Cellphone position influenced eye gaze behaviour, with drivers looking at the cellphone less frequently, and the speedometer more frequently. when the cellphone was in their lap compared to when the cellphone was positioned on the windscreen. Our results are consistent with participants driving more cautiously—checking speed and lane position more frequently—when they have a cellphone in the lap. Real-world driving data would be useful to determine whether this change in driving behaviour we observed is sufficient to offset the increased risk introduced by spending less time looking at the road ahead.Legislation frequently restricts the use of cellphones while driving. Despite this, many people continue to interact with cellphones covertly while driving, typically by concealing their device in their lap. This strategy leads to frequent diversion of the drivers’ gaze from the road ahead, potentially reducing their driving performance. To evaluate the influence of cellphone use on driving, 30 participants took part in three randomly ordered 7-min virtual reality driving simulations. In each condition, drivers were presented with either (a) no cellphone, (b) a cellphone fixed to the windscreen, or (c) a cellphone positioned at lap level. Their task was to maintain road position and observe speed limits while answering maths problems (delivered intermittently via ‘text message’) and searching for external target objects. Outcome measures included speed, lane position standard deviation (LPSD), and fixation behaviour, which were compared between trials. In trials where a cellphone was present, participants shifted fixation more frequently, drove approximately 6 km/h faster, exhibited a lower LPSD and spent more time in the correct lane on the road (compared to the no-cellphone condition; all  During real-world driving, the addition of a secondary activity such as cellphone use serves to divert the driver’s attention, as completion of the secondary task competes with the primary driving task for cognitive resources. As a result, there is a reduction in the driver's ability to process the critical information to the standard required by law2, impairing driving performance3 and increasing the risk of a traffic accident4. Driver distraction contributes to 14% of crashes in Australia5, and 9% of fatal crashes in New Zealand6. In 2018 alone, distraction accounted for 12 fatal crashes, 155 serious injury crashes and 956 minor injury crashes in New Zealand7. More concerning is that after many years of improvements, traffic injuries and deaths have recently begun increasing across the globe , with many attributing this to increased cellphone use while driving.Driving a motor vehicle is a complex task demanding precise coordination of cognitive, physical, sensory, and psychomotor skills10. The wide range of engaging and complex activities available on cellphones present the potential to be a multifaceted distraction, including auditory, physical, cognitive, and emotive components. It has been reported that cellphone use leads to a much greater reduction in driving performance that other distractions, such as passenger conversations14, with the result that drivers have four times higher risk of a road collision while using a cellphone15.Sources of driver distraction can be both internal and external to the vehicle. While external sources of distraction  are beyond the driver’s control, in-vehicle or internal sources are frequently self-imposed and avoidable. Cellphone use is seen as a singular threat to road safety, with almost two-thirds of the drivers in high-income countries admitting to using their cellphones at some time while driving17. The use of cellphones, even in hands-free mode, takes cognitive capacity away from driving, and reduces visual awareness of the surrounding environment, resulting in poorer vehicle control18. However, as drivers are no longer holding the phone, hands-free cellphone users are less cognizant of the impairment, but still face the same cognitive challenges, so are less likely to show compensatory behaviour  than drivers using cellphones conventionally. Further, hands-free texting while driving has an even greater negative impact on driving than conducting a conversation using a cellphone because texting requires users gaze to also look at the phone21. In general, receiving and sending texts while driving leads drivers to spend longer and more frequent periods (as much as 4× as long) looking away from the road24. This frequent and prolonged divergence of gaze leads to up to 23-fold increase in the risk of a serious incident while driving25. Visual distraction while driving interfers with perceptual and motor processes and poses competiting needs for vision26. Consequently, drivers engaged in texting while driving are also less likely to notice external hazards, exhibit longer reaction times, and have less stable lateral and longitudinal control of their vehicles27.While the use of cellphones in “hands-free” mode is anecdotally thought to be safer than the conventional mode of use, studies suggest that this is not the case29, and driving performance exhibits an exponential decline in reaction time and lateral vehicle control when drivers use only peripheral vision22.Apart from the cognitive distraction involved in reading or composing a text message, drivers foveating a cellphone screen are reliant on their peripheral vision for vehicle control and monitoring of external hazards. Visual acuity declines rapidly with eccentricity30), engaging in competing (secondary) mental tasks while driving may increase cognitive load, depleting cognitive resources available for driving, and affecting the driving performance26. A real-world driving experiment found that secondary mental tasks while driving under a speed limit impair the speed control ability of the drivers and lead to increased speeds, supporting the “attentional speed control theory” that the cognitive load from the secondary tasks caused diversion of attentional resources required to control speed31. However, the relationship between cognitive load and driving performance remains controversial, with some studies reporting negative effects while others reporting improved driving performance32. A cognitive control hypothesis has also been suggested to imply that the effect of cognitive load on driving performance is strongly selective and task dependent, primarily affecting performance of nonpractised tasks but not of automatized tasks32.While visual and cognitive distractions associated with cellphone divert attention away from the primary task of driving  to avoid detection by law enforcement23. Because viewing a phone that is being held in this manner necessarily increases the eccentricity at which the driver is now viewing the road, the laws that sought to improve road safety may paradoxically be promoting more dangerous driving.In an attempt to minimise the increased risk of harm from operating a cellphone while driving, many countries, including New Zealand, Australia, and most states in America, have introduced varying levels of restriction of cellphone use while driving. These measures vary from restricting to hands-free use, banning interaction with a cellphone, through to banning interaction with any electronic devices with wireless communication capabilities35, avoiding the risks and ethical issues associated with real-world experimentation, and affording greater control over the driving environment. We also recorded eye gaze within the virtual reality headset to compare gaze behaviours in different conditions.This study aimed to investigate whether the use of cellphone in a ‘covert’ position affects driving performance or eye gaze behaviour compared to use in a hands-free (positioned on the windscreen), or no cellphone use. We evaluated driving performance in an immersive virtual reality (VR) environmentThirty participants  aged between 20 and 28 years old  were took part in the study. To be included in the study, participants needed to meet the New Zealand vision standard for driving (6/12 or better), with or without correction, and to have held a minimum of a New Zealand Class 1 (Car) Full drivers' licence for at least one year. Subjects with a history of amblyopia, strabismus, presbyopia, or a self-reported susceptibility of motion sickness were excluded from the study. Participants were fully informed about the risks and benefits of the study, gave informed consent in writing, and were free to withdraw without giving a reason at any stage. Our procedures adhered to the tenets of the Declaration of Helsinki. The study was approved by the University of Auckland Human Participants Ethics Committee (reference 021195). Participants were compensated for their time with gift vouchers.The study used a randomised cross-over design, with all participants completing three trials in a randomised order—each lasting 7 min—within a single visit. In each trial, the cellphone was positioned within the virtual environment mounted either on the front windshield or down by the participant’s knee , or there was no cellphone present. Before each test, each participant engaged in 2 min of familiarisation with the task/environment before data recording commenced. This phase served to acclimatise the participant to the virtual environment and allowed the vehicle to get to speed so that the initial period of vehicle acceleration from standstill did not confound the measures. Between conditions, participants removed the virtual reality headset and rested if necessary . When participants were ready to begin a trial, they placed the headset on their head and aligned it with their eyes themselves, before the headset was secured in place with velcro straps.http://retrovalorem.wixsite.com) was modified in Blender to make it right-hand drive and incorporate additional headroom. We also added a rotating steering wheel, realistic engine sounds, and an operational dashboard with speedometer and tachometer. The car had an automatic transmission and was controlled using a steering wheel with force feedback and pedals . The force feedback added mild turn resistance, a centring force, and tactile feedback when one or more wheels were off the road.A virtual 20 km looping road, incorporating gentle left and right turns made over shallow dips and hills, was created in 3D modelling software , and then imported into a 3D game engine . We designed the road to resemble a typical rural two-lane New Zealand road, with a large flat grass verge on either side and double-yellow centre lines, which indicate vehicles are not permitted to cross the centre line. There were no intersections or other traffic on the road. A simple 3D car model  on a separate display. The timing of message arrivals was randomly distributed over the 7-min trial period, with at least 30 s between each message and the end of the trial. To encourage attentive driving, participants were also tasked with spotting roadside items (custom made 3D kiwi models), which were placed randomly on the roadside around the track. The program kept track of how many kiwi were driven past, and the percentage seen was recorded per trial. There was no other traffic nor any hazards on the road, and participants were advised of the nature of the tasks ahead of time. Participants were also advised to comply with the speed limit of 100 km per hour and to follow normal road rules.car position and speed (sampled at 90 Hz), which was used to calculate the standard deviation of lane position (SDLP). Contrary to the use of mean lane position—which would effectively force participants to drive in the centre of the lane—SDLP instead captures changes in natural lane positioning36. Similarly, the standard deviation of speed (SDS) was also calculated, as was the time spent speeding (i.e. faster than 100 km/h), the mean speed during the entire trial, and the duration of excursions from the correct lane, (measured from when the tyres of the vehicle touched either the left or right bounding road markers).Outcomes were compared within-subject between each of the three trials with a different cellphone position. There were three categories of outcome measures for each trial. The first class of outcome measures was eye gaze behaviour, which was also captured at 90 Hz. Eye gaze was nominally classified into objects of focus: either the front windscreen, driver or passenger front side window, the dashboard, the cellphone, or elsewhere inside the car. As some changes in gaze position (e.g. from the windscreen to the cellphone) also captured intermediary targets passed over during saccade (e.g. car interior), gaze data was filtered with a rolling mode with a width of 100 ms (9 samples), based on the minimum dwell time between consecutive saccades37. Number of glances and total gaze duration were compared between trials, as was the mean latency time to look at the cellphone (when present) after receiving a text message.The second class of outcome measure was Prophet, available from https://facebook.github.io/prophet/)38. The cross-validation function in Prophet was used to ensure an optimal fit to the data before the text message arrived. The time series function was then extrapolated a further 5 s beyond the arrival of the text message, with the mean absolute error (MAE) of the model against the observed driving behaviour recorded. The MAE of all ten text messages received during a single trial was recorded and taken as a mean MAE per trial. If driving behaviour was unaffected by the arrival of the text message, the time series would be expected to fit the post-text data well, giving a lower MAE  compared to the data sampling rate (90 Hz), we investigated the immediate effect of receiving a text message on driving performance by comparing driving characteristics immediately prior to and following the arrival of each text message as an interrupted time-series. Measurements of speed and lane position in the 10 s leading up to a text message were fit with an additive time-series model  = 17.68, p < 0.001, Fig. p < 0.001, None—Lap: − 18.20 mean rank, t = − 5.179, p < 0.001). There was no difference in mean speed when the cellphone was in the lap compared to when it was on the dashboard . While the mean speed was higher in trials with a cellphone present, there was no difference in the standard deviation of speed (SDS) among the three trials  = 1.51, p = 0.230, Fig. All 30 participants completed the full 7-min trial under all three test conditions. There was a significant difference in the mean speed among the trials  = 17.67, p < 0.001, Fig. p < 0.001, None—Lap: 8.73 m, t = 2.271, p = 0.027). The SDLP was higher when the cellphone was in the lap compared to when it was on the dashboard . This translated into differences in the time spent out of the correct lane  = 17.02, p < 0.001, Fig. t = 5.804, p < 0.001, None—Lap: 11.37%, t = 3.412, p = 0.002). Between the two trials in which the cellphone was present, the car spent more time out of the correct lane when the cellphone was in the lap compared with when it was on the dashboard .In terms of lane positioning, there were differences in the variation in car lane positioning across trials  = 10.40, p = 0.006, Fig. p = 0.032). In terms of lane positioning, there was also a difference in the change in SDLP between the three conditions after receiving the text message (Chi-sq(2) = 0.47, p = 0.792, Fig. To investigate any abrupt change in driving behaviour immediately after receiving a text message, a model was fit to driving behaviour prior to the text message arrival, enabling a comparison of the goodness of fit  after receiving the text message among the three different conditions. In terms of vehicle speed, there was a significant difference among the three conditions  = 47.82, p < 0.001, Fig. p < 0.001) or in the lap position . There was also a higher number of gaze changes when the cellphone was on the window compared to the lap position . There were also differences in the number of glances at the dashboard, where the speedometer was located,  = 7.52, p = 0.001), with a higher number of glances when the cellphone was in the lap (91 IQR 67–137 glances) than when the cellphone was either on the windscreen  or absent . There was no difference in the number of glances at the dashboard between the no cellphone and windscreen trials . In the two cellphone trials, all but one of the participants looked at the cellphone more frequently when it was positioned on the windscreen  than on the lap . With a cellphone present, participants spent less time looking out the windscreen  = 55.43, p < 0.001), and spent over twice as much time looking at the cellphone when it was on the windscreen  compared to when it was on the lap . Despite differences in the total number of glances at, and the total time spent looking at the cellphone, there was no difference in the mean cellphone glance duration , nor in the amount of time spent looking forwards out the windscreen between the two cellphone positions . We also compared latency between the arrival of a text message and the time taken to look at the cellphone  in each position. There was a much greater latency when the cellphone was in the lap  compared to when it was on the windscreen .Fixation behaviour differed across trials  = 2.55, p = 0.279), with almost all kiwis seen in each trial condition . However, there was a difference in the percentage of maths problems correctly answered (Chi-sq(2) = 13.85, p < 0.001), with an average of one additional error made when a cellphone was not present (mean 14% error rate) compared to when it was on the windscreen , or in the lap position .In terms of the secondary diverted attention tasks, all participants were well engaged in all three conditions. There was no difference between trials in the proportion of kiwis seen . This agrees well with the attentional speed control theory that indulging in a secondary attention-requiring task while driving compromises resources that are required to keep speed under control, resulting in an increase in driving speed31.These changes in driving behaviour are consistent with the cognitive load framework detailed by Engström48. The very brief latency to glance (median 86.2 ms) at the cellphone after receiving the text message when in the windscreen position may result from increased impulsivity when the cellphone is always in view49. However, this increase in the number of glances may not affect driving safety. A real-world driving study has shown that although drivers spent approximately 4% of their time looking at the in-vehicle information systems, they spent on average only half a second per glance, and they do so without reducing glances to the mirrors, driving equipment, or the centre of the road50. The comparative additional latency to glance at the cellphone when in the lap position could reflect an awareness of the additional cognitive distraction the position poses. Participants may be aware that looking further away from the road to check the phone would be disruptive to driving performance, so they deliberately waited for a suitable time to check the phone (e.g. immediately after negotiating a corner).The presence of a cellphone, and its position, also influenced gaze behaviour. When on the windscreen, it received more than twice the number of glances than when on the lap. A cellphone on the windscreen presents a constant temptation to glance at it, which would be especially problematic for drivers with poorer impulse controlThe high accuracy achieved in the maths tasks shows that participants were adequately attending to the secondary diverted attention tasks, and the higher score in the cellphone-present trials likely reflects the advantage of a lesser cognitive load and consequently an ability to devote greater resources for visual load, as the participants had the added benefit of visualising numbers on the cellphone and not needing to memorise the addends. Interestingly, despite having less time available to view their surroundings when looking at a cellphone, there was no difference in the number of kiwi seen between the trials. This task, in addition to being a way to ensure participant engagement, served as a proxy ‘hazard identification’ scenario, so it is reassuring that essentially all targets were correctly identified during all trials. Modification of gaze behaviour helps to explain this observation, as we found greater latency in looking at the phone after receiving the text message when it was in the lap, compared to when it was on the windscreen. This finding suggests that participants spent time waiting for an opportune moment and ensuring the car was positioned correctly, before taking their eyes off the road. This behaviour would include looking forward to potential hazards/targets.51. Our study also has limited ability to extrapolate to real-world safety, as there was no real threat to our participants, and our environment was static; if there was no hazard present before gazing away from the road, one was not going to appear suddenly. This is perhaps the most significant issue with distracted attention while driving. While known risks can be theoretically adjusted for through modified behaviour, unseen or unpredictable hazards can arise when the gaze is averted from the road. Additionally, our diverted attention task (answering text messages consisting of maths problems) would potentially present a diminished sense of urgency in checking the cellphone—answering a maths problem is unlikely to be as exciting as participating in a group chat, for example. Also, while the maths problem served as an information processing cognitive task, this too is likely different from what a cellphone using distracted driver may typically experience, and gaze becomes increasingly forward-looking with increasingly complex distraction tasks52. However, we found good engagement and comparative performance in the diverted attention tasks across trials. Nonetheless, it is unlikely that our results will directly extrapolate into real-life driving, and the results are best viewed as within-subject comparisons.A significant limitation of this study is our use of a virtual reality simulator, and a simulated text message as a distraction. A comparison of simulator versus real-world performance showed that while distractions may have a larger influence on driving performance in a simulator, comparative simulator performance, like our study design, is reasonably consistent with real-world driving53, who are known to routinely underestimate road hazards54, and admit to frequently sending text messages while driving55. As the number of young drivers on the road increases over time, the number of vehicle accidents attributable to distraction from cellphone-use is likely to continue to rise. The legislation we have in place is intended to prevent dangerous driving behaviour, but the addictive nature of cellphone use is leading drivers—despite being aware of the legislation and risks—frequently engaging in behaviour while driving that reduces their capacity to operate a vehicle responsibly. Furthermore, investigations into the impact of legislation designed to deter cellphone use while driving are clearly warranted.Most vehicle crashes involve younger driversIt is established that cellphone use while driving distracts the driver from the primary task of operating the vehicle, and puts them and others at increased risk of harm. However, legislation to prevent or restrict cellphone use runs counter to the additive nature of these devices, especially in younger age groups. We found that, while viewing a cellphone in a concealed position, drivers demonstrated inferior driving behaviour, with poorer control over lane position and speed. Further research, ideally incorporating more realistic external hazards, would be useful to determine whether this legislative changes create a safer driving environment for all.


The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer’s disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study, we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF)Thirty-six participants with sporadic PPA  as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aβ42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 , CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11.In CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5 was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF, i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13).Differential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target.The online version contains supplementary material available at 10.1186/s12974-021-02247-3. The primary progressive aphasias (PPA) are a rare group of disorders characterised by focal degeneration of the brain regions involved in language function  and fallRecent studies have shown that neuroinflammation is an important pathophysiological factor in neurodegenerative disorders . AlthougThirty-six people with sporadic PPA and available CSF and plasma were consecutively recruited through the Longitudinal Investigation of FTD (LIFTD) study at University College London Table : 11 svPPTwenty chemokines were measured in the CSF and plasma of all participants using Proximity Extension Assay technology on the Olink® neuroinflammatory panel . BrieflyAll statistical analyses were performed in STATA (v.16)) with the primary analysis focused on the results in the CSF. As this was an exploratory study, no correction for multiplicity was performed. The Shapiro-Wilk test was performed to determine the normality of distribution of each chemokine measure in each group.U tests.Within the control group, Spearman correlation coefficients were assessed for each individual chemokine between their values and the age of participants at CSF collection. Sex differences were calculated using Mann-Whitney The levels of each chemokine in the CSF were then compared between groups using a linear regression model; bootstrapping with 1000 repetitions was used if the chemokine measures were not normal.Spearman correlation coefficients were assessed for each individual chemokine between their values and each of Aβ42 and total tau (t-tau) concentrations within the control and PPA groups.In order to explore the relationship between chemokine values in CSF and plasma, Spearman correlation coefficients were assessed in each individual chemokine between CSF and plasma values within the control group as well as the disease groups.The levels of each chemokine in the plasma were subsequently compared between groups using a linear regression model as previously; bootstrapping with 1000 repetitions was used if the chemokine measures were not normal.There were no significant differences between the groups in terms of either age at CSF collection or sex Table .p = 0.016) (Supplementary Table p = 0.034).Within the control group, no significant correlations were found between chemokines and age except for CXCL9  and were not assessed further. Seven of the remaining 17 chemokines showed a significant difference between groups. In both svPPA and nfvPPA, CCL19 and CXCL6 were decreased compared with controls , and CXCL5 was correlated in svPPA .No correlations were found between Aβ42 concentrations and values of any of the chemokines within the controls or the PPA groups except for a correlation in the nfvPPA group for CXCL6: rho = 0.58, p = 0.039; CCL11: rho = 0.46; p = 0.048; CCL25: rho = 0.53, p = 0.021), the lvPPA group , and the nfvPPA group . No correlations were seen in the svPPA group.In the chemokines that were found to be abnormal in CSF across groups, none of the CSF values were correlated with plasma values within the control group or any of the PPA groups. Only chemokines for which no significant group differences were seen showed a correlation between CSF and plasma values, both within the control group  and those with FTLD . Comparing the CSF chemokine values with CSF biomarkers of amyloid and tau, CX3CL1, which was increased in lvPPA, was significantly correlated with t-tau concentrations across all of the groups.In keeping with lvPPA being associated with underlying AD pathology, the findings of increased CCL2, CCL3, and CX3CL1 in this group parallel previous studies in those with a typical AD clinical presentation –18. CCL2p = 0.068), increased concentrations of which have previously been shown to help predict progression from MCI to AD [Although non-significant, a number of other chemokines showed a trend to an increase in lvPPA compared with controls, e.g. CCL23  and nfvPPA (tau) usually differ in their primary pathological cause. Unfortunately, little is known about alterations in chemokines levels in FTD so far. Only a few small studies have investigated chemokines, showing decreased levels of CCL5 (RANTES) and increased levels of CCL2, CXCL8, and CXCL10 in CSF , 27, altWhilst central neuroinflammatory processes in neurodegenerative disorders are increasingly well-studied, fewer studies have investigated peripheral immune findings. There was generally poor correlation between CSF chemokine values and those in plasma within the controls, suggesting that peripheral values generally do not represent central levels. However, abnormal values were found in each of the PPA variants compared with controls . Certainly for svPPA, a previous study has showed an increase in systemic autoimmune disease compared with controls , but othThere are a number of limitations of the study. We did not have access to detailed behavioural or neuropsychometry data within the cohort, and it would be useful for future studies to investigate the correlation of clinical features with chemokine levels. The presence of co-morbidities such as systemic disease, mood disorders, and cerebrovascular disease  were also not evaluated: their effect on chemokine levels would be important to clarify in further analyses. Whilst each group was of similar disease duration, participants were on average around 3 to 5 years into their illness. It would therefore be helpful to study both people very early in their clinical syndrome as well as to investigate longitudinal change in chemokines in PPA in order to understand the temporal relationship within the disease.Overall, this study highlights the complex inflammatory response in the different variants of PPA and shows clear differences between those with AD and FTLD pathology. Such biomarkers may be helpful in future trials for a number of reasons including assessing the extent of neuroinflammation present , althougAdditional file 1: Supplementary Figure 1. Mean normalized protein expression values for the chemokines in controls and each of PPA groups in plasma. Significant differences with p values are shown on the graphs.Additional file 2: Supplementary Table 1. Spearman correlation coefficients and p-values comparing chemokines with age at CSF collection within the control group. Supplementary Table 2. Mean (standard deviation) normalized protein expression values for the chemokines in controls and each of PPA groups in CSF. Mean differences between the PPA groups and controls along with 95% confidence intervals and p values (significant in bold) are shown underneath. N/A = not assessed >80% values were below the lower limit of detection. Supplementary Table 3. Mean (standard deviation) normalized protein expression values for the chemokines in controls and each of PPA groups in plasma. Mean differences between the PPA groups and controls along with 95% confidence intervals and p values (significant in bold) are shown underneath. N/A = not assessed >80% values were below the lower limit of detection.


Daytime urinary incontinence (UI) is common in childhood and often persists into adolescence. UI in adolescence is associated with a range of adverse outcomes, including depressive symptoms, peer victimization, poor self-image, and problems with peer relationships. The first-line conservative treatment for UI is bladder training (standard urotherapy) that aims to establish a regular fluid intake and a timed schedule for toilet visits. The success of bladder training is strongly dependent on good concordance, which can be challenging for young people.This paper aims to describe the development of a smartphone app (URApp) that aims to improve concordance with bladder training in young people aged 11 to 19 years.URApp was designed by using participatory co-design methods and was guided by the person-based approach to intervention design. The core app functions were based on clinical guidance and included setting a daily drinking goal that records fluid intake and toilet visits, setting reminders to drink fluids and go to the toilet, and recording progress toward drinking goals. The development of URApp comprised the following four stages: a review of current smartphone apps for UI, participatory co-design workshops with young people with UI for gathering user requirements and developing wireframes, the development of a URApp prototype, and the user testing of the prototype through qualitative interviews with 23 young people with UI or urgency aged 10 to 19 years and 8 clinicians. The app functions and additional functionalities for supporting concordance and behavior change were iteratively optimized throughout the app development process.Young people who tested URApp judged it to be a helpful way of supporting their concordance with a timed schedule for toilet visits and drinking. They reported high levels of acceptability and engagement. Preliminary findings indicated that some young people experienced improvements in their bladder symptoms, including a reduction in UI. Clinicians reported that URApp was clinically appropriate and aligned with the best practice guidelines for bladder training. URApp was deemed age appropriate, with all clinicians reporting that they would use it within their own clinics. Clinicians felt URApp would be of particular benefit to patients whose symptoms were not improving or those who were not engaging with their treatment plans.The next stage is to evaluate URApp in a range of settings, including pediatric continence clinics, primary care, and schools. This research is needed to test whether URApp is an effective (and cost-effective) solution for improving concordance with bladder training, reducing bladder symptoms, and improving the quality of life. Daytime urinary incontinence (UI), which is the involuntary leakage of urine during the day, is common in childhood and is generally assumed to resolve with age. However, there is evidence from epidemiological studies that childhood UI often persists into adolescence -5. For eUI in adolescence is associated with a range of adverse outcomes, including depressive symptoms, peer victimization, poor self-image, and problems with peer relationships . Key conMost cases of UI in children and adolescents are functional , and thBladder training can be an effective treatment for UI ,13; howeThis paper describes the development of a smartphone app (URApp ) for youThe development of URApp comprised 4 stages, as follows:Review of current smartphone apps for UIParticipatory co-design workshops with young people with UI to gather user requirements for the app and to develop the wireframesDevelopment of the app prototypeUser testing of the app prototype comprising in-depth qualitative research with young people and clinicians to explore their views of URAppThe methods and results for each stage have been presented together to aid the understanding of the app development process. A flow diagram of the method sequence is shown in Ethical approval for all stages of the development process was granted by the University of Bristol research ethics committee.Input from expert clinicians was obtained throughout the app development process to ensure that URApp was compatible with clinical advice given to young people receiving treatment for UI. Clinical input was obtained from (1) stakeholders in the study steering group, including a lead consultant pediatrician in charge of a specialist bladder clinic and a specialist bladder and bowel care nurse; (2) a clinical advisory group comprising 2 specialist nurses and a nephrologist; and (3) interviews with clinicians involved in continence care as part of the user testing stage.Participants were aged between 10 and 19 years, with current (or previous) experience of functional UI or urgency, able to provide informed consent (aged 16-19 years) or assent (aged 10-15 years), and able to speak and understand English. Young people taking part in user testing were also required to have an Android or iOS smartphone.Young people who took part in the participatory co-design workshops and user testing were recruited through advertisements on the website of ERIC, The Children’s Bowel and Bladder Charity , and theClinicians were recruited through an extensive network of clinical contacts established by ERIC and the Paediatric Continence Forum . PurposiWritten informed consent was obtained from all the participants. Parent consent and child assent were obtained from participants aged <16 years.with or by members of the public rather than to, about, or for them You can change what data is shown, it’s another nice way of being able to see. [P2]I think it’s a good idea, you can see how much you’ve improved, if the app is helping you.P22Other participants preferred the summary and daily diary, as they provided a simpler overview of the data. The key feedback was that users wanted a space to record events, their mood, and any factors that might affect their symptoms, such as stressful events, changes in medication, or certain drinks:Being able to track things using your own words as well and maybe being able to track your mood, because it’s something that’s closely linked to having a bladder or bowel condition.P2Feedback on the rewards was very positive, with young people reporting that they liked all the streaks, stars, and trophies. Younger participants particularly liked the star and trophy rewards and thought this would encourage them to use the app and keep them motivated:It makes you feel more committed to achieving your goals...You achieve stuff...It makes you feel good about yourself. You have something to tell you that you’ve done it good.P14Young people also liked how similar the streak rewards were to those in other apps that they used:The language (“streaks”) makes it easy for kids to understand because it’s like other apps like Snapchat.P8Young people found the daily feedback on their drinking goals easy to understand and liked the large graphics. The feedback indicates the achieved percentage of daily drinking goals and provides an appropriate, encouraging message based on the percentage. A few participants reported that they would like to be able to see if they went over their daily drinking goal, for example, 110%.There was less engagement with the weekly feedback among some young people who did not use this feature. A small number reported that the notification to complete the feedback was not obvious enough, and they did not see the prompt. Those that did use the weekly feedback found the personalized feedback messages and linked support pages interesting but reported that they were too text heavy and long:There could be a few pictures in it, stick figures. [P15]More pictures would be useful, because how your body works is quite difficult anyway, showing the bladder has muscles that contract too much.P2A total of 8 clinicians provided feedback on the app  might have an adverse impact on bladder function in some patients.URApp was developed using a rigorous approach to intervention and app design, which is underpinned by the behavior change theory. Development methods were guided by Medical Research Council recommendations for the development and evaluation of digital interventions  and infoThe end user population was included throughout the development process. This means that URApp was centrally designed around user needs and feedback. Engaging with the app development team from the project’s outset ensured that the proposed design and functions of the app were feasible in terms of cost and delivery within the project timeline.Although our results are encouraging, this work does have limitations. User testing was restricted to young people with English as a first language and with predominantly high levels of educational ability. Further testing and refinement of URApp is needed with young people from a range of educational, socioeconomic, and ethnic backgrounds.In addition, young people included in the study had already engaged in treatment for UI, either through primary or secondary care. It is not clear if URApp would offer the same level of acceptability and utility to young people who had not yet engaged in treatment. This is an important area for further research, as the stigma of continence problems prevents many young people from seeking treatment.This study provides initial support for the acceptability and usability of URApp. The next stage is to test whether URApp is effective in aiding concordance with bladder training, and therefore, improve bladder symptoms and enhance well-being. URApp should be tested across a range of settings, including pediatric continence clinics, primary care, and schools (via school nurses). The cost-effectiveness of using URApp to support bladder training in primary and secondary care settings and in the community also needs to be examined. An interactive website  has been


Postoperative cerebrospinal fluid (CSF) leakage represents a challenge even for experienced pituitary surgeons. We aimed to quantitatively synthesize data from studies regarding the risk factors for postoperative CSF leakage after transsphenoidal surgery (TSS) for pituitary adenoma (PA).PubMed, Web of Science, The Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang database, and VIP database were searched for case–control and cohort studies, focusing on the risk factors associated with postoperative CSF leakage after TSS for PA. Pooled odds ratios (ORs) and 95% confidence intervals were calculated to determine the risk factors.A total of 34 case–control and cohort studies involving a total of 9,144 patients with PA were included in this systematic review. The overall rate of postoperative CSF leakage after TSS for PA was 5.6%. Tumor size, adenoma consistency, revision surgery, and intraoperative CSF leakage were independent risk factors for postoperative CSF leakage . By contrast, the endoscopic approach showed a slight protective benefit compared with the microscopic approach in TSS .This review provides a comprehensive overview of the quality of the evidence base, informing clinical staff of the importance of screening risk factors for postoperative CSF leakage after TSS for PA. More attention should be paid to PA patients at high risk for CSF leakage after TSS to reduce complications and improve prognosis.The online version contains supplementary material available at 10.1186/s12883-021-02440-0. Pituitary adenomas (PAs) are benign neoplasms that represent the most common type of pituitary disorder . A serieAlthough TSS for PA is considered safe , possiblElucidating the risk factors associated with CSF leakage after TSS is important and helpful for patients with PA. The identification of these factors may permit the implementation of strategies to reduce postoperative complications. However, limited attention has been paid to factors associated with such CSF leaks. Some differences have been reported among the results of previous studies on risk factors, which may be due to different inclusion criteria and small sample sizes. No comprehensive meta-analysis has been performed to examine the risk factors for CSF leakage after TSS. Therefore, the purpose of our article was to systematically review the potential risk factors associated with the development of postoperative CSF leaks after TSS in patients with PA.A search was performed in PubMed, Web of Science, The Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang database, and VIP database to identify articles published from database inception to December 2020. We used a search strategy that included truncated free text and exploded medical subject heading (MeSH) terms relevant to “pituitary adenoma,” “postoperative cerebrospinal fluid leak,” “transsphenoidal surgery,” or “risk factors.” For example, the search details for PubMed/Medline were as follows: (((“pituitary adenoma”[Title/Abstract] OR “pituitary adenoma”[All Fields] OR “pituitary tumor”[Title/Abstract] OR “pituitary tumor”[All Fields]) AND  OR “cerebrospinal fluid leak”[All Fields])) AND  AND “risk factor”). In addition, manual searches were conducted of the reference sections of retrieved articles to identify additional published work relevant to this study.All retrieved studies were reviewed for inclusion based on the following criteria: 1) patients who underwent TSS and were pathologically diagnosed with PA according to postoperative immunocytology; 2) studies mentioning CSF leakage after TSS; and 3) prospective or retrospective studies.The exclusion criteria were as follows: 1) spontaneous CSF leakage; 2) case reports, reviews, letters, or dissertation; 3) articles in other languages than English and Chinese; 4) reported only duplicate data; 5) no data regarding postoperative CSF leakage; 6) cadaver or animal studies; and 7) articles with incomplete information or incomplete data.Two reviewers independently screened the titles and abstracts of all articles for eligibility. The screening results from the two reviewers were compared, and disagreements were discussed to reach a consensus. Next, full-text reviews and data extraction were independently performed by the same two reviewers, and the results were again compared and discussed to reach an agreement. A third reviewer was consulted to assist in the resolution of unresolved discrepancies between reviewers at any stage in the article selection process.Two authors independently extracted data from the selected articles using a standard data extraction form. Data included the following study items: publication year, first author, study design, sample size, population characteristics, number of CSF leaks after TSS, and associated risk factors.Two authors independently assessed the quality of all included studies using the Newcastle–Ottawa Scale (NOS) . The NOS2 tests for heterogeneity were conducted. When the I2 value was less than 50%, indicating low heterogeneity, a fixed-effects analysis was used to estimate the assumed common effect. When the I2 value was 50% or above, indicating increased heterogeneity, a random-effects analysis was used to estimate the mean distribution of effects across all studies, yielding wider confidence intervals for the combined effect size [2 ≥ 50%). The odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were calculated for categorical variables, based on the number of postoperative CSF leakage groups and the total sample size for each risk factor. Funnel plots were used to assess publication bias and were generated for all factors that were identified in more than 10 studies included in the present study [Review Manager software  was used to perform statistical analyses. For each of the dependent factors, effect sizes were calculated separately. For each dependent variable, an overall effect size was calculated by weighting all the effect sizes calculated for each individual study according to relative sample sizes . To testect size . In addint study .A total of 14 case–control studies and 20 cohort studies were included in the present analysis. A flow diagram of the selection and exclusion processes, together with the respective justifications for exclusion, is shown in Fig. 2 = 53%, P = 0.05).A total of eight studies reported differences in the incidence of postoperative CSF leakage among patients with different tumor sizes Fig. . The anaA total of five studies reported differences in the incidence of postoperative CSF leakage depending on the adenoma consistency Fig. . The metA total of six studies provided data regarding the relationship between revision surgery and postoperative CSF leakage Fig. . The met2 = 21%, P > 0.05). Through discussion among the researchers, Tian’s study was determined to meet the inclusion criteria and was retained. Using a funnel plot, most studies were found to be distributed in the center and top of the plot, indicating little publication bias  or functional adenoma types . Similarly, total resection  and no perioperative lumbar drainage  are not risk factors for postoperative CSF leakage. We have included these non-significant factors analyzed and the related diagrams in a “Supplementary Materials”.This review quantitatively synthesized the currently available evidence on the prevalence and risk factors associated with the incidence of postoperative CSF leakage after TSS in 34 studies, which included 9,144 participants with PA, to demonstrate a pooled global prevalence of 5.6%. We evaluated the relationships between these nine factors and the risk of postoperative CSF leakage. Our data indicated that tumor size, adenoma consistency, revision surgery, and intraoperative CSF leakage were independent risk factors for postoperative CSF leakage. By contrast, the use of an endoscopic approach showed a significant protective benefit compared with the microscopic approach in TSS, whereas sex, functional adenoma type, resection rate, and perioperative LD were not found to be related to the occurrence of postoperative CSF leakage.The effect of tumor size on postoperative CSF leakage is under debate, with some studies showing that patients with giant adenoma are more likely to experience postoperative CSF leakage than those with macroadenoma or microadenoma , 10. In The current analysis showed that adenoma consistency was associated with the occurrence of postoperative CSF leakage. Most PAs have a soft texture that can easily be resected with curettage and suction . Hard  were reportedly associated with postoperative CSF leakage , the curThe present meta-analysis could not determine whether the functional adenoma type was associated with an increased risk of postoperative CSF leakage in PA patients undergoing TSS. Two studies found that postoperative CSF leakage was more common in adrenocorticotropic hormone (ACTH)-producing adenomas , 47, whiWhether the resection rate is a risk factor for postoperative CSF leakage remains controversial. A retrospective analysis of 1,641 patients with PA undergoing TSS showed that the incidence of postoperative CSF leakage in patients with total resection was significantly higher than that among patients with partial or subtotal resections . The mecThe use of LD remains under debate. In a meta-analysis , LD had The acknowledged limitations of this study should be mentioned. First, unpublished articles were not included in this systematic review, likely contributing to publication bias. Second, a lack of randomized control trials (RCTs) examining the occurrence of postoperative CSF leakage exists, which may reduce the reliability of the results of our study. Further studies using RCT designs may enrich and substantiate our results. Moreover, there were many kinds of fillers, such as gelfoam, absorbable hemostatic gauze, autologous fat, pedicled vascularized flap and so on. A specialized mesh meta-analysis is better used to compare which closure techniques can reduce the risk of CSF leakage. Despite these limitations, this study represents the first known meta-analysis to examine the risk factors associated with postoperative CSF leakage after TSS in PA patients.This study makes a significant contribution to clinical practice because our findings can focus clinical medical workers’ attention on the occurrence of postoperative CSF leakage after TSS in PA patients. We have shown that which factors are more likely to cause CSF leakage in these patients for clinicians, especially neurosurgeons. When operating on PA patients with high-risk CSF leakage, surgeons should take some targeted strategies, such as selecting appropriate surgical methods and resection techniques. In addition, clinical nurses should strengthen observation of high-risk patients in postoperative nursing, (such as more frequent ward rounds), to achieve early detection and treatment of CSF leakage.This review provides a comprehensive overview of the quality of the evidence base to inform clinical staff of the importance of screening risk factors for postoperative CSF leakage after TSS for PA. The risk factors associated with postoperative CSF leakage after TSS include tumor size, adenoma consistency, revision surgery, and intraoperative CSF leakage. However, the use of the endoscopic approach showed a significant protective benefit compared with the microscopic approach in TSS, whereas sex, adenoma functional type, the resection rate, and perioperative LD were not identified as significant risk factors for CSF leakage in this meta-analysis. More attention should be paid to PA patients with high risks of CSF leakage after TSS to reduce complications and improve prognosis.Additional file 1.


Most parameters for test–retest reliability of all thresholds did not show any fixed bias, except for the second ventilatory threshold. The feasibility of the sEMG thresholds was lower than the ventilatory thresholds, particularly of the first sEMG threshold. As expected, the sEMG thresholds, particularly the first threshold, occurred relatively earlier in time than the ventilatory thresholds in patients compared with healthy subjects. A possible explanation could be (a combination of) a difference in fiber type composition, disuse, and limited muscle-specific force in patients with neuromuscular disorders. sEMG measurements during submaximal dynamic exercises are needed to generalize the measurements to daily life activities for future use in prescribing and evaluating rehabilitation interventions.In healthy persons, there is an excellent relation between the timing of the (two) surface electromyography (sEMG) thresholds and the (two) ventilatory thresholds during exercise. The primary aim of this study was to determine the relative timing of both sEMG and ventilatory thresholds in patients with neuromuscular disorders compared with healthy subjects during a maximal ergospirometry cycling test. We hypothesized that in patients with neuromuscular disorders, the sEMG thresholds would occur relatively earlier in time than the ventilatory thresholds, compared to healthy subjects, because performance fatigability occurs more rapidly. In total, 24 healthy controls and 32 patients with a neuromuscular disorder performed a cardiopulmonary exercise test on a bicycle using a 10-min ramp protocol, during which we collected ergospirometry data: power at both ventilatory and sEMG thresholds, and sEMG data of lower leg muscles. In line with our hypothesis, normalized values for all thresholds were lower for patients than healthy subjects. These differences were significant for the first ventilatory ( Approximately 1 in every 625 persons worldwide experiences some type of neuromuscular disorder (NMD) in their lifetime . A NMD iIn healthy adults, perceptions of fatigability are predictable and transient phenomena typically brought about by prolonged exertion that diminish with rest and do not interfere with usual daily activities. Establishing an association between fatigability and fatigue complaints is an important goal for clinical research but has proven difficult for most conditions . Percept+ and lactate concentrations. Furthermore, Moreover, the majority of the patients with NMD are bothered more by performance fatigability than they are by muscle weakness, as performance fatigability highly fluctuates and is generally less predictable than muscle weakness. Although performance fatigability is a common and potentially the most prominent and disabling symptom of NMD , there iSo far, there is an excellent relation between the timing of the (two) sEMG Ths and the (two) ventilatory thresholds (VTs) during exercise in healthy controls (HC) . The firThe primary aim of this study was to determine the relative timing of both sEMG Ths and the VTs in patients with NMD compared with HC during a maximal cycling test. To do so, we aim to study the relative difference in timing between the sEMG Ths and VTs in patients with NMD and compare the findings with HC. We expect to find significantly lower normalized values for sEMG Ths and VTs in NMD patients than HC. Moreover, since in patients with NMD, compared to HC, performance fatigability is more frequently a limiting factor in daily life activities than cardiorespiratory fitness, we hypothesized the sEMG Ths to occur at relatively and absolute lower power values than the VTs in patients with NMD, compared to the HC. The secondary aims of this study were to determine and compare the feasibility and reliability of the sEMG Ths and VTs in NMD patients. We expect that the reliability of the sEMG Ths in both HC and patients will be higher than the reliability of the VTs, as the sEMG Ths are more muscle-specific and the VTs are a derivative from the muscular and metabolic system, provided that cardiorespiratory functioning is not impaired.Healthy participants were recruited through advertisements on social media, and NMD patients were recruited through the Radboud University Medical Center (Radboudumc) outpatient clinic. All patients were diagnosed with a slowly progressive NMD on clinical and genetic grounds. Participants were excluded from the study if they had cognitive impairments, used beta-blockers medication, could not cycle for 20 min, or had contraindications to conduct a maximal cardiopulmonary stress test according to the AHA guidelines . This stAll participants performed a maximal incremental ergospirometry cycle test using a steep ramp protocol. The test was performed on an electromagnetically braked leg cycle ergometer , which was connected to the Quarck Cardio Pulmonary Exercise Test (CPET) .The exercise protocol consisted of a 1-min resting phase, a 3-min warming-up at 0 W, 3-min warming-up at 10–15% of expected power output, a ramp protocol in which workload gradually increased with 5–35 W per minute (based on expected power), and a cooling down. The power increase in the ramp protocol was estimated based on gender, age, fitness level, and the Medical Research Council (MRC) score of a participant. This muscle scale grades muscle power on a scale of 0–5 in relation to the maximum expected for that muscle. The maximum performance was aimed to be achieved within 8–12 min. Patients were instructed to cycle with a pedal frequency above 60 rpm, the progressive loading phase was terminated, and a 3-min recovery phase was initiated/commenced until exhaustion. When the pedal frequency dropped below 60 rpm, the test was terminated. Participants’ feet were strapped to the pedals of the Excalibur bike. A medical doctor was present for the whole duration of the test. We performed a breath-by-breath analysis of pulmonary gas exchange using this setup, including continuous 12-channel ECG monitoring and blood pressure measurement at multiple moments throughout the test. In addition, we simultaneously measured the sEMG of several leg muscles with the TMSi Mobi . This paper combines the results of multiple smaller studies in both HC and NMD patients.2) plotted against oxygen consumption (VO2) shows a slope of slightly less than one for work below the anaerobic threshold  was used for breath-to-breath gas analysis. The minute ventilation, oxygen consumption, and carbon dioxide production were collected. The power (W) at the VT1 and the VT2 was determined with this data. The first breakpoint is VT1; the second breakpoint is VT2. VT1 and VT2 were visually detected as two break points in the linearity of the minute ventilation by two experienced independent examiners. Several methods were combined to determine the VT1 and VT2; the V-slope method, the ventilatory equivalent method, and the PET method. The V-slope method of determining the anaerobic threshold makes use of the fact that carbon dioxide production , vastus medialis (VM), rectus femoris (RF), biceps femoris (BF)] per participant were collected during the cycling test see . These mFeasibility of both the maximal incremental ergospirometry cycle test and the determination of the VTs and sEMG Ths was determined by the percentage of participants that could complete the exercise test and the percentage of participants in which the different thresholds  could be determined. The maximal incremental ergospirometry cycle test and the determination of the VTs and sEMG Ths were found feasible when they could be, respectively, performed and determined in >75% of the participants.The first step of the reliability analysis was to determine the inter-rater reliability of the power at sEMG Th1 and sEMG Th2 by calculating the intraclass correlation coefficient (ICC) and mean difference between the values scored by examiner one compared to the scores of examiner two. The second step of the reliability analysis was to determine the test–retest reliability for maximal power (Pmax) and power at VT1, VT2, sEMG Th1, sEMG Th2 of the first test compared to the second test.t-tests on the difference between NMD patients and HC. To make a relative comparison between patients and HC possible, we normalized the occurrence of both ventilatory and sEMG Ths by calculating the power at the thresholds as a percentage of the maximal power cycled.To gain insight into the relationship between the VTs and the sEMG Ths, we calculated the mean difference and limits of agreement between VT1 and sEMG Th1 and between VT2 and sEMG Th2. In addition, we determined the construct validity using student t-tests were used to test for statistical differences between HC and NMD patients. The mean group differences with 95% confidence intervals were calculated.The ICC values were calculated using a two-way mixed model with absolute agreement [ICC ]. Inter-rater reliability was acceptable if ICC > 0.7, good if ICC > 0.8, and excellent if ICC > 0.9 . Test–reAll statistical analyses were performed using IBM SPSS statistics 25.0 for Windows .p-value < 0.001). The NMD patient group consisted of a large range of conditions: bulbospinal muscular atrophy (n = 1), cardiomyopathy with involvement of muscle tissue (n = 1), chronic idiopathic axonal polyneuropathy (n = 2), chronic progressive external ophthalmoplegia (n = 1), myotonic dystrophy type 1 (n = 4), facioscapulohumeral muscular dystrophy (n = 13), Charcot Marie tooth (n = 4), myasthenia gravis (n = 1), myopathy (n = 2), necrotizing autoimmune myopathy (n = 1), poliomyelitis (n = 1), and sarcoid myopathy (n = 1). For the retest, patients bulbospinal muscular atrophy (n = 1), cardiomyopathy with involvement of muscle tissue (n = 1), chronic progressive external ophthalmoplegia (n = 1), myotonic dystrophy type 1 (n = 2), facioscapulohumeral muscular dystrophy (n = 3), poliomyelitis (n = 1), Charcot Marie tooth (n = 2), and necrotizing autoimmune myopathy (n = 1) participated in the study.In total, 56 (24 HC and 32 NMD patients) people performed an exercise test. In addition, 12 NMD patients performed two tests for the test–retest reliability. Three NMD patients were excluded from analysis as they did not complete the exercise test . The other participants all completed the exercise test, however, not all data could be used for analysis. For the HC, sEMG signals of the biceps femoris were not recorded correctly in six out of 12 participants due to a damaged sEMG cable. For the primary exercise test in NMD patients, data of 18 out of 145 (12.4%) measured muscles contained a measurement error, either due to a faulty cable, disturbance in sEMG signal, or human error.Two examiners independently determined the sEMG Ths for all valid measurements (Twelve patients performed the steep ramp protocol two times to determine test–retest reliability. p < 0.001). However, when looking at the normalized thresholds , we saw smaller differences between HC and NMD patients (p < 0.001) and VT1 (p = 0.008), and not for VT2 (p = 0.238) and sEMG Th2 (p = 0.053).To test the construct validity, the hypothesis was that the VTs and the sEMG Ths of HC were higher than NMD patients. This was indeed the case for all thresholds . Both thpatients . We hypop < 0.001) and VT1 (p = 0.008), and not for VT2 (p = 0.238) and sEMG Th2 (p = 0.053). In line with our hypothesis, the normalized sEMG Th1 (p < 0.001) and sEMG Th2 (p = 0.031) occurred at relatively lower power values than the VTs in patients compared to HC. When looking at all muscles combined, the relation between VT2 and sEMG Th2 in NMD patients shows both fixed bias and proportional bias. This indicates that the power at sEMG Th2 was significantly higher than that at VT2. In the study of The primary aim of this study was to gain more insight into performance fatigability in patients with NMD by determining the relative timing of both sEMG Ths and the VTs in patients with NMD compared with HC during a maximal ergospirometry cycling exercise test. We expected to find significantly lower normalized values for sEMG Ths and VTs  in NMD patients than HC. This was, however, only true for sEMG Th1  for all leg muscles. On the contrary, the overall inter-rater reliability for sEMG Th1 was low and only high for the right RF (0.99). The difficult detection of sEMG Th1 could be the most important reason for the low reliability. In determining the reliability, measurements for all muscles were combined. Consequently, the number of EMG measurements was higher than the number of ergospirometry measurements, which potentially biased the inter-rater reliability. The high ICC for sEMG Th2 is not surprising given the relatively small disagreements between raters.p < 0.001). This could have negatively influenced the correlation between the sEMG Th2 and the VT2. Previous studies have demonstrated that the presence of a competitor improves performance, often based on psychological and emotional responses, such as increasing motivation, positively influencing the balance of willingness to exert the required effort versus negative factors of fatigue and risk  in the retest compared to the test , both type I and IIa are activated, and during strenuous exercise [about 90% of VO2max (sEMG Th2), fibers of type I, IIa, and IIx are recruited  years, were significantly older than the HC, which were not age-matched mean age 36.4 (19.1–59.6) years, e fibers . Conseque fibers .Most studies with sEMG during exercise have been performed in the laboratory and thus have used stationary cycle ergometers. Exhaustive tests, like this incremental cycling test, are ecologically invalid, i.e., not relevant for activities in daily life. Second, it is advised to develop a more reliable method to detect sEMG Th1, e.g., artificial intelligence, as this threshold could be valuable for daily life measurements. Different sEMG Th detection methods have been used, such as visual and multi-segment linear regression methods . The matTo end, because fatigue is experienced as a multi-dimensional symptom with short-term or long-term duration, relying on one outcome measure alone can be difficult. Future studies should include performance fatigability and perceived fatigability measures to correlate objective and subjective fatigue in their subjects/patients and include age-matched HC. Further research is needed to address a multi-model approach to measure performance fatigability in NMD to differentiate performance fatigability developed from the disease itself compared to normal physiological and aging processes, understand the concomitant nature of performance fatigability and perceived effort, as well, identify appropriate therapeutic interventions to minimize performance fatigability in patients with NMD. Preferably, in future research, more homogeneous patient groups should be included to determine the influence of the specific pathology.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by Medical Ethics Review Committee Radboud University Medical Center Nijmegen, Netherlands. The participants provided their written informed consent to participate in this study.NV and MJ, the principal authors of the manuscript, conceived, designed and supervised the experiments. CS, DT, VB, and DS contributed to discussing the results and the writing and editing of the manuscript. MJ analyzed the data. NV obtained ethical approval. All authors read and approved the manuscript.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.


IJUCase Reports, Miyauchi et al. reported three living‐donor kidney transplant cases which the two donor right renal veins were reconstructed using a major Y‐shaped saphenous vein.In this issue of the In the case of living‐donor renal transplantation, the donor left kidney is usually selected because the right kidney has shorter venous length than the left kidney.The shorter length of the allograft right renal vein is relevant to greater technical difficulty at a point of the venovenostomy.To lengthening the allograft short renal vein, some techniques have been performed, including a deceased donor’s vena cava patch, a donor’s or recipient’s gonadal vein, a deceased donor’s iliac vein, a superficial femoral vein graft, and a saphenous vein graft.et al.’s study, this Y‐shaped saphenous vein graft seems to be effective in preventing outflow obstruction and to achieve the lengthening of the right allograft renal vein.When there are two veins, as reported in Miyauchi I would like to use the Y‐shaped saphenous vein graft in case of short and multiple allograft renal veins.The author declares no conflict of interest.


In multivariate regression analysis, first-day NP was independently associated with p-CFL occurrence [odds ratio (OR)=6.395, 95% confidence interval (CI)=2.236-18.290, p=0.001). After adding the NP change into the regression model, first-day NP was no longer independently associated with p-CFL, and NP change  was independently associated with p-CFL. The receiver operating characteristic curve comparison analysis showed that NP change had a significantly better predicting value than first-day NP . NP is an effective imaging marker for predicting p-CFL after endoscopic sellar and suprasellar tumors operation, and the NP change has a better predicting value.We aimed to study the relationship between pneumocephalus on non-contrast CT (NCCT) and post-operative cerebrospinal fluid leakage (p-CFL) after endoscopic transsphenoidal sellar and suprasellar tumor surgeries. Data from patients who underwent endoscopic treatment for sellar or suprasellar tumors from January 2018 to March 2020 were consecutively collected and reviewed. The NCCT pneumocephalus (NP) was measured the first day after operation and the first day after the expansive sponge was extracted. p-CFL was determined according to post-operative clinical symptoms, high resolution CT and glucose test, and expert consensus. Of the 253 patients enrolled in this study, 32 (12.6%) had p-CFL. Compared with patients without p-CFL, patients with p-CFL had a higher occurrence of intra-operative CFL, a longer operation time, a higher rate of pneumocephalus on first-day NCCT after operation , and a higher rate of NP volume change between two NCCT measurements (referred to as the NP change) (all  Endoscopic transsphenoidal surgery is increasingly performed by neurosurgeons to treat skull base lesions, but cerebrospinal fluid (CSF) leakage (CFL) is a difficult-to-avoid complication, with an incidence as high as 11% . In one Early detection of CFL is quite important. Methods reported to diagnose CFL include β2‐transferrin testing, glucose rhinorrhea content analysis, high-resolution computed tomography (HRCT), magnetic resonance imaging (MRI), and cisternography –13. HoweHere, we analyzed surgical cases of endoscopic transsphenoidal sellar and suprasellar tumors, focusing on the relationship between CFL and the occurrence and volume change of NCCT pneumocephalus (NP) to identify a new method of CFL diagnosis.Each subject or an appropriate family member provided written informed consent prior to the study, and the protocols were approved by the local ethics committee. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.The retrospective study included consecutively collected patients who underwent endoscopic treatment for sellar or suprasellar tumors from January 2018 to March 2020. Patients’ demographics, medical histories, pathological findings, and repair outcomes were recorded. Pre- and post-operative imaging, operative reports, medical records, and operative videos were reviewed. We excluded cases if (i) post-operative pathology did not show evidence of a tumor or (ii) they were missing imaging and clinical data Figure 1via lumbar cistern drainage; artificial dura repair; balloon compression; or autologous tissue like fat tamponade, fascia lata, or a pediculate nasoseptal flap . The NP volume measurement method is shown in The presence of NCCT pneumocephalus (NP) was measured on the first day after operation, and NP volume was estimated the first day after expansive sponge extraction. NP change was defined as the volume change in NP between the first day after operation and 24 h after sponge extraction, and it was divided into four categories: no NP in both NCCT measurements, NP volume decreased, NP volume remained and NP volume increased, which were abbreviated as no NP, decreased NP, unchanged NP and increased NP, respectively. The latter three categories were ascribed as NP change. NP delineation and volumetric analysis were conducted using MRIcron software (The diagnostic flow chart is shown in Post-operative CFL (p-CFL) was diagnosed if patients had➀Persistent post-operative nasal discharge regardless of the occurrence of intra-operative CFL;➁Neither intra-operative CFL nor persistent post-operative nasal discharge but positive HRCT finding (CSF leak through a defect);➂Non-persistent nasal discharge after surgery, negative HRCT, but positive glucose test (glucose rhinorrhea content ≥1.7 mmol/L). In that case, glucose was repetitively tested, and the p-CFL diagnosis was determined by two experienced neurosurgeons . When there were different diagnostic opinions, the neurosurgeons reached consensus after discussion.Patients without post-operative nasal discharge and negative CSF tests were defined as non-p-CFL.The characteristics of patients with and without p-CFL  are presented as mean and standard deviation (SD) for normally distributed continuous data, non-normally distributed variables are described as quartiles, and categorical variables are given as counts and percentages. Between-group differences were evaluated using Student’s t-tests or Mann–Whitney U-tests for continuous data and chi-square tests or Fisher’s exact tests for categorical variables.p < 0.05) were included in the binary logistic regression model. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and p < 0.05 was considered significant. Receiver operative curve (ROC) analysis was performed to test the predictive power of independent variables for the dependent variable; we calculated the areas under the ROC curve (AUC), sensitivity, and specificity. All analyses were performed after blinding the participants’ identifying information. Statistical analysis was performed using SPSS 19 . ROC curve comparison analyses were conducted by MedCalc statistical software version 15 .Variables that were significant on univariate analysis  post-operative pathology did not show evidence of a tumor (n = 12), and (ii) incomplete imaging and clinical data from admission to discharge (n = 6). Of the 253 patients, 49.6% were female, and the median patient age was 50 years .Of all the 253 patients, 40 (15.8%) showed first-day NP after operation. After the extraction of the expansive sponge, 46 patients (18.2%) showed NP change, and 32 (12.6%) were finally confirmed with p-CFL. The median test time for p-CFL was 2 days  after the removal of the expansive sponge, and 62.5% of p-CFL patients were tested beyond 2 days after the removal of the expansive sponge.2 = 48.090, p < 0.001) . After resecting tumors, patients with p-CFL showed a higher rate of first-day NP and NP change during hospitalization, a higher occurrence of high fever and infection, and a longer duration of hospitalization  , none was found of p-CFL in both NCCT measurements. Among patients with an NP change (n = 46), 10 were in the decreased-NP subgroup who initially showed first-day NP but not on follow-up NCCT and were determined not to have p-CFL. Sixteen patients who showed increased NP between both NCCT measurements were confirmed to have p-CFL, including six patients without NP on first-day NCCT but with NP on follow-up NCCT after sponge extraction Figure 1When adding first-day NP into the multivariate regression model, both the first-day NP  and operative duration time  were independently associated with the occurrence of p-CFL after adjusting for pathology type  and operative duration time  were independently associated with p-CFL , with sensitivity of 68.6% and specificity of 87.8%. The AUC of NP change for predicting p-CFL was 0.988 , with sensitivity of 100% and specificity of 93.7%. The ROC comparison showed that NP change had a significantly better predicting value than first-day NP .Klebsiella pneumoniae infection and died. Thus, it is vital to find early signs that can be used to diagnose CFL. We found that both first-day post-operative NP and its volume change over time could predict p-CFL, and the latter had a higher predictive value. Compared with patients who had no NP, those with no change and increased NP had a higher risk of having p-CFL, and 100% of increased-NP patients (n = 16) were confirmed to have p-CFL.Diagnosis and management of p-CFL can be challenging, even for the most experienced neurosurgeons . Clear rThere are two possible pathophysiologic explanations for the correlation between the presence of NP and p-CFL: the inverted bottle mechanism and the ball-valve mechanism , 27, 28.We found that the NP change after expansive sponge extraction could better predict p-CFL than the first-day NP. Previous studies considered post-operative NP as an epiphenomenon of intra-operative CSF leak which would correlate with a higher risk of p-CFL , 32. HeaIn patients with first-day NP after tumor resection, the occurrence of p-CFL was lower among those with reduced NP volume compared with those with increased or unchanged NP volume. The probable cause is that pneumocephalus was gradually absorbed after the CFL resolved. Intra-operative CFL and the loss of a large amount of CSF initially leads to pneumocephalus. However, when the CFL was properly repaired with skull base reconstruction, the post-operative pneumocephalus gradually absorbed. In contrast, no change or an increase in CT pneumocephalus suggested persistent CFL. If the CFL is completely solved, the pneumocephalus will be gradually absorbed, and CT re-examination after 3 days is sufficient to observe the pneumocephalus reduction. If there is no change or there is an increase in pneumocephalus volume post-operatively, it indicates that intracranial pressure continues to decrease and a leak still exists, so the incidence of p-CFL increases.via lumbar cistern drainage.In this study, p-CFL developed in two patients who had no pneumocephalus on the first day after the operation. Pneumocephalus was found on imaging on the fourth day after the operation, suggesting that dynamic review of head NCCT has supplementary significance for CFL evaluation. Although there was an increase in pneumocephalus volume after operation in one case, there was no CSF leakage, possibly due to excessive drainage of CSF Our study was limited by the small number of patients and single-center retrospective design, so multicenter studies with larger samples sizes are needed to confirm our findings. In addition, we did not use beta-2 transferrin or beta trace protein testing to diagnose CFL because our hospital does not routinely perform these analyses. Nevertheless, glucose rhinorrhea content testing is fast, simple, inexpensive, and can be carried out in most hospitals, which could promote the wide application of our findings. An evidence-based review also pointed out that the guidance level for glucose testing was not inferior to that of beta-2 transferrin or beta trace protein testing in identifying CFL . FinallyOur results show that NP change is a more convenient and effective imaging marker than first-day NP for predicting p-CFL after endoscopic sellar and suprasellar tumor resection. During dynamic NCCT observation, attention should be paid to the risk of p-CFL in patients with no change or increased NP.The original contributions presented in the study are included in the article/This study was approved by the ethics committee of The second Affiliated Hospital of Zhejiang University, School of Medicine. The patients/participants provided their written informed consent to participate in this study.WG, XW and SZ: drafted the manuscript. YF: acquisition of data. SZ: analysis or interpretation of data. CL, YH and WY: study concept and design. SZ and CL: help to revise the whole framework and polish the language.This work was supported by the National Natural Science Foundation of China (grant number 81801162), the Zhejiang Provincial Natural Science Foundation of China (grant number LGF22H090020) and the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (grant number 2022KY600).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.