The aim of this study is to assess the clinical results of bifocal or trifocal bone transport using unilateral rail system in the treatment of large tibial defects caused by infection.There were a total of 37 eligible patients with an average age of 40.11 ± 10.32 years  with large tibial defects due to infection who were admitted to our hospital from June 2006 to June 2016. Among the patients, 21 underwent bifocal bone transport (BF group), and the remaining 16 were treated with trifocal bone transport (TF group). The demographic data , intraoperative outcomes , postoperative variables , postoperative bone and functional outcomes evaluated by Association for the Study and Application of the Method of Ilizarov (ASAMI) scoring system, and postoperative complications evaluated by Paley classification  of the two groups were recorded and compared at a minimum follow‐up of 24 months.The mean duration of follow‐up after removal of fixator was 29.49 ± 4.34 months . There was no statistically significant difference in the demographic data, intraoperative outcomes including size and location of the defect, size of soft tissue defect, as well as postoperative complications. However, postoperative functional result in the TF group were superior to those in the BF group at a minimum follow‐up of 24 months, and lengthening speed, external fixation index (EFI), duration of regenerate consolidation and docking union were significantly reduced in the TF group when compared with the BF group.Treatment of large tibial defects caused by infection with trifocal bone transport using unilateral rail system could significantly improve postoperative functional recovery and reduce duration of regenerate consolidation and docking union. The present study provides novel insight for the treatment of large tibial defects caused by infection. Segmental bone defects represent one of the most challenging conditions to orthopaedic surgeons, especially when they are associated with infection and soft tissue loss due to their long disease course and complex treatmentThe Ilizarov method, which is used in the treatment of complicated fractures of long bones, was first introduced in 1950 by Gavril Abramovich Ilizarov in the Soviet Union. This revolutionary method for treating fractures, nonunions, deformities and other bone defects involved the use of a circular external fixator. Transport of an osteotomized vascularized bone fragment within the soft tissues to restitute a missing long bone part by distraction osteogenesis (DO) with the Ilizarov method would be an ideal method of bone plasty if not for several known shortcomings and arising problemset al.Despite the unique ability to fully induce neo‐osteogenesis, this lengthy technique is limited by undesirable long duration of the consolidation stage and a subsequent increase in the risk of complicationsBased on previous studies and our experience, we hypothesized that trifocal bone transport has advantages over bifocal bone transport regarding lengthening index, regenerate consolidation, docking union, clinical outcomes and overall complications. Therefore, the main purpose of this study are to: (i) explore the therapeutic effect of bifocal and trifocal bone transport using unilateral rail system in the treatment of large tibial defect with or without soft tissue loss; (ii) compare postoperative clinical outcomes and complications between bifocal and trifocal bone transport; and (iii) summarize the exiting limitations and the possible direction for further study. To the best of our knowledge, this is the first clinical study to compare the two techniques using a unilateral rail system in the treatment of large tibial defects caused by infection.Inclusion criteria: (i) patients aged 18–65 years old; (ii) tibial defects more than 6 cm and caused by infection with sufficient bone stock near the knee/ankle joint for Schanz screws insertion; (iii) tibial defect treated by bifocal or trifocal bone transport using unilateral rail system; and (iv) a minimum postoperative follow‐up of 24 months with good compliance.Exclusion criteria: (i) tibial defects less than 6 cm and caused by trauma without infection, excision of tumors, congenital defect, limb with vascular insufficiency; (ii) surgical area with poor skin conditions or skin diseases; (iii) severe osteoporosis; (iv) comorbid severe cardiovascular and cerebrovascular diseases, mental illness, and abnormal liver and kidney function; (v) pregnant or lactating women; (vi) autoimmune diseases and blood disorders; and (vii) patients with poor compliance and loss of follow‐up.In total, 55 patients underwent bone transport technique using unilateral rail system in the treatment of large infective tibial defects. Of these, 18 patients were unavailable for follow‐up . The remaining 37 patients were included in this retrospective study, there were 28 males and nine females with mean age of 40.11 ± 10.32 years . Permission from the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University was obtained and informed consent was taken from all patients. Data regarding patient's age, sex and side of injury, interval between initial injuries and previous operation time before bone transport were obtained from the patients themselves. All patients had a mean of 2.8 previous surgical treatments. All patients were performed by bifocal (n = 21) or trifocal (n = 16) transport using unilateral rail system (Orthofix limb reconstruction system (LRS)) after radical debridement, with or without spacer filling and soft tissue reconstruction.Comparison of the demographic preoperative data between BF group and TF group is demonstrated in Table The patients were placed in a supine position or lateral position if flap transfer is needed on a radiolucent table under continuous general or spinal anesthesia while application of Orthofix LRS  is administered.After obtaining satisfactory surgical position, incision was made according to previous surgical scars or consistent with preoperative flap design; otherwise, anterolateral longitudinal incision was performed, cutting and separating subcutaneous tissue to explore the infected bone.A complete removal of hardware, radical debridement of all necrotic and infected bone and soft tissue, and/or implantation of an antibiotic‐impregnated cement spacer to improve stability were performed prior to bone transport. Cortical bleeding, described as the so‐called “paprika sign”, was accepted as an indication of vital osseous tissueAfter debridement, the Orthofix LRS  was assembled for all patients. The external fixator was placed on the distal and proximal fragments parallel to their respective joint based on flap transfer fashion otherwise in anteromedial position . Then, sliding clamps were assembled and Schanz screws were inserted perpendicular to the mechanical axis of the tibia proximal and distal to the defect under the image intensifier control and the desired tibial length and alignment was maintained. Following this, a percutaneous minimally‐invasive osteotomy of the tibia was performed according to pre‐selected osteotomy site(s).Distraction at the osteotomy site(s) was started in both groups on a latency period of 7 to 10 days. Vancomycin or cefuroxime sodium were given intra‐ and postoperatively, and therapy changed based on bacterial culture and drug susceptibility tests results for at least 6 weeks. Passive knee and ankle joint exercises were started at day 1 postoperatively and early full‐weight‐bearing was encouraged. Transport is performed until the docking site is reached. In BF group, fragment was transported at a rate of 0.25 mm four times per day. In TF group, for bone transport in the same direction , the fragment near the bone defect was transported at a rate of 0.5 mm four times per day, and another fragment far from the defect was transported 0.25 mm four times per day. For converged bone transport, each fragment on both sides of the bone defect proceeded at a rate of 0.25 mm four times per day. The illustration of trifocal bone transport using Orthofix LRS is demonstrated in Fig. The patients were followed up in the outpatient clinic every 2 weeks, and physical and radiographic examinations were performed to detect and treat common obstacles, problems and complications. When the bridging callus appeared radiologically and limb length equalization was achieved, the frame was dynamized in order to assess the mechanical stability of the regenerated bone and then removed as a daycare procedure. At the time of removal of the external fixator, the leg was protected in a long‐leg cast or cast‐brace for 4 to 6 weeks with the patient using only partial weight‐bearing.The raw observation data for the two groups were recorded and compared as follows.The lengthening speed was calculated as the amount of lengthening (mm) by the amount of time needed in days for the transported bone segments to reach the docking. In BF group, theoretical lengthening speed was 1 mm per day (0.25 mm four times per day). In TF group, theoretical lengthening speed was 2 mm per day which was calculated by the following rate and rhythm: for bone transport in the same direction , the fragment near the bone defect was transported at a rate of 0.5 mm four times per day, another fragment far from the defect was transported at a rate of 0.25 mm four times per day, and for converged bone transport, each fragment on both sides of the bone defect proceeded 1 mm per day (0.25 mm four times per day). Lengthening speed was adjusted according to patient's endurance and follow‐up X‐ray evaluation of regeneration.The external fixation index (EFI) was calculated as a ratio of the number of days the frame was used to the length of regenerated bone (cm). The most common problem in cases of distraction osteogenesis with the bone transport technique in massive bone loss is the long duration of the fixator. The risk of potential complications  increased with longer time spent on carrying the external fixator. The time spent in an external fixator (EFI) depends on the length of distraction required and is not free of complications. The removal of the external fixation was based on the following findings: osteogenesis is sufficient in the distraction area, and no deformations were found at the docking site and distraction area when the patient walked during full weight‐bearing activities.Duration of regenerate consolidation was defined as total time (days) needed for the appearance of consolidation of at least three cortices on the anteroposterior and lateral radiographs. Duration of docking union was defined as total amount of time (days) required to develop the signs of union (presence of bridging trabeculae on three cortices and absence of pain on dynamization). Radiographs were reviewed monthly to monitor the quality of regenerate during bone transport phase and every 2 months after docking to assess consolidation of the regenerate and healing of docking union. Fischgrund criteriaBone and functional results were evaluated according to the Association for the Study and Application of the Method of Ilizarov (ASAMI) criteriaComplications were classified according to Paley classificationt‐test was used for parametric quantitative data while the Chi‐square test was used for qualitative data. Fisher's Exact Test was used for qualitative data between both groups. The P value of <0.05 indicated a statistically significant difference.All statistical analyses were performed using SPSS 21.0 software . Independent samples vs 40.05 ± 11.39 years, P = 0.844), sex ratio , mean internal duration before bone transport, mean previous operation time(s) , injured side . There was statistically significant differences regarding the mean defect size  between the two groups, and the differences can be explained by selection of bone transport technique  applied to patients based on both intraoperative defect size and surrounding soft‐tissue condition, the decision on bone transport technique  was made by the correspondence author (AY). The proportion of bacterial species growth in culture are shown in Table A total of 37 patients, 28 male and nine female with an average age of 40.11 ± 10.32 years  were enrolled for our study. The demographic data of recruited patients are described in Table The mean follow‐up time from removal of the fixator to the time of the last review of 37 patients in this study was 29.49 ± 4.34 months . We compared the postoperative outcome measures of the two groups, and the results are showed in Tables P = 0.000) between the two groups, and our results suggest that trifocal bone transport technique possess faster lengthening speed than bifocal bone transport technique which could facilitate early docking contact and potentially reduce EFI by early regenerate consolidation and docking union.The lengthening speed was 0.79 ± 0.17 mm per day in BF group, while it was 1.59 ± 0.26 mm per day in TF group. It was shown that there was statistical difference (P = 0.000). EFI in BF group is almost double than in TF group, and our results indicated that the use of trifocal bone transport technique would significantly impact on the time spent on placement of external fixation and potentially reduce postoperative complications along with psychological burdens.The mean external fixation index (EFI) was 32.94 ± 9.21 days per cm in TF group, and 62.21 ± 24.60 days per cm in BF group. There was significant statistical difference between the two groups (P = 0.000). The mean duration of docking union was 207.06 ± 40.48 days in TF group, and 299.90 ± 128.26 days in BF group. There was statistical difference between the two groups (P = 0.005). Both regenerate consolidation and docking union are time consuming processes which were also the main reason of lengthy external fixator and could increase potential risk of complications. Our results revealed that faster regenerate consolidation and docking union can be achieved by trifocal bone transport technique, which may potentially reduce postoperative complications and early removal of external fixator.The mean duration of regenerate consolidation was 138.50 ± 31.97 days in TF group, and 202.81 ± 35.22 days in BF group. There was conspicuous statistical difference between the two groups , but not in the bone results . Our results indicate that better functional results can be achieved by trifocal bone transport technique by shorter EFI and early removal of external fixator, which could motivate patients to exercise frequently without fixation placement and potentially avoid complications such as muscle contraction and joint stiffness. For more details of the whole procedures in both groups, please refer to Figs The bone and functional results at last visit (minimum of 24 months) after removal of external fixator is summarized in Table P > 0.05). Pin tract infection occurred in 33 cases (30%) which did not interfere with expected clinical results via proper management by daily dressing and applying antibiotics based on the result of culture and sensitivity testing. Muscle contraction was encountered in 27 cases (25%) among which 10 cases were recovered by intensive physiotherapy and the remaining 17 were treated by subcutaneous Achilles tendon lengthening or applying the apparatus across the joint and to distract out the contraction. Axial deviation occurred in 23 patients (21%) among which 10 cases were deviated greater than 5°; for recurvature purposes, modification of the apparatus or inserting an additional Schanz screw(s) to pull the bone out of its deviated position was required before the end of the treatment. There were two cases that suffered delayed consolidation which were successfully treated by readjusting lengthening speed or accordion maneuver. Repeated fracture at regenerate was encountered in one case and resolved by applying cast and external fixation until consolidation. Joint stiffness either in knee or ankle was classified as true complication by Paley classificationComplications were classified according to Paley classification. No case encountered joint luxation, vascular or nerve compromise in both groups and the results are shown in Table The treatment of a large tibial defect caused by infection using bone transport with external fixation has been successful. Among those bone transport approaches, Ilizarov ring fixator has become a gold standard for the treatment of massive tibial bone defects, which could eradicate infection and solve bone and soft tissue defects at the same timeet al.et al.Many surgical approaches have been proposed to reduce lengthening index, prevent its potential complications and to accomplish better clinical outcomes. Gupta et al.Ideally, trifocal bone transport equals faster docking contact which results in early docking union and removal of external fixator once regenerate consolidation are completed. Consolidation of regenerate depends on its length and, more importantly, osteotomy technique and level, and blood supply of transported bone segment. Chaddha The incidence and severity of complications encountered during bone transport have changed dramatically with studies, experience and meticulous prophylactic intervention. The complication rate was 3.1 per patient in our study, among which pin tract infection, muscle contraction and axial deviation were the top three common complications. Pin tract infection is a universal problem which can be successfully treated or even prevented from further development if it is detected in an early stage; regular dressing and improvement of patient's hygiene also plays an important role since it can spread into bone infection if not being managed properly. Muscle contraction was a result of tension generated on the muscle due to distraction and imbalance of strength between flexors and extensors which accounts for 25% of total complications in our study. Muscle contraction of most cases in our study were improved by physiotherapy, or subcutaneous Achilles tendon lengthening or applying the apparatus across the joint to distract out the contraction if needed.Our present study demonstrates that both bifocal and trifocal bone transport using unilateral rail system led to satisfactory bone and functional results in the treatment of large tibial defects caused by infection. All patients in our series reached bony union with or without bone grafting at the end of the treatment. However, trifocal bone transport led to better functional results but not bony result than bifocal bone transport; this can be explained due to the external fixator not being able to be removed sooner in trifocal group, as well as patients being willing to exercise frequently without fixation placement, which could potentially prevent muscle contraction and joint stiffness. There are many factors that can impact successful distraction osteogenesis based on our experience, such as comprehensive understanding of application of external fixator, prudent patient selection, radial excision of infected bone, timely follow‐up during and after distraction period, early detection of predicted complications and proper surgical or non‐surgical intervention and psychological counseling with in‐charge surgeon during entire treatment course.The present study had several limitations. First, considering its retrospective nature and relatively small sample size, prudent attitude should be adopted regarding the interpretations of our bone and functional outcomes. Second, longer follow‐up time is necessary to better evaluate the clinical efficacy of the two treatment strategies. Third, further investigations, especially muti‐centered trails with a larger sample size should be conducted to overcome the limitations of our study. Finally, postoperative observational indicators in this study were not comprehensive enough: for example, more accurate quality of life assessments and mental evaluations could be adopted.Based on our experience on distraction osteogenesis by bifocal or trifocal bone transport using unilateral rail system, we concluded that radical debridement and resection is the most important task in the treatment of tibial defects caused by infection. Preoperative planning is critical for both successful resection and frame mounting. Pin tract infection is a universal problem which can be avoided by regular cleaning. The decision between bifocal or trifocal approaches needs to be decided according to patient, bone quality, defect size, surrounding soft tissue condition, etc. In conclusion, both bifocal and trifocal bone transport using unilateral fixation system can be used successfully to reconstruct large tibial defects caused by infection. It could significantly reduce lengthening index with better functional outcome by trifocal bone transport compared with bifocal bone transport approach.


Old age and female sex are risk factors for the development of osteoarthritis (OA) and chronic pain. We investigated the effects of sex and age on pain modulatory networks in a healthy state and during OA progression. We used functional MRI to determine the effects of sex and age on periaqueductal gray functional connectivity (PAG FC) in a healthy state (pre‐OA) and during the early and late phases of monosodium iodoacetate‐induced OA in rats. We then examined how sex and age affect longitudinal changes in PAG FC in OA. In a healthy state, females exhibited more widespread PAG FC than males, and this effect was exaggerated with aging. Young males had moderate PAG FC changes during the early phase but recruited additional brain regions, including the rostral anterior cingulate cortex (ACC), during the late phase. Young females exhibited widespread PAG FC in the early phase, which includes connections to insula, caudal ACC, and nucleus accumbens (NAc). Older groups had strong PAG FC with fewer regions in the early phase, but they recruited additional brain regions, including NAc, in the late phase. Overall, our findings show that PAG FC is modulated by sex and age in a healthy state. A widespread PAG network in the early phase of OA pain may contribute to the transition from acute to chronic OA pain and the increased risk of developing chronic pain for females. Enhanced PAG FC with the reward system may represent a potential mechanism underlying chronic OA pain in elderly patients. In a healthy state, females exhibit widespread periaqueductal gray functional connectivity (PAG FC), and this effect is exaggerated with aging. Young females have widespread PAG network in the early phase of osteoarthritis (OA) pain. PAG FC with rostral anterior cingulate cortex in young males in the late OA phase may facilitate descending pain inhibition. Enhanced PAG FC with the reward system is seen in old groups in the late OA phase. The coupling of activation between different brain areas indicates that they are involved in the same underlying functional process and are thus interpreted as functionally connected  was determined based on previous publications and power analyses   and old (20–24 months old) age were obtained from the National Institute on Aging. All animals were housed in a temperature‐controlled room under a 12:12‐h light–dark cycle with access to food and water ad libitum. All imaging scans were conducted in the morning (between 8:00 and 11:30 AM). The animals were monitored throughout the duration of the study to reduce unnecessary stress and/or pain. All procedures were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and under a University of Maryland‐approved Institutional Animal Care and Use Committee protocol. There were no animals missing from analysis; all rats survived the intra‐articular injections and experimental protocol. We did not exclude any outliers from the analysis. Sample size (4.2Monoiodoacetate (MIA—Sigma‐Aldrich) was dissolved in sterile saline. A single intra‐articular injection of MIA  was made through the infra‐patellar ligament of the left knee using a 30‐gauge needle  and scanned each 3 times. We chose the time points after the MIA injection based upon prior literature showing sex and age differences in pain behavior and based upon distinct peripheral mechanisms between the early and late phases of the MIA‐induced OA model  and a 40‐mm circular polarized volume coil. During scanning, rats were anesthetized with a constant mixture of 1.5% isoflurane in oxygen‐enriched air, and respiration and heart rate were monitored with a small animal monitoring and gating system and software . T2‐weighted anatomical images were obtained using a 2D RARE . An rsfMRI scan was acquired using an echo planar imaging sequence . The anatomical and rsfMRI scans were performed for each rat at baseline  and in the early (7 days) and late (28 days) phases of MIA‐induced OA model. Thus, we performed 96 MRI sessions in total, since we used 32 rats (4.4http://www.fil.ion.ucl.ac.uk/spm/). We used seed‐based analysis to assess how FC between the PAG and the whole brain varies between groups and time points. We selected PAG as the region of interest (ROI) based upon prior literature showing its involvement in descending pain inhibition  analyses used to address our hypothesis were the following: (1) Two‐Way ANOVA with sex and age as main factors and comparisons between the four groups to show sex and age differences in PAG FC with the whole brain separately at baseline, early OA phase, and late OA phase. (2) One‐Way ANOVA within‐subjects to show brain regions with increased and decreased FC with PAG in the early OA phase compared to the late OA phase in each group. In addition, we used two‐Way ANOVA for baseline, early OA phase, and late OA phase with sex and age as main factors , to examine the main effects of sex (combined young and old groups) and age , as well as the sex effects in age‐matched groups (young rats and old rats separately) and age effects in sex‐matched groups .p < 0.05, 0.01, and 0.005 for group comparisons, and all significant clusters were illustrated on the brain template. We used a cluster‐extent based thresholding approach due to its relatively high sensitivity to account for the fact that individual voxel activations are not independent of their neighboring voxels’ activations and as a correction method for multiple comparisons between all voxels in the brain  and GraphPad Prism 8.12. All data including code, ROI, and the template brain are available upon request and in NeuroVault (Da Silva, Second level maps used cluster‐forming thresholds at All authors declare that they have no conflicts of interest.All authors were involved with drafting the article or revising it critically for important intellectual content and all authors approved the final version to be published. Dr. Da Silva had full access to all of the data and takes responsibility for the integrity of the data and the accuracy of the data analysis.involved in study conception and design. Da Silva, Tricou, Zhang, and Tofighbakhsh involved in acquisition of data. Da Silva, Ro, and Seminowicz involved in analysis and interpretation of data.Da Silva, Ro, and Seminowicz Figures S1–S2Click here for additional data file.


Sensorimotor networks are implicated in SoA, however little evidence exists on brain functionality during agency processing. Concurrently, it has been suggested that the brain's intrinsic resting‐state (rs) activity has a preliminary influence on processing of agency cues. Here, we investigated the relation between performance in an agency attribution task and functional interactions among brain regions as derived by network analysis of rs functional magnetic resonance imaging. The action‐effect delay was adaptively increased  and behavioral measures correlated to indices of cognitive processes and appraised self‐concepts. They were then regressed on local metrics of rs brain functional connectivity as to isolate the core areas enabling self‐agency. Across subjects, the time window for self‐agency was 90–625 ms, while the action‐effect integration was impacted by self‐evaluated personality traits. Neurally, the brain intrinsic organization sustaining consistency in self‐agency attribution was characterized by high connectiveness in the secondary visual cortex, and regional segregation in the primary somatosensory area. Decreased connectiveness in the secondary visual area, regional segregation in the superior parietal lobule, and information control within a primary visual cortex‐frontal eye fields network sustained self‐agency over long‐delayed effects. We thus demonstrate that self‐agency is grounded on the intrinsic mode of brain function designed to organize information for visuomotor integration. Our observation is relevant for current models of psychopathology in clinical conditions in which both rs activity and sense of agency are altered. We investigated the relation between agency and functional interactions among brain regions using network analysis. Self‐agency is grounded on the intrinsic mode of brain function designed to organize information for visuomotor integration. This is relevant for current models of psychopathology in clinical conditions in which both brain functional activity and sense of agency are altered. All subjects were carefully screened for a current or past diagnosis of any DSM‐5 Axis I or II disorder using the SCID‐5 Research Version edition  “A multifactorial intervention for successful aging” CUP J84I20000250005.2.3The experiment took place in two separate sessions. The two behavioral tasks Figure  were admagency attribution task measures participants' control judgments over a subsequent consequence of an action by asking to make an explicit attribution  of a visual event. The sense of self‐agency here measured was experimentally manipulated by introducing visuomotor temporal incongruity (see below), and personally graded delay conditions were provided as to derive the individual time window for the action‐effect integration. The task was generated and stimulus presentation controlled using E‐Prime 2.0 , the delay between the key press and the ball appearance was systematically varied using two different staircase procedures: a descending one  and an ascending one (70 trails with a starting delay of 90 ms) in a total of 140 trials. The delay range was chosen on the basis of previous reports  “my space bar press directly triggered the ball”; (b) “the computer triggered the ball”, who was the agent that caused the ball appearance. We defined the first response “full control” and the second “no‐control”. Participants laid two fingers of their right hand on two keys of the numeric keypad  and they had to respond as rapidly as possible by pressing one of the response keys.time and color discrimination task was administered to measure individual perceptual sensitivity in temporal perception and working memory abilities directly implied in the self‐agency indexes here quantified. Within the two (time and color) conditions the trial structure and stimuli used were identical, with the only difference being whether participants were asked to make time or color judgments  with a (T2*)‐weighted imaging sequence sensitive to blood oxygen level‐dependent (BOLD) . A thirty‐two channel receive‐only head coil was used. A high‐resolution T1‐weighted whole‐brain structural scan was also acquired (1 × 1 × 1 mm voxels). Subjects were instructed to lay in the scanner at rest with eyes open. For the purposes of accounting for physiological variance in the time‐series data, cardiac and respiratory cycles were recorded using the scanner's built‐in photoplethysmograph and a pneumatic chest belt, respectively.Several sources of physiological variance were removed from each individual subject's time‐series rs‐fMRI data. For each subject, physiological noise correction consisted of removal of time‐locked cardiac and respiratory artifacts (two cardiac harmonics and two respiratory harmonics plus four interaction terms) using linear regression . Head motion estimation parameters were used to derive the frame‐wise displacement (FD), which in turn was used, together with its derivative, to correct data by a regression process. Time series were then demeaned, detrended, despiked and band‐pass filtered in the frequency range 0.01–0.25 Hz, using custom software written in Matlab (The Math Works). For group analysis, a two‐step registration process was performed. rs‐fMRI data were transformed first from functional space to individual subjects' structural space using FLIRT (FMRIB's Linear Registration Tool) and then non‐linearly to a standard space  using Advanced Normalization Tools . Finally data were spatially smoothed .rs‐fMRI data were then preprocessed as follows: correction for head motion and slice‐timing and removal of non‐brain voxels . Therefore, 37 subjects  composed the final study sample.Agency attribution data were modeled using Matlab (The MathWorks) and color‐duration discrimination data were analyzed using R. In the former, for each participant, the normalized  number of full control responses across the sampled delays was fitted to a Gaussian function. One participant was excluded from further analyses due to bad fitting results (tPSE), representing the delay time at which probabilities for “full control” and “no‐control” responses are equal (50%). The curve peak value expressed how rapidly performance changed with changes in delay: the highest the value, the fastest subjects reached their PSE, being very consistent in their agency attributions. Indeed, the adopted psychophysical procedure increased the delay between the key press and the effect when the latter was attributed to the self. Therefore, small delays at which participants tended to have a full‐fledged sense of control over the ball were not shown again, while delays at which participants tended to experience a partial sense of control were repeatedly sampled. The curve SD expressed the range of delays at which uncertainty was high: the wider the curve, the strongest the temporal grouping between the action and its effect, as subjects tended to have a sense of control over the ball at both small and longer delays.The delay corresponding to the curve peak value was taken as the Point of Subjective Equality , significance was set at a False Discovery Rate (FDR) , combined in seven networks, and including cortical and sub‐cortical regions based on a rs‐and task‐based fMRI atlas characterized by functionally and connectionally homogeneous parcellations  was chosen. Indeed, the forward stepwise procedure starts with no variables in the model and it tries out the variables one by one, including them if they are statistically significant, thus identifying the best set of predictors that gives the biggest improvement to the model. Simple linear regressions were preliminarily performed to include, in subsequent multiple regressions analyses, only variables significantly (p < .05) related to the behavioral measures considered. Multicollinearity between variables was tested by calculating the tolerance value of each viable predictor, that is, the proportion of variation in each predictor independent from the correlation between regressors  was 625 ms (SD ± 288.52), while the mean curve peak value, was 0.21 (SD ± 0.06). Across subjects, variability within delays determining self‐agency attenuation was 16 ms. A significant negative correlation across subjects was found between the curve peak and the tPSE,  as well as between the curve peak value and the curve SD . No significant (using an FDR = 0.05) correlation was observed between individual curve peak values, SD of individual curves and neuropsychological testing raw scores indexing attentional and executive abilities. A significant negative correlation was observed between TCI‐r derived measures of the harm avoidance temperament dimension and the peak value of individual curves . A significant positive correlation was also observed between the peak value of individual curves and the personality trait of cooperativeness . A significant negative correlation was additionally found between the SD of individual curves and the personality trait of self‐directedness .At the group level, the mean curve peak delay  implying a very high sensitivity in discriminating the sampled temporal intervals. Mean accuracy in the color condition was 74% (±0.15 SD). No significant (using an FDR = 0.05) correlations were observed between time and color discrimination accuracy and values expressing how rapidly performance changed with changes in delay or variability within delays at which uncertainty was high. Table 3.33.3.1The covariance between the explicit attribution judgment of self‐agency and the centrality of nodes within the whole functional connectivity network was investigated. Results from simple linear regressions showed significant positive correlations between curve peak values and the degree centrality in bilateral frontal, parietal and occipital regions, as well as between the curve peak values and the clustering coefficient in left temporal and right parietal and occipital cortices  related to dispersion of delays determining self‐agency attenuation, and such relationship explained more than 40% of observed variance. Figure 4Here we map the brain topological organization related to information processing and signals integration essential for self‐agency attribution. From a behavioral point of view, we find that the time window for self‐agency attribution was 90–625 ms while feeling of control over the effect decreased for delays ranging from 658 to 1,600 ms. While no correlation was observed with measures of cognitive processes known to impact the SoA , somatomotor and association networks increases as consistency in the action‐effect integration at a definite delay increases. Specifically, the brain intrinsic functional organization sustaining consistency in the action‐effect integration at a certain delay is characterized by high connectiveness in the secondary visual cortex and by regional segregation in the primary somatosensory area. Motor and attentive control areas do not influence the information flow. Such functional network configuration, observable at rest, implies that a biological function, that is, the brain's on‐going intrinsic activity, is essential when action‐related perceptual and motor information have to be combined as to derive a feeling of control over external events.This finding is highly informative for current models of SoA as it unearths the brain circuit organization underlying the conscious attribution of a delayed effect to one self's action. It also crucially demonstrates that self‐agency is grounded in the brain's intrinsic operations involved in the maintenance of information and representations central for interpreting and responding to the environment  are highly central and richly connected when consistency in the action‐effect integration at a certain delay is considered. Associative visual cortices have been previously implied in SoA, particularly in the self‐other distinction  influencing external agency. Nevertheless, the correlation here investigated between the brain topological organization at rest and the behavioral phenotype might have captured even low‐level processes involved in SoA. Indeed, the functional measure adopted is unconfounded by processing of specific stimuli and cognitive demands, as resting state networks are more “natural” and “core” with respect to the functional division derived from task‐evoked patterns of activity  and behavioral performance is debated, and might be regarded as minimally informative respect to processes that are inherently task‐related. Nevertheless, the function here investigated presumes an inner‐oriented mental activity while the brain's intrinsic resting‐state activity has a preliminary influence to later processing of agency cues (Robinson et al., d (Cohen, η2 (Richardson, Finally, the studied sample was not numerous, and this constitutes an additional potential limitation of the present investigation. Nevertheless, the computed correlations between behavioral measures of perceived control over the effect and centrality indices always resulted in intermediate to large effect sizes (Cohen's d Cohen,  between To sum up, here we provide unique experimental evidence that perceived control over subsequent delayed effects is based on intrinsic brain processes that link somatosensory representations residing in the primary somatosensory area to incoming visual and proprioceptive information. Conversely, extended self‐agency over long‐delayed effects is grounded on the intrinsic mode of brain function designed to organize information for visuomotor integration. We also demonstrate that whereas the self‐agency experience arises from the optimal multisensory integration occurring in a sensory area, these internal non‐conceptual computations are available to other cognitive systems for further processing. Indeed, visuomotor integration processes and previous beliefs regarding the person impacted the explicit propositional representation of the self as an external agent.These findings bear important clinical implications since activity attenuation in somatosensory cortices and aberrant resting‐state activity in self‐referential regions of the brain of individuals with schizophrenia have been shown to impact their attribution of agency (Robinson et al., The authors declare no potential conflict of interest.The study was approved and carried out in accordance with the guidelines of the IRCCS Santa Lucia Foundation Ethics Committee.Subjects gave written informed consent to participate after the procedures had been fully explained.


At the University of California, Irvine, School of Medicine (UCISOM), the COVID‐19 pandemic is accelerating the transition of face‐to‐face didactic lectures to online platforms. Institutions nationwide have opted to transition their lectures into remote instruction for the upcoming Fall 2020 academic year. UCISOM’s pre‐clerkship Medical Immunology course in the Spring 2020 serves as a template for other medical courses to successfully transform lecture content into virtual presentations. To help facilitate successful large‐scale transition to online courses, UCI developed institutional support and implemented a Division of Teaching Excellence and Innovation (DTEI) Fellowship and iMedEd programs to support medical educators throughout Summer. Previously developed E‐learning modules for renal and acid‐base physiology serve as the foundation for novel pulmonary E‐learning modules at UCISOM. In preparation for the new academic year, in a collaboration between faculty, UCISOM’s top performing second‐year medical students (MS2s) and DTEI fellows worked together during the summer to transition UCISOM’s Medical Physiology and Pathophysiology course online. With over 100 first‐year medical students attending the Medical Physiology course over live synchronous Zoom instruction, formative and summative assessments were incorporated into Canvas modules along with peer‐led review sessions and new E‐learning modules to educate and monitor student progress. The course will maintain existing in‐person active learning activities for students to get hands‐on experience using the latest medical devices while maintaining social distancing. Successful transition to online medical education at UCISOM will depend on increasing use of formative assessments, increased utilization of peer‐led review sessions, and efficient communication to help foster self‐directed learning. The COVID‐19 pandemic is accelerating the transition to online instruction.Proper institutional support is essential for medical educators in successful implementation of didactic virtual lectures along with formative assessments to monitor student progress.Previously developed E‐learning modules for medical physiology will be expanded in the Fall of 2020.Current medical students will expand their role in tutoring first‐year medical students.1Educating medical students during the COVID‐19 pandemic and maintaining compliance with the ever‐shifting public health guidelines provide unique challenges and opportunities to reform medical education. Improving student learning outcomes involves implementation of innovative remote learning approaches and expanding past successful approaches that focus on virtual instruction. The University of California, Irvine, School of Medicine (UCISOM), Department of Physiology and Biophysics is striving to meet the needs of learners for successful knowledge transfer, while maintaining an interactive environment comparable to that in a face‐to‐face setting.PHYSIO 543: Medical Physiology and Pathophysiology is a cornerstone course in UCISOM’s first‐year pre‐clerkship curriculum (MS1). In Fall 2020, Medical Physiology will be the largest course taught almost entirely online in UCISOM history. Fortunately, the Medical Physiology course began our transition to online education in 2013 with the implementation of interactive computer‐assisted E‐learning instruction in acid‐base physiology for mobile computer platforms.When compared to traditional in‐person learning, online instruction results in similar outcomes on health professionals’ skills and knowledge.2PHYSIO 544: Medical Immunology was the first pre‐clerkship course in undergraduate medical education at UCISOM to be taught entirely through remote learning due to the COVID‐19 pandemic, beginning on March 30 and ending May 11, 2020. As such, this course was UCISOM’s and the Department of Physiology and Biophysics’ test lab to determine the best paths to move forward into remote instruction in the pandemic era. Lessons learned from this course are now being analyzed and best practices will be implemented in the upcoming MS1 PHYSIO 543: Medical Physiology and Pathophysiology course scheduled for Fall 2020.Similar to the other courses in the UCISOM pre‐clerkship curriculum, the Medical Immunology course utilizes diverse teaching modalities, including lecture‐based didactics, small group formative assessments, pre‐exam review sessions, post‐exam review sessions, a self‐directed learning module (SDL), and formal summative assessments. Transition of the course to remote instruction occurred with less than a month's notice and was further complicated by the need to incorporate emerging coronavirus clinical and basic science research into the course, particularly around the immunopathogenesis of COVID‐19.The course director and lecturing faculty succeeded in the transition to remote instruction. Fortunately, the Department of Physiology and Biophysics have pioneered online instructional modalities, including E‐learning modules and online SDL activities, prior to the COVID‐19 pandemic. In addition, faculty were supported by the UCISOM Division of Educational Technology team to ensure a smooth transition throughout the process. In previous years, SDL activities were entirely online through Canvas, a UCI supported interface learning management system, making this the easiest portion of the course to maintain online. Other sessions, including didactics, formative assessments, pre‐exam, and post‐exam review sessions were held live through the Zoom videoconferencing software. To maintain a glimmer of normalcy, the course sessions were taught synchronously at their previously scheduled times. Zoom links were distributed by email and posted in the Canvas course management software. Lecturing faculty logged into Zoom as a host and presented didactic material via screen share, with students maintaining engagement by logging in at the same time and asking questions by utilizing the chat features for Q&A on Zoom. Small group formative assessments typically involve groups of eight students answering quiz questions related to a previously assigned clinical research article while lecturing faculty migrate through the small groups, clarifying difficult concepts. This year, the formative assessments were maintained and held through Zoom, but the small group format was scrapped. Quiz questions were distributed immediately prior to the scheduled session, and lecturing faculty were available through Zoom to clarify concepts and answer questions prior to quiz submission. Pre‐exam and post‐exam reviews were also held through Zoom, where the lecturing faculty prepared exam‐relevant content and fielded student questions through the Q&A and chat features in Zoom. The course director attended every session, using the Zoom record feature to record and upload the class sessions to Panopto, an online video editing platform, allowing students to review the course material at later dates. Summative assessments occurred at their previously scheduled times and were proctored remotely through the ExamSoft software, relying on the student honor code to fend off potential academic dishonesty. Students were required to sign a statement attesting to knowledge of the honor code and consequences of honor code violation prior to each exam.The conversion to remote instruction was remarkably successful, both by student evaluations and exam scores. In student evaluations collected following completion of the course, students rated the course at >4.25/5.00 for every evaluation criterium measured, including 4.84/5.00 in the “effectiveness of the course director in running the course,” the highest marks received over the past 5 years. Exam scores had similar distributions compared to the past year, including an average final exam score of 83.0% (compared to 81.2% in 2019), suggesting that the honor code approach to academic honesty was largely successful. Written student feedback discussed how they missed the social interaction with their peers throughout the course, but student narrative feedback was uniformly positive, particularly regarding the incorporation of clinically relevant research related to COVID‐19 pathology and epidemiology. Students acknowledged the efforts involved in adapting to the new conditions of the COVID‐19 pandemic and that the course quality did not suffer despite the transition to remote learning.3While conversion to online learning in the Spring 2020 semester was largely successful without advanced planning, UCI faculty have used the summer to extensively prepare for teaching in the Fall 2020 semester to accommodate the need for extended online instruction due to the ongoing pandemic. UCISOM guidelines regarding 2020 medical education currently mandate the continuity of remote instruction until January 2021 and may potentially extend guidelines beyond this date. Educational sessions that do not involve a tactile‐learning component, such as lectures and small group discussions, will transition to online, distance‐learning modalities starting in Fall 2020. Activities that involve a tactile‐learning component, including anatomy dissection laboratories and sessions that teach clinical/medical skills, may remain in‐person so long as they adhere to the United States Center for Disease Control and Prevention (CDC) safety guidelines and uphold proper social distancing practices. For such activities, the number of persons per room should be limited to as few persons as practical, ideally to 10 or less persons per learning space. Physical distancing throughout the sessions as well as universal masking or use of face‐shields, as appropriate for the activity, will be enforced. Tactile learning activities will also rely on students and faculty to self‐triage prior each session; individuals with a fever, cough, or any other COVID‐19 symptoms will refrain from attending the activity and suitable learning alternatives will be provided for them.To comply with newly developed remote learning guidance, UCI has implemented two unprecedented programs to assist the faculty in the transition to remote instruction for fall 2020. First, the main campus Division of Teaching Excellence and Innovation (DTEI) supported and trained graduate students to serve as teaching assistants to assist each basic science course director with the transition to online learning. Second, UCISOM’s Division of Educational Technology implemented the Summer 2020 iMedEd Faculty Development seminar series. Topics included the following: Teaching with Zoom: Overview, Teaching with Zoom: Breakout Rooms, Teaching with Zoom: Other Features, Teaching with Canvas: Discussion Boards, Teaching with Canvas: Group Assignments, Teaching with Podcasts: Panopto, and Inclusive Teaching Considerations. Live faculty development seminars were offered entirely online though Zoom, and these sessions were recorded and provided to all SOM faculty to review at later times.DTEI, in collaboration with UCI Graduate Division, developed the DTEI UCI Summer Fellowship program to train graduate fellows to assist faculty in developing high quality online courses. Interested UCI graduate students submitted applications detailing their academic field and prior teaching experience to aid in pairing with faculty in similar disciplines. The summer program spanned 10 weeks with an expectation that graduate fellows would dedicate 20 hrs per week for curricular support following an initial 180 hr training workshop. Graduate fellows regularly met with pre‐clerkship course directors throughout the summer to strategize, implement, and test new teaching technologies and resources. In preparations for the Medical Physiology course, MS2 students were included in these meetings to provide valuable input on potential pitfalls and insights into the best paths forward.Graduate fellows received comprehensive training on several online pedagogical components that could be applied to lectures developed for remote instruction. Lecturers from across the UCI main campus presented training modules over Zoom with a Q&A sessions at the end, familiarizing fellows to Zoom functions. Training topics included pedagogical fundamentals, remote instruction, synchronous and asynchronous remote instruction, and working with faculty. Additionally, training included a review of pedagogical fundamentals such as backward design, student learning outcomes and objectives, active learning techniques, overview of the Family Educational Rights and Privacy Act (FERPA), and most importantly inclusive teaching. All lectures were recorded live and posted online for fellows or instructors to revisit.The weeklong DTEI fellowship workshop included additional training on third party software to introduce tools to promote interactive E‐learning in a synchronous or asynchronous class setting. Zoom training included establishing administrative controls such as only allowing UCI email accounts to join lecture sessions to avoid Zoom bombing (Zoombies) and generating Zoom polls in advance, saving more time for lectures. Another feature on Zoom that was emphasized was the breakout room option to enhance student interactions by enabling students to work together on class assignments in a remote environment. Graduate fellows were trained on transcription software for conversion of live and pre‐recorded lecture content into text which can be easily integrated into Zoom for students to utilize at their discretion. In addition, fellows were trained on Panopto software and Canvas to familiarize themselves with the functions available for building modules, assignments, quizzes, and integration of pre‐recorded videos.4Medical Physiology is a cornerstone course in the UCISOM pre‐clerkship curriculum and is horizontally integrated with the first‐year histology, anatomy, and clinical foundation courses. In compliance with the guidelines detailed above, the 2020 Medical Physiology course is adjusting our established didactic lectures, active learning sessions, self‐directed learning, peer‐led review sessions, and existing E‐learning content. Lectures will be provided remotely over live‐Zoom during scheduled time slots to provide students with a structured schedule mimicking in‐person curriculum. All Zoom lectures will be recorded as video podcasts and be made available within 24‐hrs for viewing on Canvas. Each lecture will be attended by the course director, in addition to the lecturer, to facilitate student Q&A, and handle any technical problems that may arise during the lecture. Students attending the live sessions will have the opportunity to ask questions via the Zoom‐live chat‐box and those questions will be addressed by either the course director or lecturer throughout the session.As permitted by current policy, active learning sessions that include hands‐on activity by students can be held in‐person so long as safe‐social distancing practices are maintained in the educational facility. In previous years, medical physiology students participated in an electrocardiogram (ECG) active learning activity, in which they would record their own ECGs using AliveCor KardiaMobile medical devices. As this activity has been demonstrated to be both a valuable and enjoyable learning experience in the past, the course will continue hosting it in the 2020/2021 academic year. The session will be structured as an in‐person, small‐group activity that limits the number of students and faculty per group and maintains social distancing guidelines within each group.As implemented in previous years in order to satisfy LCME element 6.3 (LCME element 6.3), which states students must participate in some form of self‐directed learning as a means of promoting life‐long learning, students will participate in a “Cardioblog” during the cardiovascular block of medical physiology. Cardioblog utilizes a discussion forum on the Canvas platform that allows students and faculty to both post content and respond to others’ posts. The goal of the Cardioblog is to encourage students to perform a PubMed search on a topic in cardiovascular physiology, read the relevant literature on that topic, and write a short essay on an article of their choosing. Students will then post their essays to the Canvas Cardioblog forum and receive feedback from faculty on their literature searching strategies. Additionally, students will read one of their peers’ posts and respond to it in a manner that provides constructive feedback, a recommended follow‐up reading, or a personal experience that pertains to the original article shared.®) offers a variety of question‐and‐answer formats, including true/false, single‐ and multiple‐answer multiple choice, drop‐down list selection, number entry, graphical “hotspot” identification, and drag‐and‐drop graphical manipulation. All question‐and‐answer formats will be utilized and will be important for promoting and maintaining student interest and engagement in the content. Acid‐base physiology will be similarly presented with three content modules and three related question‐and‐answer modules. In addition, three active‐learning case‐study modules will guide students through the acid‐base physiology of asthma, diabetic ketoacidosis, and chloride‐depletion metabolic alkalosis. Each E‐learning module can be completed within an hour's time, and students will have the flexibility to complete the modules at their own pace. To discourage students from waiting to access the E‐learning content immediate prior to the exam, weekly formative assessments (3–4 point quizzes) will be implemented following an in‐person review session that will include in‐class practice problem‐solving exercises  during both the cardiovascular and endocrinology blocks. The quizzes will be administered remotely utilizing ExamSoft and will be preceded by a faculty‐led review/practice problem session over live‐Zoom. As with the cumulative block exams, UCISOM will rely on the student honor code to uphold academic integrity with remote assessments, and students will be required to sign an attestation prior and during each assessment that lists the academic integrity policy as stated in the UC Irvine School of Medicine Student Handbook. For the final National Board of Medical Examiners (NBME) exam, we will implement the stringent security protocols required by NBME.The Medical Physiology course has traditionally included in‐person, peer‐led review sessions prior to each organ system‐focused block exam.The Medical Physiology course will continue hosting the peer‐led review sessions as described above, however, they will also transition to online platforms. During Summer 2020, two lead tutors were selected by the course director to structure the review sessions, facilitate the transition to remote instruction, and recruit the MS2 content tutors. The lead tutors were provided with a list of the highest scoring MS2 students in the 2019 Medical Physiology course, from which twelve were offered a content tutoring position and two were asked to serve as additional lead tutors. The twelve MS2 content tutors were each assigned two physiology topics: hematologic, neurologic, respiratory, cardiovascular, gastroenterological, endocrine, musculoskeletal, or renal physiology. The four lead tutors, as in previous years, will act as liaisons between the Physiology course director and the twelve content tutors. All communication between the lead tutors, content tutors and course director will occur via Zoom meetings.To remain adherent to UCISOM 2020 social distancing guidelines, the 2020 MS1 class will be provided with an option for both in‐person and online peer‐led review sessions for each exam review. The online and in‐person review sessions will cover identical material that will be taught by the same set of content tutors. Live‐Zoom will be utilized for the online sessions in order to retain several key advantages of in‐person review: the ability to ask questions and/or clarifications in real‐time, the ability to host discussions between students and tutors, and the ability for students to collaboratively problem solve within breakout rooms. The in‐person sessions will occur at the UCISOM Medical Education Building where students will be divided into rooms with 10 (or less) students with content tutors rotating between rooms. The Medical Education Building has adequate space to host the entire MS1 class in a small group format with maintained social distancing, however, based on previous years’ attendance and the establishment of the online review session we do not anticipate this high of a turnout. At the end of the course, students will be given a second survey where they mark which sessions they attended for each exam (online versus in‐person), explain their reasoning for choosing one modality over the other, and provide feedback about the review session structure. Student responses will be used to gauge the effectiveness of online peer‐led review sessions in comparison to their in‐person counterparts, and thus, improve future transitions to distance learning.Finally, anticipated structural challenges posed by the pandemic will likely exacerbate underlying educational inequities that the normal UCISOM medical education infrastructure is designed to combat. Students often utilize the institutional resources such as medical libraries, computer access, and high‐speed wireless internet that may not be available at home. These resources will be difficult to obtain while the main campus remains shuttered and the medical campus strictly complies with public health guidelines. Adhering to social distancing guidelines may force students to rely on alternative sources to connect to their online class, which may be limiting. For students to adapt to online instruction, the course director and lecturing faculty will provide constant communication, clarifying expectations and defining course goals. These structural limitations will also make accessibility a critical aspect to ensure all students have access to adequate resources to fulfill course objectives. Using the aforementioned tools and strategies, Medical Physiology at UCISOM is positioned to safely and effectively implement a pandemic‐appropriate curriculum for our future physicians.5There has long been a call for curriculum reform and greater research in UGME,As the new academic year comes to a start, re‐launching Medical Physiology at UCISOM will likely run into potential roadblocks in its infancy. Unforeseen difficulties may reveal themselves despite our extensive preparation. Some of the challenges that may arise include miscommunication between the course director and lecturing faculty, students spending more time than they need to on modules, technical difficulties accessing Zoom or Canvas platforms, and pandemic‐driven exacerbations of underlying educational inequities, including access to stable internet connectivity and adequate study spaces. Although some of these issues can be quickly addressed, it is important for an open line of communication between the course director, faculty, and the students to avoid any delays or confusion on assignments in lectures. There must be a balance between the student's needs and student learning outcomes with specific and well‐defined course objectives mapping to the curricular objectives. With success, first year medical students can have a positive impact in enabling successful remote medical physiology instruction, all the while maintaining the same level of professionalism experienced during in person lectures. During these unprecedented times, UCISOM will strive to uphold the highest of standards of quality medical education with the goal of maximizing student success, and we hope that this manuscript serves as a model for other institutions to follow.


Sir: Metaplastic papillary tumour of the fallopian tube (MPT) is an extremely rare lesion. To the best of our knowledge, only 12 cases of MPT have been documented in the literature to date, usually detected incidentally upon examination of fallopian tube segments removed for sterilisation postpartum. Only one case has been reported to be unrelated to pregnancy.KRAS and BRAF,Debate exists as to whether this lesion represents a true neoplasm or a metaplastic proliferative lesion.Herein, we report the first case of a 35‐year‐old woman with an MPT, which has been analysed by next‐generation sequencing (NGS). Ethical approval for this study was obtained from the Ethikkommission Medizinische Universität Graz (Votum32‐045 ex 19/20) on 31 October 2019.The fallopian tubes of our reported patient were removed postpartum for sterilisation. Macroscopic examination did not detect any abnormalities. The tissue samples were routinely processed and stained by haematoxylin and eosin staining (H&E), according to our standard protocol.Histological examination revealed an exophytic lesion within the tubal lumen of the right salpinx measuring 1 mm in its greatest dimension, involving only part of the mucosa Figure . The proDue to the eosinophilic or apocrine‐like morphology, immunohistochemistry (IHC) with an antibody against androgen receptor was performed on a Dako Autostainer, but otherwise, due to limited material, molecular diagnostics were conducted instead of immunohistochemistry. After manual microdissection, mutational analysis was performed using the Ion Torrent Comprehensive Cancer Panel , covering 409 genes frequently implicated in cancer, accompanied by low‐density whole‐genome sequencing to detect copy number variations.Androgen receptor immunoreactivity of the eosinophilic cells was reduced compared to the slightly positive normal tubal epithelium Figure . No somaKRAS and BRAF mutations.Serous borderline tumour of the fallopian tube is an extremely rare lesion, which resembles the ovarian counterpart, showing a hierarchical branching pattern with irregular papillae, branching from large to smaller papillae. The lining epithelium consists of non‐stratified and stratified cuboidal to columnar cells. The tumour cells are polygonal or hobnail‐like with eosinophilic cytoplasm and moderately enlarged nuclei. Borderline tumours of the ovary, spreading to the tube are more likely than borderline tumours of the tube. These lesions harbour BRCA1 or BRCA2 mutation which confers a high risk of developing this neoplasm. The neoplastic epithelium shows pleomorphic stratified and non‐ciliated cells with an increased nuclear‐cytoplasmic ratio and loss of polarity; 92% of STIC show TP53 mutations.Most STICs are found in the distal tube, particularly in women with KRAS and BRAF mutations in 50–60% of cases.Low‐grade serous carcinoma of the fallopian tube is morphologically identical to its ovarian counterparts and is characterised by glands haphazardly infiltrating the stroma. It is usually associated with serous borderline tumour and harbours The differential diagnoses considered included serous borderline tumour (SBT), serous tubal intra‐epithelial carcinoma (STIC) or low‐grade serous carcinoma, as follows.The fact that the reported cases of MPT in the literature with available follow‐up information showed no recurrence of or death due to tumour,Hence, we emphasise the importance of not misdiagnosing this entity as serous borderline tumour, serous tubal intraepithelial carcinoma or low‐grade serous carcinoma to avoid overtreatment.The authors state that they have no conflicts of interest.


To provide insight into the types of questions asked to medical physicists by patients during one‐on‐one physicist–patient consults at one institution.Medical physicists trained in patient communication techniques met with patients to provide an overview of the treatment planning and delivery processes, discuss the patient's treatment plan, and answer any technical questions. From August 2016 to December 2019, 152 physicist–patient consults were conducted. In the initial months of the study (August 2016—December 2017), following each physicist–patient consult, all patient questions were documented by the physicists. For the remaining time period (January 2018—December 2019), any newly encountered questions were periodically added to the list. The questions were compiled into a comprehensive list and organized into categories.There were a total of 88 unique patient questions. These questions fit into four topical categories. Fifty‐four questions (61.4%) were in the “Treatment Planning and Delivery Questions” category, 15 questions (17.1%) were in the “General Radiation Questions or Concerns” category, 13 questions (14.8%) were in the “Safety and Quality Assurance Questions” category, and 6 questions (6.8%) were in the “Medical Questions” category. Overall, patients were primarily concerned about how radiation works, the treatment planning and delivery processes, and what is being done to keep them safe throughout their treatment.Physicist–patient consults provided an opportunity to address the technical aspects of radiation therapy with patients in greater detail. The fact that patient questions could be conveniently grouped into only four topical categories indicates that it may be straightforward for other medical physicists to prepare for effectively addressing technical questions during physicist–patient consults. Common misconceptions and preconceived notions about radiation and radiation therapy frequently result in patients having multiple questions about the medical and technical aspects of their treatment.Studies have shown that information available online is often too complex or convoluted for the general public.There have been efforts to help address some of these issues by bringing physicists into the patient consultation process.The purpose of this work is to provide insight into the types of questions asked to medical physicists by patients during one‐on‐one physicist–patient consults at one institution.2Four medical physicists completed a comprehensive training program to participate in physicist–patient consults.Patients were chosen to participate in the physicist–patient consult program as part of a pilot study (randomly selected from participating physician services), a clinical trial , or an ad hoc request . The only requirements for participation were that the patient be receiving, or scheduled for, external beam radiation therapy and fluent in the English language.Each patient received two physicist–patient consults. The first physicist–patient consult took place immediately prior to the computed tomography (CT) simulation appointment, and the second physicist–patient consult took place immediately prior to the first treatment appointment. A single physicist–patient consult occurred when patients or staff requested an ad hoc meeting with a physicist outside of the standard physicist–patient consult program.In the first physicist–patient consult, the medical physicist explained the role of a medical physicist and provided an overview of the CT simulation, treatment planning, and treatment delivery processes. During this meeting, the medical physicist also explained that they would be the primary resource for all of the technical aspects related to the patient’s radiation therapy treatment.In the second physicist–patient consult, the same medical physicist from the first consult met with the patient to provide information about the patient’s specific treatment plan and treatment delivery technique. For this consult, three infographics were created for the patient. These educational materials were used to guide the discussion, ensure that all of the relevant topics were covered, and help facilitate patient questions. The first infographic was used to explain how the CT simulation images were used to delineate the target and normal tissues. This infographic was personalized for the patient by including an image from the patient’s CT scan, with the target and relevant normal tissues labeled. The second infographic was used to describe how various beam angles or arcs were utilized to deliver the prescription dose to the target, while avoiding unnecessary dose to the surrounding normal tissues. This infographic was personalized for the patient by including an image from the patient’s CT scan, with the dose colorwash and beam angles overlaid. The third infographic was designed to explain the treatment delivery process, including when and how imaging will be utilized to align the patient before treatment and how the linear accelerator shapes the treatment beam to deliver the radiation. This infographic was the same for all patients. Ancillary devices used for respiratory motion management or surface image guidance were also discussed during this physicist–patient consult, when applicable. Creating the personalized infographics for each patient helped standardize the physicist–patient consult process. The infographics ensured that every patient received the same information about their radiation treatment, hopefully mitigating any potential cognitive biases on the part of the physicists.In the initial months of the study (August 2016–December 2017), following each physicist–patient consult, all patient questions were documented by the physicists. The questions were compiled into a comprehensive list. For the remaining time period (January 2018–December 2019), any newly encountered questions were periodically added to the list. Patients often asked the same question in different ways, so similar questions were combined into a single question where appropriate. One hundred fifty‐two physicist–patient consults were included from August 2016 to December 2019. The physicists participating in the physicist–patient consult program reviewed the questions together for two purposes: (a) to combine similar questions, and (b) to determine a number of topical categories to further group questions. An example of two questions that were combined into the same question is “Are there different types of radiation?” and “Is all radiation the same?”. Therefore, the number of questions grouped into topical categories will be less than the total number of questions asked during the 152 patient consults.3The patient cohort included multiple external beam radiation therapy treatment sites, palliative and curative intents, stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) techniques, and respiratory motion management and surface image guidance ancillary devices. A total of 88 unique questions were asked during the 152 physicist–patient consults. The first consult (prior to CT simulation) required approximately 15 min of preparation time and approximately 15 min of time with the patient, and the second consult (prior to the first treatment) required approximately 1 h of preparation time and approximately 30 min of time with the patient. The majority of the preparation time for the first consult was devoted to reviewing the patient’s chart. The majority of preparation time for the second consult was devoted to reviewing the patient’s treatment plan and creating the personalized infographics. On average, patients asked more questions during the second physicist–patient consult (prior to the first treatment) than the first physicist–patient consult (prior to the CT simulation).Grouping the questions resulted in four topical categories: (a) Treatment Planning and Delivery Questions, (b) General Radiation Questions or Concerns, (c) Safety and Quality Assurance Questions, and (d) Medical Questions. The number and percentage of patient questions in each category after similar questions were combined into a single question, along with five questions that were frequently asked during physicist–patient consults in each category, are shown in Table 4More questions fell into the “Treatment Planning and Delivery Questions” category than the other three categories combined. This may be due to the standardized process of the physicist–patient consults and the personalized infographics. Both of these guided the conversations and appeared to help patients form questions targeted at this topic. Patients were most interested in understanding how their treatment was customized for their disease and what was being done to limit radiation to normal healthy tissues.The infographics provided a way to facilitate questions from the patients. Some patients came into the consults with a list of questions they wanted to ask. Others were slow to ask questions, until they became comfortable in the consult. Often patients would initially comment that they did not have any questions, but once they saw the personalized infographics, they began asking questions.The fewest number of patient questions were in the “Medical Questions” category. This was expected because during the initial physicist–patient consult with each patient, the differences between a medical physicist and a radiation oncologist were clearly articulated. This introduction helped to ensure that patient questions were related to the technical aspects of treatment. However, when medical questions did arise, they were most frequently related to potential side effects. Patients appeared to be comfortable with the physicist not answering the medical aspects of those questions, while informing the patient that the physicist will bring the question to the attending radiation oncologist for follow‐up at their next meeting  or by a phone if the question was urgent.One limitation is that the results of this study were not controlled for patient demographics or socioeconomic factors. Although information such as community type  or health literacy could potentially be beneficial in predicting what types of questions patients ask, it was beyond the scope of this study. This could be a topic for future work.5Physicist–patient consults provided an opportunity to address the technical aspects of radiation therapy with patients in greater detail. The fact that patient questions could be conveniently grouped into only four topical categories indicates that it may be straightforward for other medical physicists to prepare for effectively addressing technical questions during physicist–patient consults.No conflict of interest.Dataset S1. Complete list of patient questions.Click here for additional data file.


The Northern Territory (NT) of Australia has a mix of climates, sparsely distributed population and a large proportion of the populace are Indigenous Australians, and influenza is known to have a disproportionate impact upon this group. Understanding the epidemiology of influenza in this region would inform public health strategies.To assess if there are consistent patterns in characteristics of influenza outbreaks in the NT.Laboratory confirmed influenza cases in the NT are notified to the NT Centre for Disease Control. We conducted analyses on notified cases from 2007‐2016 to determine incidence rates , seasonality of cases and spatial distribution of influenza types. Notified cases were linked to laboratory datasets to update information on influenza type or subtypeThe disparity in Indigenous and non‐Indigenous notification rates varied by age group, with rate ratios for Indigenous versus non‐Indigenous ranging from 1.58  for ages 15‐24 to 5.56  for ages 55‐64. The disparity between Indigenous and non‐Indigenous notification rates appeared higher in the Central Australia region. Indigenous versus non‐Indigenous hospitalisation and mortality rate ratios were 6.51  and 5.46  respectively. Inter‐seasonal peaks during February and March occurred in 2011, 2013 and 2014, and were due to influenza activity in the tropical north of the NT.Our results highlight the importance of influenza vaccination across all age groups for Indigenous Australians. An early vaccination campaign targeted against outbreaks in February‐March would be best focused on the tropical north. These epidemics usually occur in the winter months of temperate regions, but in tropical regions, influenza is reported to circulate widely outside this season.Australia's Northern Territory has several features which are likely to make the epidemiology of influenza in this area unique. First, climatic conditions are variable across the Northern Territory. The northern section of the Northern Territory (known as the “Top End”) has a tropical climate, whereas the southern half of the Northern Territory  has a desert climate. The potential for circulation of the virus outside the typical influenza season in this tropical region could impact upon the optimal time for vaccination in this area.Second, 30% of the Northern Territory’s population are Indigenous Australians, making the proportion of Indigenous Australians living in the Northern Territory over 5 times higher than that of any other jurisdiction in Australia.Given the increased rates of influenza infection and severe outcomes from infection amongst the Indigenous population, beginning in 1999, the Australian Government funded influenza vaccination for Indigenous Australians aged 50 and older and those 15 and older that had a comorbid medical condition.22.1In the Northern Territory, laboratory‐confirmed influenza cases are notified to the Northern Territory Centre for Disease Control. The Centre for Disease Control collects meta‐data for each case including details about the patient’s age, sex, Indigenous status, residential location, influenza type, diagnosis date, hospitalisation status, dates of hospital stays  and mortality. We analysed notifications from 2007 to 2016.Following laboratory confirmation of influenza infection by pathology providers, further analysis of samples is carried out by PathWest Laboratory Medicine, Perth, or the WHO Collaborating Centre for Reference and Research on Influenza, Melbourne. Results of typing and subtyping performed by these groups on samples corresponding to notified cases were accessed.Population denominator data were obtained from the Australian Bureau of Statistics.2.2Duplicate notifications were deleted. Notifications for patients who resided outside the Northern Territory were excluded from the calculations of rates but included in analyses that used raw count data. Hospital admissions that occurred >14 days after or more than 3 days before influenza diagnosis were considered not to be influenza associated. Notifications missing hospitalisation dates were excluded from analysis of hospitalisations.The location of each patient was classified into 2016 Statistical Area 2 (SA2) level groupings, as defined by the Australian Bureau of Statistics,The notification data set was linked to corresponding patient samples stored at PathWest Laboratory Medicine, Perth, or the WHO Collaborating Centre for Reference and Research on Influenza, Melbourne. Notification data were linked to samples by matching sample date and at least one of the fields of patient name and date of birth. Information present on the databases of these laboratories was used to update information on influenza type or subtype in the notifications data set. For analyses of spatial distribution and seasonality, cases of co‐infections with type A and B were counted as separate notifications for each type.Case notification rates in each age group in the Northern Territory by Indigenous status and age group were calculated. Rates of hospitalisation and death from influenza infection were calculated and standardised by age group to the 2007 population of the Northern Territory. Plots of numbers of cases by month and proportion of each year’s cases by month and region were constructed. Case notification rates per 100 000 population and proportion of influenza A and B cases in each region were mapped. To examine which areas consistently showed higher notification rates, each area’s incidence rate was ranked, and the median rank for each area over the 10‐year period was calculated. Maps showing the ratio of the Indigenous case notification rate to the non‐Indigenous case notification rate were constructed by pooling remote SA2 areas into broad areas due to low case numbers. Only areas that contained at least 5 notifications in the broad area for a given year and a notification for an Indigenous and non‐Indigenous population member were analysed. Statistical analyses were performed using Stata version 15.1 (StataCorp).2.3Ethical approval for the study was obtained from the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (reference number: 2017‐2894), Central Australia Human Research Ethics Committee (reference number: CA‐18‐3031), the West Australian Aboriginal Health Ethics Committee (reference number: 851) and Melbourne Health Human Research Ethics Committee (reference number: 2018.119). A waiver of consent was approved by the reviewing committees. This study was conducted in accordance with the Australian Code for the Responsible Conduct of Research.33.1Between 2007 and 2016, there were 6891 notified cases of influenza in the Northern Territory. The annual population during this period averaged 233 162. Influenza A made up of 5650 (82.0%) and influenza B 1222 (17.7%) of the cases. The remainder were co‐infections (9 cases) or untyped (10 cases). The subtype or lineage of 3756 (54.5%) of cases was known. Notification rates after 2009 were consistently higher than notification rates prior to 2009 Table .In most years and age groups, Indigenous Australians had higher notification rates than non‐Indigenous Australians Figure . The gre3.2Maps of notification rates by SA2 groupings demonstrated considerable variation by area and year  amongst Indigenous Australians . Mortality was 5.46 times higher  than that for non‐Indigenous Australians .3.4For most seasons, a typical Southern Hemisphere influenza epidemic curve is seen with peaks in August‐September Figure , with in3.5The proportion of type A and type B cases in each SA2 area by year is shown in Figure 4Our analysis of notifications of laboratory‐confirmed influenza cases has revealed consistently higher rates of influenza cases in the Indigenous population of the Northern Territory. Influenza had a particularly disproportionate impact upon older Indigenous adults and Indigenous children aged 0‐4. We have also demonstrated that influenza outbreaks in the February‐March period in the Northern Territory are occurring in the tropical Top End.The increased influenza rates within the Indigenous population seen in this study during both pandemic and non‐pandemic periods Figures  and 3 coThe higher rates of severe outcomes from infection are consistent with previous data that Indigenous populations are disproportionately affected by influenza. A study examining severe influenza A(H1N1)pdm09 cases in the Indigenous and non‐Indigenous populations of countries across the Americas and the Pacific found that rates of hospitalisations from A(H1N1)pdm09 were 3.0‐ to 7.7‐fold higher for the Indigenous population compared to the corresponding non‐Indigenous population.Genetic factors may contribute to the higher rates of severe outcomes from influenza infection in the Indigenous population.Comorbid medical conditions are reported to be more prominent in the Indigenous population than the non‐Indigenous population in this region,The data provide some guidance as to priorities for vaccination strategies. Given the consistently higher rates of notifications seen in the Indigenous population, it is important that good vaccination coverage is maintained in the Indigenous population. The extremely large difference in notification rates seen in the 0‐4 age bracket and older adults highlights the importance of maintaining high immunisation rates amongst this group. Since the change in government policy in 2015 to cover the cost of vaccination in Indigenous Australians aged 6 months to under 5 years, vaccine uptake for Indigenous Australians in the Northern Territory in this age group has increased, from <10% in 2007‐2014, to over 50% in 2015 and 2016.The peak in influenza activity outside the typical influenza season seen in the northern Top End of the Northern Territory bears similarity to tropical countries such as Columbia, Ecuador, Costa Rica and Thailand which show 2 peaks in influenza activity.Influenza activity during the February‐March period presents challenges to effective vaccination. In the Northern Territory, influenza vaccinations are available to the public from March‐April onwards. There is growing evidence to suggest a decline in the effectiveness of the influenza vaccine over time but the rate at which the effectiveness of the vaccine declines is unclear.The possibility of re‐vaccinating individuals against potential outbreaks in February‐March could be considered. A randomised controlled trial in Singapore found that semi‐annual vaccination led to a significant increase in the proportion of participants with antibody titres ≥1:40 for H1N1 virus only.Given that influenza outbreaks in the February‐March period are occurring in the Top End, a vaccination campaign against these outbreaks would be best focused on this region. However, it appears difficult to judge in which years an outbreak in February‐March would occur. It would be useful if forecasting models were developed to allow for the detection of interseasonal outbreaks, thus allowing for better informed decisions to be made on whether to revaccinate individuals in the Top End against influenza later in the year. However, recent attempts at forecasting influenza outbreaks in tropical areas have had limited success.There are some limitations associated with this data set. First, the data set is restricted to patients who present to medical care and receive a laboratory test for influenza. Since not all those infected with influenza will seek medical care and few are swabbed for influenza, the true influenza burden is underestimated. Furthermore, comparison of rates between the different regions is only valid if patients in the different regions are equally as likely to present to medical care and receive laboratory tests when presenting with influenza‐like illnesses. Laboratory testing practices have changed over the period of the study, with consistently higher rates of notifications in post‐pandemic years Table . FinallyBy analysing notifications of influenza infection in the Northern Territory, we have highlighted the unequal burden of influenza on the Indigenous population and thus the importance of maintaining good vaccination coverage, especially for those in the areas of Tanami and the Tiwi Islands. Furthermore, by demonstrating that influenza outbreaks in the Northern Territory during the February‐March period are occurring in the tropical Top End, we have established which area of the Northern Territory to target vaccination campaigns towards in order to prevent outbreaks during this period.Dr. Tong reports grants from National Health and Medical Research Council, during the conduct of the study.Aaron Lawson Weinman: Formal analysis (lead); Investigation (lead); Project administration (lead); Visualization (lead); Writing‐original draft (lead); Writing‐review & editing (supporting). Sheena Sullivan: Formal analysis ; Investigation ; Supervision ; Visualization (supporting); Writing‐review & editing . Dhanasekaran Vijaykrishna: Supervision ; Writing‐review & editing . Peter Markey: Data curation (lead); Resources (lead). Avram Levy: Resources (supporting); Writing‐review & editing (supporting). Adrian Miller: Supervision (supporting). Steven Tong: Conceptualization (lead); Formal analysis ; Funding acquisition (lead); Investigation ; Project administration (supporting); Supervision (lead); Visualization (supporting); Writing‐review & editing (lead).Table S1Click here for additional data file.


Granulomatous dermatitis (GD) is the most common among a variety of skin reactions that may occur in the varicella‐zoster virus (VZV) reactivation area. It is thought that the formation of granulomas may be the result of a delayed hypersensitivity reaction to viral envelope glycoproteins. Immune checkpoint inhibitors (ICIs), such as nivolumab stimulate T cells and promote hypersensitivity reactions, leading to the formation of granulomas in VZV wrapping proteins, thus triggering VZV‐GD. Few cases of the use of ICIs in patients diagnosed with VZV‐GD have been reported in the literature. Here, we report the clinical case of a patient with metastatic lung cancer which was treated with nivolumab who subsequently developed VZV‐GD. Accurate clinical diagnosis and prompt treatment with antiviral agents have resulted in a complete resolution of the clinical picture.Treatment with ICIs may result in VZV reactivation.Accurate differential diagnosis and early treatment led to the resolution of VZV‐GD.Few cases of ICI and VZV reactivation have been reported in the literature.Full and timely resolution of VZV‐GD allowed the continuation of ICI treatment. Varicella‐zoster virus (VZV‐GD) is a cutaneous reaction that can appear in the area in which a reactivation of the VZV takes place. It may occur during treatment with ICIs but very few cases are described in the literature.A differential diagnosis of dermatological adverse events (dAEs) related to treatment with ICIs should be carried out. dAEs occur in 34%–45% of patients treated with ICIs.Here, we report the clinical case of a patient with metastatic lung cancer which was treated with nivolumab who subsequently developed VZV‐GD. Accurate clinical diagnosis and prompt treatment with antiviral agents have resulted in a complete resolution of the clinical picture.A 65‐year‐old woman presented to the clinic, following the appearance of supraclavicular lymphadenopathy with a diameter of 20 mm. A biopsy was performed, with a subsequent diagnosis of lung adenocarcinoma with mutation Exon 19 EGFR, ALK and ROS not rearranged, PDL‐1 negative.Positron emission tomography (PET) and computed tomography (CT) scans were performed which indicated multiple mediastinal lymphadenopathy. Treatment with Afatinib was initiated and the disease was subsequently controlled for seven months. Following progression of the disease, no T790M mutation was detected in the circulating DNA, or after a new biopsy of the lesion.The patient then commenced chemotherapy with six cycles of pemetrexed and cisplatin and whilst complete metabolic remission of a very short duration was achieved, it was followed by a rapidly evolving relapse. A PET/CT scan showed diffuse adenopathies, right adrenal loggia nodularity (SUV 12.1) right iliac adenopathies and cruralw inguin (SUV 13.7). The patient commenced treatment with nivolumab and achieved a complete response which was documented by PET scan. After six months of treatment, there was widespread erythema evident at the level of the humeral‐scapula articulation, with severe itching and pain. Subsequently, 2–3 days later, maculae and papules appeared which evolved into vesicles and then pustules. The area was affected throughout by severe itching and pain.Treatment with nivolumab was subsequently temporarily discontinued. The patient commenced treatment with valaciclovir, 1000 mg three times a day for seven days in addition to fusidic acid cream which was applied twice a day to the damaged skin.Dermatological diagnosis was a grade 3 dAE due to VZV‐GD, with interesting scapular and supraclavicular cutaneous areas Figs a and 1b.A clinical reassessment after three weeks from the diagnosis of the infection documented a good resolution of the clinical picture with improvement in the cutaneous erythema, the rash had dried with the formation of crusts and almost complete disappearance of the symptoms of itching.At the time of writing this report, the patient is continuing treatment with nivolumab with excellent disease control.The primary infection of VZV is chickenpox, manifested by viremia with a diffuse rash and seeding of multiple sensory ganglia where the virus establishes life‐long latency.There are more than one million cases of HZ in the United States each year with an annual rate of three to four cases per 1000 people. Most cases of HZ can be diagnosed clinically.Nivolumab is a human immunoglobulin monoclonal antibody, which binds to programmed death‐1 receptor (PD‐1) and blocks its interaction with the PD‐L1 and the PD‐L2. Interaction of the PD‐1 with the PD‐L1 and PD‐L2 ligands, which are expressed by the antigen‐presenting cells, cancer cell or by other cells in tumor microenvironment, involves inhibition of T cell proliferation and cytokine secretion. Nivolumab strengthens T cell responses, including antitumor responses.Most frequent adverse events during treatment with ICIs are dAEs, which may range from vesicular, maculopapular, follicular, papular to exfoliative lesions or lupus‐like reactions.According to the European Society for Medical Oncology guidelines on the management of dAEs, the first requirement is to rule out any other etiology of the skin problem Table . 8 In ouNo authors report any conflict of interest.