N = 566) and comparing the metastability of the brain's large‐scale resting network architecture at rest and during the performance of several tasks. Metastability was estimated using a well‐defined collective variable capturing the level of 'phase‐locking' between large‐scale networks over time. Task‐based reasoning was principally characterised by high metastability in cognitive control networks and low metastability in sensory processing areas. Although metastability between resting state networks increased during task performance, cognitive ability was more closely linked to spontaneous activity. High metastability in the intrinsic connectivity of cognitive control networks was linked to novel problem solving or fluid intelligence, but was less important in tasks relying on previous experience or crystallised intelligence. Crucially, subjects with resting architectures similar or 'pre‐configured' to a task‐general arrangement demonstrated superior cognitive performance. Taken together, our findings support a key linkage between the spontaneous metastability of large‐scale networks in the cerebral cortex and cognition.Despite resting state networks being associated with a variety of cognitive abilities, it remains unclear how these local areas act in concert to express particular cognitive operations. Theoretical and empirical accounts indicate that large‐scale resting state networks reconcile dual tendencies towards integration and segregation by operating in a metastable regime of their coordination dynamics. Metastability may confer important behavioural qualities by binding distributed local areas into large‐scale neurocognitive networks. We tested this hypothesis by analysing fMRI data in a large cohort of healthy individuals ( Although metastability between resting state networks increased during task, cognitive performance was more closely linked to the intrinsic or spontaneous metastability of network interactions.High resting state metastability in cognitive control networks was linked to novel problem solving or fluid intelligence, but was less important in tasks relying on previous experience or crystallized intelligence.Subjects with resting state architectures similar or 'pre‐configured' to a task‐general configuration demonstrated superior cognitive performance linked to efficient switching of network states. Although metastability was evoked by task, cognitive performance was more closely aligned with the metastability of the brain's intrinsic network dynamics.22.1https://www.humanconnectome.org/data). All participants were screened for a history of neurological and psychiatric conditions and use of psychotropic drugs, as well as for physical conditions or bodily implants. Diagnosis with a mental health disorder and structural abnormalities  were also exclusion criteria. All participants supplied informed consent in accordance with the HCP research ethics board. The subset of subjects comprising monozygotic and dizygotic twin pairs were excluded from the present study. All subjects attained at a minimum a high school degree.Data were obtained through the Washington University‐Minnesota Consortium Human Connectome Project  adapted from Aesop's fables, followed by a 2‐alternative forced‐choice question that asked participants about the topic of the story. The math task also presented trials auditorily and required subjects to complete addition and subtraction problems . The task consisted of indicating when the current stimulus matched the one from two steps earlier.Gambling/reward learning: participants were asked to guess the number on a mystery card in order to win or lose money. Participants were told that potential card numbers ranged from one to nine and that the mystery card number was more than or less than five : participants were presented with short video clips (20 s) of objects  that either interacted in some way, or moved randomly on the screen. After each video clip, participants were asked to judge whether a mental interaction had occurred; did the shapes appear to take into account each other's thoughts and feelings?  and motor responses. These included:Full timing and trial structure for the seven tasks are provided as 2.4p < .05) three of the seven tasks satisfied this criterion including relational reasoning , language processing  and working memory . Of the other four tasks, the gambling task accuracies were no better than chance (participants were asked to guess if a mystery card was higher or lower than five). The emotion  and social  task accuracies were perfect or near perfect for most subjects and hence showed a strong ceiling effect. Finally, the motor task accuracy scores were not recorded . All seven tasks showed normally distributed reaction time data, as confirmed by a one‐sample Kolmogorov–Smirnov test (p < .05).Task performance was evaluated using behavioural accuracy and reaction time data. Only those tasks which showed normally distributed behavioural accuracy scores were subject to linear regression analyses : measures fluid intelligence via non‐verbal reasoning using an abbreviated version of the Raven's Progressive Matrices Form A developed by Gur and colleagues  and sometimes in the opposite direction (incongruent). Scoring is based on a combination of accuracy and reaction time.Cognitive performance was also evaluated using test scores obtained outside the scanner. These included two complementary factors of general intelligence: fluid and crystallised intelligence. The former linked to novel problem solving and the latter to previously acquired knowledge and experience .All three cognitive measures were consistent with a normal distribution as confirmed by a one‐sample Kolmogorov–Smirnov test (2.6p < .01), if more than 20% of a subject's resting state frames exceeded FD > 0.5 mm they were excluded from further analysis. Based on these criteria, 566 out of 890 subjects were retained for further analysis. To preserve the temporal structure of the signal no data 'scrubbing' was performed . Motion was defined as the SD in FD. A positive relationship between motion during rest and motion during task was identified in each of the seven domains. These included emotion perception , relational reasoning , language processing , working memory , gambling/reward learning , social cognition  and motor responses .All pre‐processing was conducted using custom scripts developed in MATLAB 2017a . Motion between successive frames was estimated using framewise displacement (FD) and root mean square change in BOLD signal . Briefly, this processing includes motion correction and averaging  tool fslmaths  was being driven by alternating blocks of task and fixation, task blocks were concatenated. Since artificially concatenating a series of disjoint task blocks resulted in a discontinuous time series, the analysis was also performed with cue and fixation blocks included. Overall, retaining cue and fixation blocks did not alter the pattern of metastability between large‐scale networks . The present analysis pertains to the case where cue and fixation blocks are removed. To ensure that any observed differences were due to dynamics rather than bias associated with signal length, the same number of contiguous frames from task and rest were utilised; the resting state scan was truncated to match the length of the task run (after cue and fixation blocks were removed).Since each task comprised two runs (one from each session) both runs were concatenated into a single time series. The individual signals were demeaned and normalised by 2.7https://balsa.wustl.edu; Van Essen et al., Mean time series were extracted from regions of interest defined by the Gordon atlas . In both cases, the lengths of the vectors is constant and metastability is zero.The Hilbert transform permits temporal relationships between brain regions to be analysed by extracting the phase of a signal and discarding its amplitude. Accordingly, the result of the Hilbert transform may be conceptualised as a set of phase oscillators rotating around the circumference of the unit circle. The length of the vector pointing from the centre of the circle to the mean phase of the group is commensurate with the synchrony between oscillators. Variation in the length of this vector over time, from zero (no synchrony) to one (full synchrony), provides a measure of the system's overall metastability. Although two systems may differ in terms of synchrony, as reflected by vectors of different lengths, both can share the same metastability as reflected by a vector of constant length over time. The situation is illustrated by two oscillators rotating in‐phase  versus two oscillators rotating 2.9Given that (1) the current formulation of metastability permits calculation between a group of regions; and (2) interconnected subnetworks convey more behaviourally relevant information than functional connections observed between pairs of regions observed in isolation, we advocate for a method that exploits the clustering structure of connectivity alterations between functionally related networks. For this reason, we applied the NBS to estimates of empirical metastability obtained from fMRI data at the network rather than regional level  in topological space whilst controlling the family wise error rate (FWER). To date, several studies have used the method to identify pairwise regional connections that are associated with either an experimental effect or between‐group difference in functional connectivity  were classified using a modified CNN architecture Figure . BrainNek‐fold cross validation where To reduce the number of parameters we included only a single edge‐to‐edge layer . Subsequent Tukey post hoc test revealed significantly higher global metastability during the seven tasks as compared to the resting state . These included emotion perception , relational reasoning , language processing , working memory , gambling/reward learning , social cognition  and motor responses . Changes in metastability are compared among the seven tasks as a supplemental analysis.The metastability of fMRI BOLD signal was examined during the resting state and during the execution of several cognitively demanding tasks Figure . One‐way3.2The NBS was subsequently used to identify changes in the metastability of fMRI BOLD signal of individual network connections (task vs. rest). In total, 566 resting state interaction matrices were compared to 566 task‐based interaction matrices within each of the seven behavioural task domains. The null hypothesis, namely, that there was no difference in metastability between rest and task, could then be rejected at the level of individual network connections.p < .01; corrected) increases in metastability between several large‐scale networks during task engagement relative to the more unconstrained resting state. A single test statistic threshold, that is, 16, was selected for all seven tasks so as to permit visualisation of the increases in metastability between large‐scale networks on the same scale  were summed to reveal the total number of network connections recruited for each task Figure . Increas3.4The highly correlated properties of metastability and synchrony  with 14 others. Thus, guided backpropagation produced a 14 × 14 matrix of gradients. A consensus across all subjects for a particular task was obtained by setting each subject's top 10% of gradients (the most positive gradients) to one and the remaining entries to zero, summing the matrices and dividing by the total number of subjects. Entries important for correct classification in more than 90% of individuals were set to zero in the input (the interaction matrix). The performance of the pre‐trained classifier was then re‐evaluated based on the occluded input data. In a separate experiment, retraining on the occluded inputs also produced extremely poor classification accuracy (not shown).3.5So far, we have demonstrated that increases in metastability can be distinguished from increases in synchrony in two ways: (1) their overall network size, that is, increases in metastability encompass a wider network of cognitive‐related brain systems than those based on synchrony; and (2) their discriminatory utility, that is, tasks can be identified with high accuracy based on a small subset of network changes in synchrony (but much less so in terms of metastability). Taken as a whole, these findings led us to hypothesise that commonalities between tasks may be centred on a metastable core of task‐general network interactions.To quantify the degree to which the seven task‐based configurations shared features in common, we used a dimension‐reduction tool–PCA–to reduce a larger set of variables (the seven task‐based interaction matrices) to a smaller set  retaining most of the information. Accordingly, entering the seven task‐based interaction matrices based on metastability into a PCA yielded a single task‐general architecture for each subject. On average, the first principal component accounted for 78% of the variance between the seven tasks. The loadings were positive and distributed equally between the seven tasks suggesting that each task‐based configuration contributed equally to the task‐general structure. These included emotion perception = 0.37, relational reasoning = 0.37, language processing = 0.36, working memory = 0.36, gambling/reward learning = 0.36, social cognition = 0.37 and motor responses = 0.38. This result likely speaks to the high similarity between task‐based configurations engaged by different behaviours . Three additional cognitive measures acquired outside the scanner were also analysed. These included fluid intelligence, crystallised intelligence and executive function. Across the three measures, several network connections demonstrated a significant positive association between intrinsic metastability and cognitive performance . The addition of reaction time data across the six tasks did not increase the percentage of explained variance in cognitive performance. In a separate linear regression analysis, no statistically significant associations between behaviour/cognition and network synchrony were identified .We next examined the metastable interactions of large‐scale networks during task engagement for evidence that they informed behaviour. Behavioural accuracy scores for each subject were entered into a linear regression analysis as the dependent variable with one of 196 (14 × 14) task‐based network connections (estimated in terms of metastability) as predictors. Overall, metastable interactions between networks during task did not explain the variance in cognitive ability. Resting state metastability was then entered as an additional independent factor. Across the three in‐scanner tasks, several network connections demonstrated a significant positive association between intrinsic metastability and cognitive performance . For this reason, we correlated the metastability of individual network connections with update efficiency and obtained the slope of the regression equation . As expected, these results are in accord with the structure of the task‐general configuration  relationships between performance and update efficiency were identified in the three in‐scanner tasks. These included relational reasoning , language processing  and working memory . Since metastability and update efficiency are correlated (in some connections) and since update efficiency predicts performance, we also confirmed that the efficiency‐performance relations survived in the face of controlling for global metastability. Overall, these findings suggest that cognitive ability is contingent upon resting state architecture being similar or 'pre‐configured' to a task‐general arrangement.We next examined whether cognitive performance and the efficiency of the transformation between rest and task‐based neural architectures are related  between neural networks is actively enhanced by task engagement Figures  and 3. EThe present study used one measure of connectivity–metastability–to assess the dynamic stability~flexibility within and between large‐scale networks of the brain. Increased stability of dynamic functional connectivity appears to be a general property of cognitive engagement across multiple behavioural paradigms irrespective of the type of dynamic functional connectivity method employed Cohen, . ConsistTask engagement was principally characterised by enhanced metastability in the connectivity of cognitive control networks Figure . These iThe seven in‐scanner tasks showed remarkably similar patterns of increased metastability between large‐scale networks Figure . Such fiEven during periods of apparent 'rest' a subject's network connectivity continued to display strong integrative and segregative tendencies linked to cognitive performance. Remarkably, a subject's ability to answer questions correctly, both in and out of the scanner, related to their intrinsic neural dynamics Figure . CuriousMetastable network dynamics displayed a combination of trait‐ and state‐like properties. Resting state metastability was significantly lower on Day 2 scanning sessions versus Day 1 scanning sessions (see Figure rather than simply reflecting invariant structural anatomy, historical co‐activation patterns, or internal dynamics of local areas, intrinsic activity predicts subsequent perceptual processing (Busch, Dubois, & VanRullen, So why is metastability at rest predictive of behavioural and cognitive performance as opposed to metastability during the task itself? The idea that functional couplings between regions at rest contain information relevant to cognition, perception and behaviour is supported by substantial empirical evidence (Sadaghiani, Cognitive performance was also linked to the efficiency of the transformation between rest and task‐based network architectures. Specifically, subjects whose resting state was similar to the task‐general architecture garnered the highest cognitive scores. Successful cognition is likely contingent on possessing an adequate a priori dynamic configuration before the onset of task‐relevant stimuli, as opposed to simple ad hoc adjustments after the fact (Bolt, Anderson, & Uddin, Potential limitations of the findings should be noted. Firstly, it is worth emphasising that the division of neural activity into intrinsic and task‐evoked activity may be an artificial distinction and not an actual division respected by neural properties (Bolt et al., Taken together, our findings suggest that the metastable regime of coordination dynamics (Bressler & Kelso, Data S1 Supporting Information.Click here for additional data file.


Surface guided radiation therapy (SGRT) is increasingly being adopted for use in radiation treatment delivery for Head and Neck (H&N) cancer patients. This study investigated the improvement of patient setup accuracy and reduction of setup time for SGRT compared to a conventional setup. A total of 60 H&N cancer patients were retrospectively included. Patients were categorized into three groups: oral cavity, oropharynx and nasopharynx/sinonasal sites with 20 patients in each group. They were further separated into two (2) subgroups, depending on whether they were set up with the aid of SGRT. The Align‐RT™ system was used for SGRT in this work. Positioning was confirmed by daily kV‐kV imaging in conjunction with weekly CBCT scans. Translational and rotational couch shifts along with patient setup times were recorded. Imaging setup time, which was defined as the elapsed time from the acquisition of the first image set to the end of the last image set, was recorded. Average translational shifts were larger in the non‐SGRT group. Vertical shifts showed the most significant reduction in the SGRT group for both oropharynx and oral cavity groups. Pitch corrections were significantly higher in the SGRT group for oropharynx patients and higher pitch corrections were also observed in the SGRT groups of oral cavity and nasopharynx/sinonasal patients. The average setup time when SGRT guidance was employed was shorter for all three treatment sites although this did not reach statistical significance. The largest time reduction between the SGRT and non‐SGRT groups was seen in the nasopharynx/sinonasal group. This study suggests that the use of SGRT decreases the magnitude of translational couch shifts during patient setup. However, the rotational corrections needed were generally higher with SGRT group. When SGRT was employed, a definite reduction in patient setup time was observed for nasopharynx/sinonasal and hypopharynx cancer patients. Setup errors could potentially result in significant underdose to the tumor and/or overdose to one or more OARs. Traditionally, patient positioning adjustments have been made by aligning surface marks on thermoplastic marks or marker tattoos placed at the time of CT simulation and then fine‐tuned by orthogonal kV imaging (kV‐kV), cone‐beam CT (CBCT), etc. However, due to the complexity of the anatomy within the head and neck area, the internal organs at risk are still subject to an average of 2–3 mm displacement with the immobilization devices after the initial setupSurface‐guided radiation treatment (SGRT) was designed to determine in real‐time the position of an object by tracking the positions of either active or passive infrared markers attached to the object.Wiant et al.The above‐mentioned studies established that employing SGRT resulted in a high level of accuracy for the fractionated treatment of head and neck cancers. These studies also showed that patient anxiety and claustrophobia levels were in general lower when an open mask used for SGRT replaced the conventional closed mask traditionally used for head and neck treatments. At least two of these studies also concluded that when SGRT was employed the treatment times were similar to those for non‐SGRT fractionated IMRT head and neck radiotherapy treatments. All these studies employed CT scans  to establish the accuracy of SGRT for head and neck treatments. None of the above‐mentioned studies explored in detail the potential role of daily kV‐kV imaging in conjunction with weekly CBCT to establish the accuracy of SGRT treatments for head and neck radiotherapy. These studies also did not consider the potential reduction in the need of pre‐treatment imaging and patient setup time when SGRT guidance was employed for patient setup.The primary objective of this study was to assess the improvement of patient setup accuracy and reduction of setup time when SGRT was employed compared to conventional non‐SGRT setup for head and neck radiotherapy using Volumetric Modulated Arc Therapy (VMAT) treatment delivery. A secondary objective was to determine if SGRT could benefit all the sub anatomical structures at different levels and depths within the HN region, such as oropharynx, oral cavity and nasopharynx/sinonasal. A tertiary objective was to assess the potential reduction in patient setup time when SGRT guidance was employed as compared to conventional patient setup methods.22.AA total of 66 head and neck patients who underwent either definitive or post‐operative radiation therapy between 2014 and 2018 were retrospectively included in this study. Based on different treatment sites, the patients were initially categorized into four groups including oral cavity, oropharynx, nasopharynx/sinonasal, and hypopharynx/larynx groups. The analysis of the hypopharynx/larynx group failed to proceed due to an insufficient patient population with SGRT aided treatment at the time of analyses. Therefore, 60 patients remained in the study from the other three treatment site groups with 20 patients in each group. The patients were further separated into two (2) subgroups, depending on whether the patients were set up with the assistance of the surface imaging tracking system or purely with physical marks drawn on the open thermoplastic mask by the therapists. Ten patients were included in each subgroup.2.BAll patients were simulated on a Philips Brilliance Big Bore computed tomography (CT) scanner  and all treatment planning CT scans were acquired with 2 mm slice thickness. The widely used optical tracking system AlignRT  was used in this study. It consists of three ceiling‐mounted stereoscopic camera pods in the treatment room. The system was calibrated monthly and verified daily, using a calibration plate per manufacturer’s recommendations as well as departmental quality assurance policies and procedures. The non‐SGRT group was treated in a conventional closed thermoplastic S frame mask  to cover the head and shoulder regions Fig. , whereasThree CT radio‐opaque/metal (BB) markers were placed on the masks at the time of simulation to assist with treatment localization. On the patient’s first treatment fraction, after aligning the patient to the treatment isocenter using kV imaging, marks were drawn on the thermoplastic masks for the guidance of the remaining treatment fractions. For the SGRT patients, the target region of interest (ROI) was defined in the center of the opening in the S‐frame thermoplastic mask fabricated during CT simulation and the patient’s surface contour generated from the CT dataset was imported into the SGRT system. Similar to the approach used in the study by Zhao et al.,On the day of treatment, SGRT patients were first set up to surface marks and subsequently with optical image guidance to the reference parameters. Beam hold thresholds were set at 2 mm for translational shifts  and 2° for rotational shifts  [Fig. 2.CData for this study were obtained through Aria Version 13.6 record and verify database  using International Classification of Diseases (10th Edition), codes for nasopharynx (11.0–11.9), sinonasal (31.0–31.9), oral cavity (2.0–6.9), hypopharynx (12.0–13.9) and larynx (32.0–32.9). Six degrees of freedom couch adjustments  after on‐board imaging were compared between the SGRT group and non‐SGRT group. Systematic error, the standard deviation of the individual patient’s mean couch position for SGRT patients, was also calculated.33.AComparing the setup shifts of two groups, the average translational shifts were generally larger in the non‐SGRT group Fig. . Out of 3.BOn the other hand, the overall kV‐kV rotational corrections (pitch and yaw) displayed different patterns for different correction categories Fig. . Pitch c3.CSystematic errors were generally higher for the non‐SGRT group Fig. . Overall3.DFurthermore, we separately analyzed the CBCT data and two hundred sixty‐six 266) CBCT scans were extracted from SGRT and non‐SGRT patients for setup shift comparison. The results are summarized in Table 66 CBCT s3.EOral cavity patients were observed to have larger vector shifts in the most fractions, with on average 41% of fractions requiring a vector shift >5 mm, 17% fractions requiring a shift >7 mm and 5% fractions requiring a shift >10 mm. When comparing non‐SGRT and SGRT groups, both nasopharynx/sinonasal and oral cavity patients were observed to have a higher percentage of fractions requiring >5 mm, >7 mm and >10 mm vector shifts for the non‐SGRT group Fig. . Oral ca3.FThe average setup time when both on‐board imaging and SGRT guidance were employed was shorter for all three treatment sites although no significant difference was observed Fig. . The lar4Since the application of SGRT in radiation therapy, a multitude of clinical data has been published on various anatomical sites. Deep inspiration breath‐hold (DIBH) treatments for breast cancer radiotherapy, using SGRT, reduce the doses to surrounding OARs, such as the heart, left anterior descending coronary artery and ipsilateral lung.The accuracy of patient setup using daily kV imaging coupled with weekly CBCT and comparing the open‐face and the conventional mask has not yet been presented in the literature. Compared with previous studies using SGRT for HN radiation treatment, our study design is different in that it focusses on assessing different treatment sites within the HN region including nasopharynx/sinonasal, oropharynx, and oral cavity. Due to varying anatomical depth and level for these three treatment sites in the HN region, different outcomes such as translational and rotational corrections were expected. In addition, we focused especially on the treatment setup with six‐dimensional couch shift and imaging preparation time. Our data are for the most part in line with the findings of the study by Zhao et. al. who assessed the feasibility and setup accuracy of minimal face and neck mask immobilization with SGRT and compared the setup shifts based on CBCT between the patients treated with shoulder cushion and shoulder retractors.In this study, it has been shown that SGRT combined with hand‐placed marks as initial setup reference could lead to more accurate positioning. The average translational shifts were reduced with SGRT, especially the vertical shift. This indicates that the 3D matrix projected on the patient could potentially provide better guidance compared to the three physical marks on the thermoplastic immobilization mask. Utilization of SGRT has shown to have the most impact on the vertical shift. That may be because it is inherently difficult to mark the isocenter accurately on the thermoplastic mask so as to exactly align with the actual treatment isocenter. Since the mark was only placed on the patient’s mask on day one, it would only reflect the initial isocenter location. Patient’s anatomy may also be changing due to tumor response or weight loss during the course of radiation therapy. The physical marks would not be able to capture the change accordingly. On the contrary, when SGRT was utilized the reference image for every fraction was recorded post alignment with kV‐kV imaging and used as the baseline for the next day’s treatment. Thus employing the SGRT workflow could potentially limit the impact of the change in patient’s anatomy on the treatment setup. Surprisingly, the rotational corrections were increased with SGRT with the pitch being the most distinctive. This could be attributed to the rigid registration algorithm employed by the SGRT system.Comparing different parameters within each treatment site groups, we determined that each group benefitted from SGRT application in one way or another. Oropharynx and oral cavity setups showed the greatest improvement in the translational couch shift. Systematic error showed a decreasing pattern in all three treatment groups with SGRT. The percentage of fractions in which the patients needed relatively larger shifts after the initial setup decreased with the utilization of SGRT for the nasopharynx/sinonasal and oral cavity groups. The rotational error increased in all three treatment sites but to a different extent(s). For example, the maximum vertical shift was −3.7 mm in the oropharynx group and decreased to −2.0 mm after implementing SGRT. The maximum yaw was −5.9°, which increased marginally to −7.9° after SGRT was employed.The patient setup time using image guidance, a parameter of paramount importance as far as clinical resources is concerned, showed a decreasing trend when SGRT was utilized for nasopharynx/sinonasal patients. Utilization of SGRT results in a shortening of the overall treatment time, thus reducing potential patient discomfort and maintaining effectiveness. Also, limiting the imaging time decreases imaging radiation exposure.One of the limitations of this study was that only one ROI was selected for SGRT tracking. The mid‐face area, which is typically selected as the ROI, is closer to the level of the nasopharynx region, but it is more distal from the oropharynx and oral cavity regions. Thus, anatomically it might not be the ideal area to place the ROI. Using thermoplastic masks that have an additional opening in the neck region could allow a second ROI to be tracked and thus potentially compensate for the discrepancy caused by the different anatomic levels. Another limitation is the small number of patients treated to the hypopharynx, which precluded any meaningful analysis of this patient group. Since the hypopharynx sits inferiorly to the other three anatomical regions, it would be interesting to determine if SGRT with the mid‐face ROI still improved patient localization.5In this study, we have presented data comparing treatment setup and pre‐treatment imaging time with and without SGRT in the H&N patients. Our results suggest that the use of SGRT decreases the magnitude and systematic errors of translational couch shifts during the patient setup, especially for oropharynx and oral cavity patients. Thus, it potentially improves setup accuracy by decreasing couch positioning uncertainty. However, the rotational corrections needed were generally higher with SGRT group, which suggests SGRT is best utilized in tandem with onboard radiographic imaging. When SGRT was employed, a definite time reduction in patient setup time was observed for nasopharynx/sinonasal cancer patients.The authors declare no conflict of interest.


Thunderstorm asthma is induced by specific weather conditions causing breakdown and widespread distribution of allergens. Thunderstorm asthma had previously been considered unlikely to occur in New Zealand (NZ), given its local weather patterns. Storm events on 2 December 2017 led to increased asthma presentations at Waikato Hospital in Hamilton. Analyses of patient presentations led us to conclude that these presentations were similar to international descriptions of thunderstorm asthma. This is the first time such presentations have been reported in NZ. Documenting these events accurately is important as this is the first step to making a plan that would enable paramedics and emergency facilities across NZ to respond to any larger scale thunderstorm asthma events in the future. Thunderstorm asthma had previously been considered unlikely to occur in New Zealand (NZ), given its local weather patterns. Storm events on 2 December 2017 led to increased asthma presentations at Waikato Hospital in Hamilton. Analyses of patient presentations led us to conclude that these presentations were similar to international descriptions of thunderstorm asthma. This is the first time such presentations have been reported in NZ. Thunderstorm asthma is an asthma‐related symptom brought about by the combination of specific weather conditions and the presence of high allergen concentrations. It is often but not necessarily associated with thunderstorms and can result in a large acute increase in the number of asthma‐related presentations. Importantly, people with little history of asthma can be affected, leading to delays in their presentation, diagnosis, and treatment.The postulated mechanism of thunderstorm asthma involves pollen grains being lifted into clouds by storm updrafts typically in the late spring to early summer when the pollen count is high. Within the cloud, pollen grains are fragmented in the presence of water vapour into small particles. These small particles are then dispersed by the storm down‐drafts. Intact pollen grains, typically 12–60 μm, are trapped in the nasopharynx and upper airways and may cause allergic rhinitis. The fragmented pollen particles are much smaller (<10 μm) and can pass into the small airways where they can induce allergen‐mediated bronchoconstriction. Electrostatic deposition of pollen fragments may also occur in the small airways due to charge imbued on the fragments by the weather conditions [A thunderstorm on 2 December 2017 was followed by an increased number of acute asthma exacerbation presentations at after‐hours healthcare facilities in the Waikato region of New Zealand (NZ). Waikato Hospital is the only secondary care provider for Hamilton and surrounding areas. The following data were collected by reviewing all the medical records of presentations to emergency services from 0000 h 2 December 2017 till 0000 h 4 December 2017.Fourteen adults  presented with asthma symptoms to the emergency department (ED) of Waikato Hospital during this period and gave clear histories of symptom onset during or following the storm. Ten of these 14 patients did not require inpatient treatment. Fifty percent of these ED‐discharged patients (5/10) only had a prior history of allergic rhinitis, and developed asthma symptoms for the first time after the storm while five patients had a previous diagnosis of asthma. All 10 patients rapidly improved following bronchodilator and oral steroid treatment and were discharged from the ED. Four patients required inpatient management due to the severity of their symptoms, and were admitted overnight under the respiratory medicine service. Three of these four patients gave a history of allergic rhinitis but no prior diagnosis of asthma. The fourth patient was 34 weeks pregnant, had a prior history of hay fever, and had been recently diagnosed with asthma during the pregnancy. All four patients gave clear histories of outdoor exposure at the time of the storm. They were formally diagnosed as cases of thunderstorm asthma by the attending respiratory physician. All of these patients rapidly improved following standard treatment for asthma exacerbation including systemic corticosteroids, inhaled corticosteroids, and short‐acting inhaled beta‐agonists.For comparison, over a similar period in the preceding year (0000 h 2 December 2016 till 0000 h 4 December 2016), only five patients presented to the Waikato ED with asthma‐related symptoms and only one patient required hospital admission.Anglesea Urgent Care is the only facility other than Waikato Hospital in the Hamilton region that provides 24‐h care. The authors were given access to patient records from 0000 h 2 December 2017 till 0000 h 4 December 2017 (day of the thunderstorm and 24 h afterwards), as well as the same period in December 2016 for a baseline comparison.n = 11) presenting at the clinic. A summary of patient details is presented in Table Anglesea Urgent Care managed 24 cases of asthma exacerbation presentations over the 48‐h period from 0000 h 2 December 2017 till 0000 h 4 December 2017. Of the 24 cases, 10 (42%) had an established diagnosis of allergic rhinitis, but no asthma prior to this event. They all reported typical asthma exacerbation symptoms for the first time in their lives after the storm. The remaining 14 patients had an established asthma diagnosis previously, and presented with an exacerbation during this time frame. In comparison, the same time period in 2016 saw half the number of patients  interviewed by the authors also reported that there were increased asthma presentations in the four to five days following the thunderstorm event. These were often patients who did not have an existing asthma diagnosis and presentations were delayed because they did not know how to interpret the symptoms. A formal review of the local emergency respondent call‐outs was not conducted.3/day, and storms with higher lightning events.Although thunderstorm asthma is a recognized entity, cases are likely under‐reported because small outbreaks may go unnoticed . Cases tFollowing the Melbourne outbreak, there was local speculation on whether similar cases can occur in NZ. Interestingly, a national newspaper took the view that “while possible, such an event was unlikely in NZ” . On the We also observed a high proportion of people of Asian or Indian descent in our cohort. This is in keeping with previous reports of the Melbourne event in 2017 . HoweverA significant proportion of people affected by thunderstorm asthma do not have a prior history of asthma. They are at higher risks of poor outcome during an asthma exacerbation as they do not have prior education to recognize symptoms and seek appropriate medical attention. They also do not have ready access to reliever bronchodilator inhalers. These patients are likely to present late and have more severe exacerbations on presentation. Management of these patients is also likely to be challenging as they do not give a history of established asthma with increased potential for misdiagnosis and thus ineffective treatment. Many patients presenting simultaneously may also overwhelm local healthcare services. Following the Melbourne outbreak, calls have been made to establish a public warning system and increased community resources ; howeverIn conclusion, the number of asthma presentations to emergency and urgent care increased more than twofold compared to historical volumes over the 24 h following a thunderstorm on 2 December 2017 in Hamilton, NZ. We describe a case series of 18 patients with classical features of thunderstorm asthma with no previous asthma history, prominent symptoms of allergic rhinitis, and exposure to outdoor conditions. This figure is likely an underestimate as many affected do not develop severe enough symptoms requiring immediate treatment. To our knowledge, this is the first description of thunderstorm asthma in NZ. Recognition and appreciation of this phenomenon will better enable local healthcare services to prepare, anticipate, and respond to these outbreaks.Appropriate written informed consent was obtained for publication of this case report and accompanying images.


Enteric tube (ET) placement is approached with caution in patients with esophageal varices (EV) due to concern of causing variceal bleeding. Data are limited on rates and predictors of gastrointestinal bleeding (GIB) in these patients. This study aims to assess the rate and predictors of bleeding from EV after ET placement.U test, and univariate logistic regression model.We performed a retrospective chart review on patients requiring ET access with known EV. Inclusion criteria were age >18 with endoscopically proven EV who required ET placement. Patients who were admitted with, or developed a GIB prior to placement of ET were excluded, as were patients admitted for liver transplantation. Primary outcome was incidence of GIB within 48 h of tube placement. Secondary outcome was a >2 g/dL drop in hemoglobin within 48 h of placement without evidence of bleed. Statistical analysis was performed using Fischer's exact test, Mann–Whitney P = 0.026) and EV located in the lower third of the esophagus (P = 0.048).A total of 75 patients were included in the analysis. The most common etiology of cirrhosis was alcohol (44%). The most common location of EV was in the lower third of the esophagus (61%). The primary outcome was observed in 11 (14.6%) patients. The secondary outcome was found in eight (10.6%) patients. On univariate analysis, GIB was associated with higher MELD‐Na  is associated with low risk of bleeding. Elevated MELD‐Na and lower EV location conferred a higher risk of bleeding. Esophageal varices (EV) are a complication of portal hypertension and are prevalent in about 30% of patients with compensated cirrhosis and 60% of those with decompensated cirrhosis. They carry an annual spontaneous bleeding rate of around 12% and a mortality rate of 15–20%.Malnutrition in chronic liver disease is seen in 20% of patients with compensated cirrhosis and 60% of those with decompensated cirrhosis.The lack of clarity on the risks of enteric tube (ET) placement in this patient population poses a particular dilemma for health‐care providers. Resident trainees and other health‐care providers in various specialties are often asked to place nasogastric or orogastric tubes in patients with known EV at bedside without knowledge of the risks associated with blind placement. What is known is that placement of enteric feeding tubes in patients with EV is generally approached with caution due to the concern that bedside blind placement of an ET may trigger a variceal bleed by way of blunt trauma to the varix. The data surrounding this topic have been limited, with no data available on risks and predictors of gastrointestinal bleeding (GIB).We performed a retrospective chart review on patients requiring ET access (orogastric or nasogastric) with known EV at two academic liver transplant centers. At one academic medical center, the timeframe for data collection ranged from January 2010 to January 2017. At another academic medical center, the timeframe ranged from 2015 to 2018. Approval for this study was obtained from the institutional review boards of the participating institutions.Inclusion criteria were patients aged >18 years with a history of cirrhosis and endoscopically proven EV who required nasogastric or orogastric tube placement after presenting to the hospital with a non‐GIB chief complaint. Patients who were admitted with or developed a GIB during their inpatient stay prior to placement of an ET were excluded, as were patients with EV who underwent ET placement during admission for liver transplantation.Data were collected on baseline demographics , etiology of liver disease, endoscopic grade and location of EV, use of nonselective beta blocker for EV prophylaxis, previous EV bleed or banding, history of encephalopathy, presence of ascites, baseline labs , and model of end‐stage liver disease (MELD‐Na) score. The primary outcome was incidence of GIB, defined as hematemesis, bloody NG aspirate, or melena within 48 h of ET placement. The secondary outcome was a >2 g/dL drop in hemoglobin (Hb) within 48 h of ET placement without evidence of bleed. We define a clinically significant drop in hemoglobin as >2 g/dL.Continuous variables are reported as the means ± SD, while categorical variables are reported as the numbers with percentages (%).U test (Wilcoxon test).Categorical variables were compared using Fisher's exact test and Chi square test as appropriate, while continuous variables were compared using the Mann–Whitney P values of <0.05 were considered statistically significant. Analysis was performed using the Statistical Package for Social Sciences .Predetermined A total of 75 patients were included in the analysis. Baseline characteristics are summarized in Table P = 0.0487), more so than varices in any other location of the esophagus. An increasing MELD score was also associated with an increased risk of bleeding, (P = 0.0263), with an OR 1.1 (CI 1.01–1.19) for each 1 point increase in MELD‐Na.The primary outcome of GIB was seen in 11 (14%) patients. The secondary outcome of a >2 g/dL drop in Hb was seen in nine (12%) patients. Of the variables analyzed, location of EV and MELD‐Na score were both associated with increased risk of bleeding. EV located in the lower esophagus demonstrated an increased risk of bleeding  and location of EV in the lower third of the esophagus. Despite no difference in mean INR and platelet levels between cohorts that experienced GIB and those that did not, we believe that the higher mean MELD‐Na scores contributed to higher risks of bleeding due to various factors, including worse renal function through uremia‐induced platelet dysfunction,vs guided), each method carries its own risk profile. Bedside, unguided placement is the most common technique and can be complicated by malpositioning (0.5–16%), with tracheal, pulmonary, or pleural placement in 0.3–15%.It is important to note that this study is the first in 30 years to evaluate the risk of upper GIB in patients with EV who had ETs placed. There have been multiple studies that delineate the risks of ET placement in the general population. Depending on the method of placement  who had experienced a bleed postET placement suffered a Hb drop of more than 2 g/dL, which we defined as a clinically significant Hb drop. We hope that further studies can distinguish between clinically and nonclinically significant GIB postET insertion in patients with EV.We believe that our study provides insight into a common clinical question asked by health‐care providers caring for patients with cirrhosis. It provides insight into the risks and predictors associated with a commonly performed procedure in a notoriously vulnerable patient population. We hope this study provides a platform for providers to weigh the risks and benefits of ET placements in a subset of at‐risk patients while easing concerns of performing this procedure in lower‐risk patients. We hope this study provides the impetus for further studies to be carried out addressing this question, including larger multicenter studies and prospective studies.


The coronavirus disease 2019 (COVID‐19) pandemic is disrupting health services worldwide. We aimed to evaluate the provision of obstetrics and gynaecology services in the UK during the acute phase of the COVID‐19 pandemic.Interview‐based national survey.Women's healthcare units in the National Health Service.Junior doctors in obstetrics and gynaecology.Participants were interviewed by members of the UK Audit and Research in Obstetrics and Gynaecology trainees' collaborative between 28 March and 7 April 2020. We used a quantitative analysis for closed‐ended questions and a thematic framework analysis for open comments.We received responses from 148/155 units (95%), most of the participants were in years 3–7 of training . Most completed specific training drills for managing obstetric and gynaecological emergencies in women with COVID‐19  and two‐person donning and doffing of Personal Protective Equipment (PPE) . The majority of surveyed units implemented COVID‐19‐specific protocols , offered adequate PPE  and operated dedicated COVID‐19 emergency theatres . Most units reduced face‐to‐face antenatal clinics  and suspended elective gynaecology services . The 2‐week referral pathway for oncological gynaecology was not affected in half of the units , but half reported a planned reduction in oncology surgery .The provision of obstetrics and gynaecology services in the UK during the acute phase of the COVID‐19 pandemic seems to be in line with current guidelines, but strategic planning is needed to restore routine gynaecology services and ensure safe access to maternity care in the long term.Provision of obstetrics and gynaecology services during the acute phase of COVID‐19 is in line with current guidelines, strategic planning is needed to restore routine services and ensure safe access to care in the long term. Provision of obstetrics and gynaecology services during the acute phase of COVID‐19 is in line with current guidelines, strategic planning is needed to restore routine services and ensure safe access to care in the long term. This paper includes Author Insights, a video abstract available at https://vimeo.com/rcog/authorinsights16313 In less than 4 months, the emerging coronavirus disease 2019 (COVID‐19) pandemic has sent shock waves through the global health system, significantly disrupting care provision with high levels of morbidity and mortality worldwide.In times of crisis, much morbidity arises from poor access to health services and depletion of valuable resources.Efficient assessment and feedback are key to refining the planned responses facing this pandemic and ensuring the safety of both the patients and their caring professionals. We aimed to provide a snapshot assessment of current service provision in obstetrics and gynaecology in the NHS by surveying junior doctors in all women's healthcare units in the UK.We conducted an interview‐based survey with junior doctors in obstetrics and gynaecology across all training units in the NHS. Participants were contacted via the UK trainees' collaborative for Audit and Research in Obstetrics and Gynaecology (UK ARCOG) networkThe interviews included a mixture of closed‐ and open‐ended questions to capture current practice and the adoption of guidance from the World Health Organization and Royal College of Obstetricians and Gynaecologists on the safe management of women with COVID‐19.Data were collected by a nominated UK ARCOG representative at each Local Educational Training Board (LETB) using a standardised electronic data collection tool. Data were harmonised and merged centrally by the same moderator (MPR) and quality checked for any entry errors.P < 0.05.We reported data using natural frequencies and percentages. Where relevant, we used Kruskal–Wallis test to compare medians of non‐parametric data with significance at excel .We analysed open comments thematically using a framework analysis to understand the participants' experiences and perspectives.No core outcome sets exist for this area of research. We did not seek input from patients when developing this tool as it sought to seek responses from healthcare staff only.We contacted all 155 training units in the UK across 16 LETBs. We received responses from 148/155 units (95%). The majority of participants were junior doctors in years 3–5 of their training , followed by years 6–7 , 1–2  and non‐training trust grade doctors . We did not receive responses from the remaining seven units because of lack of engagement.P = 0.15) (Table P = 0.08). In total, 62.8% of junior doctors felt that they were adequately supported by senior staff when dealing with this health crisis  and two‐person donning and doffing of PPE , though only 80% had a face‐mask  fit tested  Table . Most pais Table .Most included units had developed departmental protocols on the management of pregnant women with suspected or confirmed COVID‐19 on the labour ward , though some participants reported that these protocols were changing rapidly, leading to confusion and unclear interpretation by staff members , offering more telephone or virtual consultations  and identifying dedicated clinic areas for pregnant women with suspected or confirmed COVID‐19 . More than one‐third altered their screening pathways to reduce in‐hospital attendance  with some participants reporting the use of fasting blood sugar and HbA1c instead of oral glucose tolerance test to reduce in‐hospital stay and reduction of the frequency of serial growth scans as common measures  with some units operating virtual clinics , but half reported a planned reduction in oncology operating lists . Only a minority moved oncology surgery to a COVID‐19‐free site such as the premises of non‐NHS private hospitals  as well as postoperative wards .Our findings offer a rapid comprehensive overview of the provision of obstetrics and gynaecology services in the NHS in response to the COVID‐19 pandemic.Overall, the majority of units seem to be following national guidance during the acute phase of the crisis but variation in practice and misinterpretation of guidance were expressed by our participants, especially where limited evidence is available to inform practice such as the emergency gynaecology care.Our findings are limited by the scope of the interview questions and the limited representation of each unit (one participant per unit). A detailed analysis is likely to yield more information on the current practice and to identify areas for improvements in women's healthcare provision. This is especially relevant for topics such as the availability of PPE, which could change daily across the surveyed units. Still, our findings are comprehensive and contemporary to evaluate the COVID‐19 response across all women's healthcare units.The COVID‐19 crisis is likely to have both short‐term and long‐term impacts on women's healthcare services worldwide. Our findings suggest an overall good initial response in the NHS during the acute phase of this pandemic in line with current evidence‐based health policies and clinical guidelines. Still, some alarming features emerged, such as the suspension of elective gynaecology, the deferring of antenatal screening tests and the reduction of oncology operating capacity. Prolonged suspension of these essential services is likely to increase morbidity in the long term.Strategic planning is, therefore, required to mitigate the risk of the adverse outcomes to women's health seen during similar crises.Rapid testing and triaging systems for COVID‐19 patients are urgently needed, especially beyond the acute phase, to minimise the risk of exposure of unaffected women and their healthcare professionals. This is likely to become a daily practice as we transform to the ‘new normal’ over the next 18 months until reliable treatments and vaccines are developed.Using innovative interventions to reduce inpatient stay in hospital has been pivotal in managing this crisis powered by the rapid uptake of telemedicine technology.As with every new endeavour, efficient data collection and analysis are essential elements to advise our response to this global pandemic. Our findings shed some light on the impact of COVID‐19 on obstetrics and gynaecology healthcare services in the UK, but more stringent long‐term data collection and sharing are needed to fully evaluate the impact of this pandemic on women's health outcomes and to coordinate a global response to eliminate it.The provision of obstetrics and gynaecology services in the UK during the acute phase of the COVID‐19 pandemic seems to be in line with current guidelines, but strategic planning is needed to restore routine gynaecology services and ensure safe access to maternity care in the long term.None declared. Completed disclosure of interests forms are available to view online as supporting information.BHAW and MPR conceived the idea, wrote the protocol, analysed data and wrote the final manuscript. All other co‐authors actively helped in data collection and drafting of the final manuscript.Not required.None.Table S1. Thematic analysis of participants’ open comments on the provision of obstetrics and gynaecology care in the NHS during the acute phase of the COVID‐19 pandemic.Click here for additional data file.Appendix S1. Questionnaire on the provision of obstetrics and gynaecology services in the NHS response during the acute phase of the COVID‐19 pandemic.Click here for additional data file.Video S1. Author Insights.Click here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.


A major goal for the field of regenerative medicine is to enable the safe and durable engraftment of allogeneic tissues and organs. In contrast to autologous therapies, allogeneic therapies can be produced for many patients, thus reducing costs and increasing availability. However, the need to overcome strong immune system barriers to engraftment poses a significant biological challenge to widespread adoption of allogeneic therapies. While the use of powerful immunosuppressant drugs has enabled the engraftment of lifesaving organ transplants, these drugs have serious side effects and often the organ is eventually rejected by the recipient immune system. Two conceptually different strategies have emerged to enable durable engraftment of allogeneic therapies in the absence of immune suppression. One strategy is to induce immune tolerance of the transplant, either by creating “mixed chimerism” in the hematopoietic system, or by retraining the immune system using modified thymic epithelial cells. The second strategy is to evade the immune system altogether, either by engineering the donor tissue to be “invisible” to the immune system, or by sequestering the donor tissue in an immune impermeable barrier. We give examples of research funded by the California Institute for Regenerative Medicine (CIRM) in each of these areas, ranging from early discovery‐stage work through clinical trials. The advancements that are being made in this area hold promise that many more patients will be able to benefit from regenerative medicine therapies in the future. For cell and tissue therapies to become widely accessible will ultimately require the success of off‐the‐shelf allogeneic products that can be administered to patients regardless of immune compatibility with the donor tissue. Since the long‐term use of immunosuppressive drugs renders patients subject to infectious disease and other side effects, it is critical to develop alternative methods to overcome immune barriers to engraftment. The California Institute for Regenerative Medicine (CIRM) has funded multiple programs, in different disease areas and at different stages of therapeutic development, that are tackling this challenge. This article summarizes the main approaches that are being taken in this rapidly moving field and gives examples of specific programs that CIRM has funded in these different areas.1Successful therapeutic transplantation of allogeneic cells or organs requires overcoming immunological rejection of the graft by the recipient. Although transplantation of donated tissues has saved many lives and treated many diseases, patients must undergo chronic immune suppression to prevent rejection of the life‐saving tissue, typically with a cocktail of drugs including a purine metabolism inhibitor, a calcineurin inhibitor, and steroids. These drugs are associated with cumulative side effects that increase the risk of cardiovascular disease, diabetes, hypertension, infection, cancer, and nephrotoxicity.2Table 2.1One approach to induce tolerance of an allogeneic donor graft is through generation of “mixed chimerism,” characterized by coexistence of donor and recipient blood and immune cells. Persistent mixed chimerism has been demonstrated to be required for immune tolerance, minimizing, or preventing both graft rejection by the host and GVHD.The aforementioned clinical trial led by Dr Strober also found that approximately half of patients receiving kidneys from haploidentical donors achieved stable mixed chimerism and kidney graft tolerance with reduced immune suppression (tacrolimus monotherapy), but that loss of chimerism and graft rejection occurred if immune suppression was completely withdrawn.A mixed chimerism approach is also being taken by Dr Joseph Rosenthal at City of Hope Medical Center, who is conducting a CIRM‐funded phase 1 trial to treat sickle cell disease (SCD) patients with a haploidentical HSCT using nonmyeloablative conditioning  are critical for inducing central immune tolerance by causing the elimination of self‐reactive T cells. Thus, the ability to generate functional TECs from human pluripotent stem cells (hPSCs) may help overcome immune barriers to engraftment of other cells or tissues derived from those same stem cells. Toward that end, Dr Mark Anderson and his team at UCSF were funded by CIRM to develop a novel method for generating thymic epithelial precursors (TEPs) from hPSCs Table . They shA similar approach of using TEC for the purpose of inducing tolerance was taken by Dr Gay Crooks at UCLA, as part of a CIRM‐funded project in which she generated organoids composed of human fetal TEC and thymic mesenchyme cells that also are capable of supporting T‐cell differentiation Table .15 Dr 3Table 3.1Genetic manipulation of hPSC can be used to enable hPSC‐derived therapeutics to evade the immune system, rather than be tolerated by it. To prevent T cell‐mediated rejection of the transplanted tissue, it is necessary to remove the HLA class I and II from that tissue. This can be done by disrupting the B2M gene, an essential component of HLA class I, and the CIITA gene, which is required for the transcription of HLA class II genes.Multiple CIRM grantees are starting to use similar cell engineering approaches to develop nonimmunogenic allogeneic cell therapiesIn a variation of the above approaches, Dr Sonja Schrepfer at UCSF was funded by CIRM to couple HLA class I and II disruption with CD47 overexpression in human iPSC, followed by derivation of cardiomyocytes, smooth muscle, and endothelial cells that were used to create a hypoimmunogenic cardiac patch. In preclinical testing, this patch evaded immune rejection after transplantation into fully major histocompatibility complex (MHC) mismatched allogeneic recipients.Naturally occurring suppressors of the immune system have also suggested other ways to engineer cellular therapies to prevent recognition by the host immune system. CIRM‐funded research led by Dr Yang Xu at UCSD has found that the expression of checkpoint molecules CTLA4 (CTLA4‐Ig) and PD‐L1 in human ESC line HUES3 was sufficient to prevent rejection of differentiated tissues  in mice bearing humanized immune systems.We note that the above strategies, should they be successful, would prevent the immune system from recognizing donor tissue even if became infected or cancerous. Therefore, many researchers also include an inducible “kill switch” such as iCasp93.2Among the strategies to avoid the immune system, encapsulation is perhaps conceptually the simplest way to protect a cellular therapeutic while at the same time being the most limited in its application. Both microencapsulation devices, in which relatively small numbers of cells are embedded in matrices such as alginate, polyethylene glycol (PEG), or gelatin, and macroencapsulation devices (>1 mm), capable of containing larger amounts of cells, have arisen as viable approaches to evading the immune system.In this area, CIRM has supported the development of ViaCyte's Encaptra macroencapsulation device for the treatment of T1D with hESC‐derived pancreatic precursor cells (PEC‐01 cells).Dr Tejal Desai at UCSF has also received CIRM funding to develop a macroencapsulation technology for T1D based on flexible nanoporous thin films designed to support the long‐term viability and function of allogeneic human ESC‐derived insulin producing beta cells. Dr Desai has placed an emphasis on the composition of her device being able to avoid a scar‐forming foreign body response that would affect the viability and function of the beta cells. Encellin, a San Francisco‐based biotechnology company, has licensed Dr Desai's technology for commercialization.Dr Shuvo Roy, also at UCSF, is developing a CIRM‐funded intravascularly implanted macroencapsulation device, a bioartificial pancreas (iBAP) for T1D, that is conceptually different from the Viacyte and Encellin devices. Instead of relying on the proximity of surrounding vasculature to allow exchange of oxygen, glucose, and insulin between the encapsulated cells and the blood system, the iBAP is implanted directly in‐line with a blood vessel to provide enhanced kinetics of glucose sensing and insulin secretion while still isolating the allogeneic human stem cell derived pancreatic beta cells from the immune system using a silicon nanopore membrane.4The ability to use allogeneic cells and tissues for regenerative medicine will be critical to enable large‐scale, reproducible manufacturing that will both increase availability of the treatment and manage the cost of the products. Thus, as more regenerative cell therapies enter the clinic and begin to show efficacy in patients, it is critical, in parallel, to develop safe and easily implemented methods to overcome immunological barriers in order to facilitate durable engraftment of transplanted allogeneic tissues. Herein, we have described some of the approaches being taken by CIRM grantees to enable successful engraftment of allogeneic tissues, which are a small subset of the many efforts being made in this field. For example, other methods being used to induce immune tolerance include adoptive transfer of cell types such as Tregs, tolerogenic dendritic cells, and mesenchymal stromal cells.The authors declared no potential conflicts of interest.L.C.K., R.M.O., S.T.: conception and design, manuscript writing and final approval of manuscript.


The coronavirus disease 2019 (COVID‐19) pandemic has seen the cancellation of elective cardiac surgeries worldwide. Here we report the experience of a cardiac surgery unit in a developing country in response to the COVID‐19 crisis.From 6th April to 12th June 2020, 58 patients underwent urgent or emergency cardiac surgery. Data was reviewed from a prospectively entered unit‐maintained cardiac surgery database. To ensure safe delivery of care to patients, a series of strict measures were implemented which included: a parallel healthcare system maintaining a COVID‐19 cold site, social isolation of patients for one to 2 weeks before surgery, polymerase chain reaction testing for COVID‐19, 72 hours before surgery, discrete staff assigned only to cardiac surgical cases socially isolated for 2 weeks as necessary.The mean age at surgery was 59.7 ± 11 years and 41 (70.7%) were male. Fifty‐two patients were hypertensive (90%), and 32 were diabetic (55.2%). There were three emergency type A aortic dissections. Forty‐seven patients underwent coronary artery bypass graft surgery with all but three performed off‐pump. Fourteen cases required blood product transfusion. One patient had postoperative pneumonia associated with chronic obstructive pulmonary disease. The median length of stay was 5.7 ± 1.8 days. All patients were discharged home after rehabilitation. There were no cases of COVID‐19 infection among healthcare workers during the study period.These strategies allowed us to maintain a service for urgent and emergency procedures and may prove useful for larger countries when there is decrease in COVID‐19 cases and planning for the restart of elective cardiac surgery. It is essential to reflect on the effects of the pandemic foremostly to validate and inform practice in the likely event of a second wave, but also to contribute to the global understanding of response to this disease. As such, the goals of this communication are to report on the conditions that allowed continuation of emergency and urgent elective cardiac surgical cases during the COVID‐19 pandemic.2From 6th April to 12th June 2020, 58 patients underwent cardiac surgery in two hospitals, St. Clair Medical Center, a private hospital, and Eric Williams Medical Sciences Complex (EWMSC), a public hospital. The cardiac surgical service at both hospitals is covered by the same surgical team. The study was performed as part of an approved audit, according to the specifications of the Declaration of Helsinki. We reviewed prospectively entered data from the unit maintained cardiac surgery database of consecutive patients.During the reported COVID‐19 period we did not operate on elective cases. A patient was defined as elective if they do not require urgent surgery and has been placed on a waiting list (before COVID‐19 the waiting list was around 2‐3 months). The number of procedures performed before COVID‐19 was approximately 35 cases per month.All patients were reviewed in our preoperative clinic with enforced social distancing in waiting rooms and mandatory mask wearing. Cases were screened by a multidisciplinary cardiac surgical team. Patients were selected on the basis of requiring urgent intervention  or emergency (acute type A aortic dissection).Urgent patients identified according to the above criteria by the multidisciplinary cardiac surgical team were asked to socially isolate themselves at home before scheduled surgery for at least 7 to 14 days. Because of patient bed limitation, it was not possible to keep those patients in hospital for the required period of isolation. At St. Clair Medical Center, patients had a 72 hours preoperative COVID‐19 polymerase chain reaction (PCR) test. In the public hospital, EWMSC, cases were tested only if symptomatic (because of limited availability of reverse transcription‐PCR [RT‐PCR] testing) in concordance with the Ministry of Health's management of the ongoing crisis. The three emergency dissections were operated in the private hospital and tested for RT‐PCR.All patients were intubated with minimum staff in the operating theater including an anaesthetist and an assistant with appropriate PPE (N‐95/visor) to protect the team and diminish the chance of in‐hospital “community spread.” The surgical team wore standard surgical masks, gowns, and protective loupes. All cardiac surgical patients were managed in an intensive care unit (ICU) and high dependency unit (HDU) (not exposed to noncardiac surgery patients) by staff dedicated to their care only.3The demographic and clinical data are summarized in Table The mean age at surgery was 59.7 ± 11 years and 41 (70.7%) were male. Fifty‐two patients were hypertensive (90%), and 32 were diabetic (55.2%). There were three emergency type A aortic dissections. Forty‐seven patients underwent coronary artery bypass graft surgery with all but three performed off‐pump. Fourteen cases required blood product transfusion. One patient had postoperative pneumonia associated with chronic obstructive pulmonary disease. The median length of stay was 5.7 ± 1.8 days  complete cessation of elective surgery with centralization of emergent and urgent services to a few dedicated centers, (b) meticulous multidisciplinary triage of patients with divergence to interventional services where appropriate due to associated shorter length of stay, (c) redeploying of cardiac surgical staff, equipment and beds to expand critical care services, and (d) largescale uptake of virtual and tele‐medicine.The population of our twin‐island state is small relative to many of the worst hit countries worldwide, standing at a modest 1.35 million.In the period examined, 58 cases deemed urgent or emergency were performed, with no hospital mortality. To optimize outcomes and protect both patients and staff in these instances, consideration of patients' COVID‐19 status was viewed as paramount. All cardiac surgery patients at the private center, were required to self‐isolate for one to 2 weeks and underwent PCR testing 72 hours before surgery. Isolation was also implemented for patients in the public hospital. However, we were unable to routinely screen patients for PCR in the public hospital, classified as a COVID‐19 cold site, given the limited availability of testing nationally. It is important to note that, postoperative cardiac surgical patients in the ICU require intense chest physiotherapy and nebulizing for the purposes of coughing and expectorating. As both procedures are aerosolizing coupled with inapplicability of surgical masks, asymptomatic patients were duly screened with PCR when possible not only for the safety of other patients, but for healthcare workers as well. Similar protective strategies were also employed in the postoperative period, as cardiac patients were batched and cared for in one designated ICU/HDU. Visitors were also limited. The net effect of these precautionary steps facilitated individual patient safety, contributed to maintaining the integrity of parallel, discrete healthcare systems, and created a setting that allowed for the unencumbered continuation of cardiac surgery throughout the pandemic.While our smaller population confers these advantages, there are also associated drawbacks. The period of lockdown saw an absolute decrease in blood donations, which in the context of a smaller population created a national shortage of blood products. Notably, the routine practice of our cardiac surgical team is off‐pump coronary surgery which is associated with a decreased rate of blood transfusions compared with on‐pump procedures.We recognize that these strategies proven viable in Trinidad cannot necessarily be generalized regardless of population size or infections rates, as many other confounding factors exist between countries and healthcare systems. Despite this however, several lessons may be derived from our unique situation, which may prove useful in guiding our neighbors' own unique circumstances. To ensure safe delivery of care to patients, a series of strict measures were implemented which included: a parallel healthcare system maintaining a COVID‐19 cold site, social isolation of patients for one or 2 weeks before surgery, whenever possible PCR testing for COVID‐19, 72 hours before surgery, discrete staff assigned only to cardiac surgical cases socially isolated for 2 weeks as necessary. Screening of patients should be an essential component of any major elective cardiac surgical service that plans to continue throughout the pandemic or in the event of a second wave. These strategies allowed us to maintain a service for urgent and emergency procedures and may prove useful for larger countries when there is decrease in COVID cases and planning for the restart of elective cardiac surgery.5Urgent and emergency cardiac surgery can be safely performed during the COVID‐19 pandemic provided that certain precautions are taken. This experience confidently yet cautiously prepares us if there is a second wave of COVID‐19 infections worldwide.