of community development need. For example, applicants could be streamed according to three pools of funding: (i) microgrants for capacity building/safe to fail experimentation, including very limited reporting requirements; (ii) grants to develop evidence or programme evaluation to prepare for scale-up; and (iii) commissioning fund for state-wide or long-term roll-out, ongoing support for ‘core’ activities.More work is needed to determine the ideal mix of ways to fund prevention. Recent initiatives have promoted community decision-making through collaborative community budgets  in the absence of continued funding (as in pools 1 and 2) should not be expected. Instead, a narrative about how the grant has made residual capacity better could be more appropriate. Applications could also be assessed with flexible timing, rather than having all applicants submit at the same time. This would have the advantage of suiting the community pace of change.Some of these processes are already underway in our project, as the funding body has used findings from GR interviews to inform quality improvement. Recognizing the grant process favours those with experience and pre-existing resources (including grant-writing skills), the funding body has made grant application processes more accessible to a wider range of organizations. Measures such as plain language documents and user-friendly systems have been introduced. Efforts have been made to even the playing field through introducing forums, skill-building sessions, sharing experiences of successful applicants and practical support to help applicants move from an idea to application. Similar to Marsh and colleagues , the fundaac115_suppl_Supplementary_AppendixClick here for additional data file.


Physicians are increasingly using Twitter as a channel for communicating with colleagues and the public. Identifying physicians on Twitter is difficult due to the varied and imprecise ways that people self-identify themselves on the social media platform. This is the first study to describe a reliable, repeatable methodology for identifying physicians on Twitter. By using this approach, we characterized the longitudinal activity of US physicians on Twitter.We aimed to develop a reliable and repeatable methodology for identifying US physicians on Twitter and to characterize their activity on Twitter over 5 years by activity, tweeted topic, and account type.In this study, 5 years of Twitter data (2016-2020) were mined for physician accounts. US physicians on Twitter were identified by using a custom-built algorithm to screen for physician identifiers in the Twitter handles, user profiles, and tweeted content. The number of tweets by physician accounts from the 5-year period were counted and analyzed. The top 100 hashtags were identified, categorized into topics, and analyzed.Approximately 1 trillion tweets were mined to identify 6,399,146 (<0.001%) tweets originating from 39,084 US physician accounts. Over the 5-year period, the number of US physicians tweeting more than doubled . Across all 5 years, the most popular themes were general health, medical education, and mental health, and in specific years, the number of tweets related to elections (2016 and 2020), Black Lives Matter (2020), and COVID-19 (2020) increased.Twitter has become an increasingly popular social media platform for US physicians over the past 5 years, and their use of Twitter has evolved to cover a broad range of topics, including science, politics, social activism, and COVID-19. We have developed an accurate, repeatable methodology for identifying US physicians on Twitter and have characterized their activity. Twitter has become a popular communication tool, with almost 200 million daily active users and more than 500 million tweets being sent out every day . Around Over the past 15 years, physicians have started to use Twitter as a platform for sharing scientific information, frontline experiences, and opinions on various topics -12. StudStudies have already demonstrated the use of Twitter in building early warning systems for adverse drug reactions, understanding discussions about various diseases, and characterizing public perceptions regarding COVID-19 -24. One Although some studies have investigated the use of Twitter among physicians in narrow use cases, such as a specific specialty, no study has characterized the overall activity of US physicians on Twitter across multiple years . Part ofWe conducted an in silico analysis of physicians’ Twitter usage over a 5-year period. We identified physicians by using a 3-stage process  comprisi@username), names , and bios for every tweet that was posted during the 5-year study period (2016-2020). The Boolean logic identified all tweets that included some indication of a Twitter user’s status as a physician . The Boolean logic included a corpus that contained every specialty and subspecialty listed by the Accreditation Council for Graduate Medical Education and the American Osteopathic Association. A third-party software  was used to review the user accounts and tweets generated from the Boolean algorithm to ensure the accuracy of the Boolean logic expression. With each iteration, the first 1000 tweets were manually reviewed for any tweets that did not originate from a physician-owned account. Appropriate logic was added to filter out false positives. Examples of false positives are provided in Initially, a Boolean logic was developed  to scan Once the Boolean logic was finalized, all tweets that were written in English; originated from the United States; were posted between January 1, 2016, to December 31, 2020; and met the Boolean criteria were acquired from a third-party vendor .MD to indicate the state of Maryland; accounts of physician recruiting services that used variations of MD and jobs in their usernames and profiles; and premedical and medical students who used aspiring MD, aspiring physician, future physician, or similar terms in their profile were filtered out by using logic coded in R.The data were imported into RStudio , where additional rules were programmed in R  and applied to filter out nonphysician Twitter accounts. The next phase of algorithm refinement involved filtering out more nuanced cases that the Boolean logic could not catch. Accounts that used #job or #jobs in the text were identified. Among these tweets, any accounts that included the word medical or surgery in the account name were eliminated . This 2-step process of screening accounts—analyzing the tweet text first and then identifying false-positive usernames and names—was used to filter out the final batch of nonphysician accounts.The algorithm was further refined by identifying patterns in the tweet text itself and then applying filtering logic to the accounts of those tweets. For example, to filter out more physician recruitment accounts, tweets that used the hashtags We used Twitter’s verified accounts  as the validation set to test the accuracy of the algorithm. Twitter uses a rigorous verification process to confirm the identities of verified account users, which includes checking for an official government-issued identification document or an official email address .All of the tweets that originated from a verified Twitter account were separated from the larger 5-year data set. A team manually reviewed each unverified account by visiting the associated Twitter profiles and searching the internet to confirm the details of a user’s status as a physician . A false-positive error rate was calculated based on the number of verified accounts that belonged to Twitter users who were not actually physicians.In order to calculate the false-positive rate of unverified accounts, around 5%  of the unverified accounts in the data set were randomly selected. The accounts were manually reviewed by the team to calculate a false-positive rate for the unverified physician accounts identified by the algorithm.stringi, stringr, and tokenizers. All words that followed a pound sign were identified and separately stored within a data frame in RStudio. For every tweet, each hashtag was counted and tallied across all tweets for each year (2016-2020). Researchers (KN and NTY) reviewed the list and grouped any terms that were related. For example, the COVID-19 topic was comprised of hashtags such as #covid19, #coronavirus, #sarscov2, #covid19coronavirus, and other related hashtags. Further, both the #blacklivesmatter and #blm hashtags were used for the Black Lives Matter topic’s tally and rank.The top 100 hashtags used by US physicians were identified, tallied, and ranked for each year. Each tweet was tokenized, stemmed, and normalized, and stop words were removed. This was done by using the following R packages: wordcloud, wordcloud2, and ggplot2. Second, we identified the top 100 hashtags and categorized them into broad thematic areas. In order to analyze thematic trends between years, hashtags were organized into the following themes: general health care, COVID-19 and public health, politics, social activism, mental health and well-being, health technology, conferences, patient groups, specialties and subspecialties, medical conditions and procedures, and medical education. For the general health care theme, tweets that included generic health care–oriented hashtags like #healthcare, #doctor, #medtwitter, and #medicine were combined and tallied, and the proportion of such tweets was calculated as a percentage of all tweets for each year. For the COVID-19 and public health theme, hashtags like #covid19, as well as hashtags that conveyed public health messages like #maskup, #socialdistancing, and #flattenthecurve, were included. For the politics theme, any hashtag related to politics and elections, such as #trump, #vote, #election2020, #tcot , and #newsmax, were used [We analyzed hashtags in two ways. First, we created word clouds for a visual representation of Twitter activity. A word cloud was generated for each year of the study period; words were color-coded based on their frequency of use. Word clouds were generated by using the following R packages: ere used ,30. OnlyNo application for an ethics review board assessment was submitted, since this study involved third-party data sets with no experimental activities. Therefore, this study was deemed a quality assurance/quality improvement activity .Of the 216 Twitter-verified accounts that the Boolean algorithm identified as physician accounts, 12 were not physician accounts, resulting in an accuracy rate of 94.4% (204/216). Of the 43,328 unverified accounts in the data set , 1978 accounts were randomly selected for manual review as part of the 5% validation sample. Of the 1978 randomly-selected unverified accounts, 204 were not physician accounts, resulting in an accuracy rate of 89.7% .The number of US physicians who were active on Twitter increased from 2016 to 2020. The number of unique physician accounts tweeting increased from 12,675 in 2016 to 26,897 in 2020—a 112.2% increase in the number of active physician users over the 5-year period . The num#health, #healthcare, #doctor, #medicine, #meded, #mentalhealth, and #wellness consistently ranked among the most frequently used hashtags across all 5 years of the study period  and 10.6%  of all hashtags used in 2020, respectively. Donald Trump–related hashtags were consistently ranked among the top 50 hashtags from 2016 to 2019, and in 2020, US physicians used COVID-19–related hashtags in 137,107 tweets, making them the most used hashtags during the entire 5-year study period .Among US physicians using hashtags in their tweets, y period . In 2016y period , with #h#COVID-19) and 1 hashtag in orange (#medtwitter); all other hashtags are in green .The word clouds provide a visual representation of the frequency and distribution of the hashtags used each year. The frequency of words was color-coded; gray represents the most frequently used hashtags, green represents the least used hashtags, and other colors  represent the different levels of frequency in between the two extremes. Once hashtags were organized into themes, the results showed that the general health care topic was the most consistently discussed topic across all 5 years and represented 5%  of the total tweets in 2020 . In apprThis is the first longitudinal report of physician activity on Twitter. Physician activity on Twitter has been increasing over the past 5 years, with more physicians creating accounts and joining the platform every year. The diverse range of topics that are discussed on the platform, from social activism and politics to memes, demonstrate that Twitter is becoming a mainstream communication tool for everyday physicians.The trends in the last 5 years likely indicate that the early adopters phase of Twitter use among physicians is sunsetting, and Twitter is becoming a mainstream platform for physicians . This isWe also want to acknowledge the role of misinformation and disinformation on the internet. Although this was not the focus of this study, this topic is inextricably linked to the roles and responsibilities that physicians have on Twitter, social media, and the internet. The study period included the 2016 US presidential election and the COVID-19 pandemic, of which both involved the sharing of misinformation and disinformation related to these events -36. PhysPhysicians discuss a broad range of topics on Twitter and are not shy about opining on topics that are relevant to society beyond strictly medical topics. Physicians are unlikely to find an equivalent platform  where ordinary clinicians’ voices can be shared and heard globally in such a public, transparent way. This was illustrated by the outsized influence that physicians like Bob Wachter (@Bob_Wachter), physician influencers like Kevin Pho (@kevinmd), and ordinary clinicians have had by using Twitter during the COVID-19 pandemic. Among the hundreds of millions of tweets shared in 2020 [#meded and #foamed  were consistently ranked in the top 10 and top 100 hashtags, respectively  were ranked in the top 100 hashtags across the majority of the 5-year study period  from the trillions of tweets generated worldwide.Although numerous studies have analyzed the Twitter activity of the entire Twitter population, the complexity of this task increases significantly once subgroups need to be identified and analyzed. We believe that the methodology outlined in this study offers a robust, scalable, and repeatable method of identifying physician accounts on Twitter. We also recognize that this approach is not perfect and hope that this study serves as a foundation for future work to further improve the identification of physician accounts for future analyses.The computational requirements for mining approximately 1 trillion tweets and analyzing millions of tweets should not be underestimated. Once the data set reaches beyond a few months of Twitter data, the data set is too large for manual assessment. As such, algorithmic approaches to filtering and analyzing the data are recommended. Analyzing this amount of data often exceeds the computational limits of a typical laptop or desktop, and more high-performance graphics processing units or high-performance computing clusters in the cloud are recommended to analyze the data in a reasonable amount of time, particularly if a real-time analysis is desired.This study had 3 main limitations. First, all physicians who were identified as active users on Twitter were self-reported physicians. One’s status as a physician can be very difficult to validate unless this information is cross-referenced against state licensing data. Physicians with verified accounts on Twitter  are the most reliable, since Twitter has a rigorous verification process that involves checking credible sources, such as health system websites and media sources, and using other means for verification . Since aThere are many opportunities to build on this study. We are planning future studies to focus on specific events, such as the COVID-19 pandemic. For example, by segmenting the physician tweets by state and correlating them with epidemiological data, we plan to study whether there was increased physician activity during pandemic surges. Similarly, machine learning and statistical analyses could be used to explore whether physicians’ Twitter activity can be used as a predictor for public health alerts in the future. Physician activity could also be used as a potential real-time barometer for physician well-being at a regional or national level; by applying natural language processing techniques, such as sentiment analysis, such a data set could provide a baseline measurement of physician morale at any given point in time. We are exploring more in-depth analyses of Twitter bios; topic modeling; and the correlation of self-reported identities with validated physician registries, such as medical licensing boards. Finally, we feel that our methodology and this first comprehensive study of physician activity on Twitter offer a foundation to building more accurate and precise algorithms for identifying physician accounts nationally and globally. We also provide a more complete characterization of the social media activity of US physicians than what has been possible in the past.More physicians are using Twitter and covering a wider range of topics in their tweets. Twitter is entering a new phase of mainstream use among physicians, even though physician activity still represents a tiny fraction of total Twitter activity. These trends are evidence that Twitter can be a valuable source of data that can be used to understand social trends, interests, and the perceptions of the physician community. Unlike the more stringent settings of clinical practice, physicians are opening up on social media and showing a different side of themselves that is typically protected in the professional clinical setting. Physicians on Twitter may be offering a unique, more comprehensive view into the physician psyche, making Twitter an intriguing platform for further study and exploration.


In cancer, neutrophils are an important part of the tumour microenvironment (TME). Previous studies have shown that circulating and infiltrating neutrophils are associated with malignant progression and immunosuppression in gliomas. However, recent studies have shown that neutrophils have an antitumour effect. In this review, we focus on the functional roles of neutrophils in the circulation and tumour sites in patients with glioma. The mechanisms of neutrophil recruitment, immunosuppression and the differentiation of neutrophils are discussed. Finally, the potential of neutrophils as clinical biomarkers and therapeutic targets is highlighted. This review can help us gain a deeper and systematic understanding of the role of neutrophils, and provide new insights for treatment in gliomas. Gliomas are heterogeneous and primary malignant tumour in the brain. Glioblastoma (GBM) is the most lethal form of glioma, accounting for 70-75% of all diagnoses of diffuse glioma and having a median overall survival (OS) time of 14-17 months , 3. The Neutrophils play various roles in different diseases. Neutrophils exert antimicrobial and inflammatory functions through phagocytosis, degranulation, release of neutrophil extracellular traps (NETs) and antigen presentation , 13. NeuIncreasing evidence reveals that the numbers of circulating and tumour-infiltrating neutrophils are relevant to immunosuppression, poor survival and a poor prognosis in patients with cancer –27. HoweHowever, our understanding of the roles of neutrophils in gliomas is still limited to date. This article aims to review neutrophil research in cancer patients. The search was focused on the association of circulating neutrophils and tumour-infiltrating neutrophils with prognosis in glioma patients. A PubMed search using the keywords “neutrophils”, “gliomas”, “tumour microenvironment”, “myeloid-derived suppressor cells” and “neutrophil-to-lymphocyte ratio” was performed. Reference lists were then searched for additional articles. Available data were obtained from patients with glioma to elucidate the roles of neutrophils with various phenotypes in gliomas. In addition, we dissected the pathways that mediate the transport of neutrophils to the tumour site, described their role once they arrived in the tumour microenvironment, and integrated this with the current understanding of glioma progression. A vast body of evidence supports the importance of the neutrophils in the progression of gliomas, and the possibility of neutrophils in the treatment of glioma is further discussed in this paper in combination with recent studies. Therefore, elucidating the mechanisms by which glioma cells interact with neutrophils can uncover multiple potential therapeutic targets for clinical applications.11 neutrophils per day  express specific cell-surface proteins  and PMN-MDSCs (CD14- CD15+ CD66b+ CD16+ CD11b+ CD33+ HLA-DR-) , early-stage MDSCs (eMDSCs) and monocytic MDSCs (M-MDSCs) are the main types of MDSCs that have been detected , 63. Basproteins . In micetrophils . MDSCs aow Ly6G+ . A more HLA-DR-) –73 (The HLA-DR-) Table 1.Circulating neutrophils are non-negligible component of the inflammation, which plays important roles in cancer development and progression . The NLRConcerning gliomas, the NLR is a widely used parameter for diagnosis and OS prediction , 81. TheThe baseline neutrophil count is a current biomarker used to predict the efficacy of bevacizumab in the treatment of GBM . It has Taken together, these findings illustrate that circulating neutrophils play important roles in the diagnosis, OS, immunosuppression, tumour growth promotion, and treatment resistance of patients with glioma. Data demonstrate the association between elevated peripheral blood NLR levels and increased TANs infiltration . HoweverThe normal brain has traditionally been recognized as an immune-privileged organ due to the presence of the endothelial blood-brain barrier (BBB) and the absence of a conventional lymphatic system . HoweverGBM cells produce cytokines, chemokines, growth factors and extra-cellular matrix modifying enzymes, extracellular vesicles and proteins to construct a favourable tumour microenvironment . Also, c+ T helper (Th) cells and CD8+ cytotoxic T lymphocytes (CTLs) within the T cell population have been shown to infiltrate gliomas  that promotes the activity of the NOS-ID4 signalling axis, which converts GBM cells into GSCs, this conversion is negatively associated with survival and radiation therapy outcomes  release levels might be responsible for the role of antineoplastic neutrophils. Unfortunately, as the tumour progressed, neutrophils lost the ability to prevent tumour progression . The ant−)  . M-MDSCs−) , 171. Be−) , 164. MD−) . NO is t−) –168. ROS studies –174. MDSal blood . Compari+ granulocytic MDSC (PMN-MDSC) subsets are dominant in glioma tissue  to enhance neutrophil antitumour cytotoxicity for targeted therapy of glioma  (KFZZ202203).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.