Peripartum depression and anxiety disorders are highly prevalent and are correlated with adverse maternal and neonatal outcomes. Antenatal care in Germany does not yet include structured screening and effective low-threshold treatment options for women facing peripartum depression and anxiety disorders. Mindfulness-based interventions (MBIs) are increasingly becoming a focus of interest for the management of such patients. Studies have shown a decrease in pregnancy-related stress and anxiety in expectant mothers following mindfulness programs.The aim of this study was to explore the clinical effectiveness of a 1-week electronic course of mindfulness on prenatal depression and anxiety in hospitalized, high-risk pregnant women. We hypothesized that participating in a 1-week electronic MBI (eMBI) could alleviate symptoms of depression and anxiety during the hospital stay.A prospective pilot study with an explorative study design was conducted from January to May 2019 in a sample of 68 women hospitalized due to high-risk pregnancies. After enrolling into the study, the participants were given access to an eMBI app on how to deal with stress, anxiety, and symptoms of depression. Psychometric parameters were assessed via electronic questionnaires comprising the Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI-S), and abridged version of the Pregnancy-Related Anxiety Questionnaire (PRAQ-R).P<.03). Regarding pregnancy-related anxiety, participants who completed more than 50% of the 1-week course showed lower scores in PRAQ-R in the second assessment (P<.05). No significant changes in the EPDS scores were found after completing the intervention.We observed a high prevalence of peripartum depression and anxiety among hospitalized high-risk pregnant women: 39% (26/67) of the study participants in the first assessment and 41% (16/39) of the participants in the second assessment achieved EPDS scores above the cutoff value for minor/major depression. The number of participants with anxiety levels above the cutoff value (66% [45/68] of the participants in the first assessment and 67% [26/39] of the participants in the second assessment) was significantly more than that of the participants with anxiety levels below the cutoff value, as measured with the STAI-S. After completing the 1-week electronic course on mindfulness, the participants showed a significant reduction in the mean state anxiety levels (Peripartum anxiety and depression represent a relevant health issue in hospitalized pregnant patients. Short-term eMBIs could have the potential to reduce anxiety levels and pregnancy-related anxiety. However, we observed that compliance to eMBI seems to be related to lower symptoms of pregnancy-related stress among high-risk patients. eMBIs represent accessible mental health resources at reduced costs and can be adapted for hospitalized patients during pregnancy. Mental disorders are highly prevalent during pregnancy and impose a major burden for the expectant mother, her environment, and the health care system. The prevalence rate of depression has been reported to be 11%-17% in women during the peripartum period, depending on the gestational age . For insHormonal changes in pregnant women may play a major role in their emotional well-being, and associations of these hormonal changes with prolactin, steroids, and cortisol levels have been discussed previously ,9. If coPeripartum mental disorders have been identified as a potential risk factor for adverse obstetric, fetal, and neonatal outcomes. Studies suggest that there is a link between untreated symptoms of depression, anxiety, or stress and increased rates of birth complications, preterm birth, and fetal or infant growth impairment ,16. ConsInterest in mindfulness-based programs has increased substantially during the last 2 decades . SeveralAlthough the benefits of MBIs are well supported, less attention has been paid to the potential harm of MBIs. Recent studies and popular media articles suggest that mindfulness or meditation practices might have negative effects such as increased anxiety and unpleasant experiences ,27. HoweIncorporating mindfulness programs in the prenatal care structure could offer vulnerable pregnant women a stigma-free strategy for addressing these issues . The stiThe general conclusions about the efficacy of electronic MBI (eMBI) programs cannot be drawn according to the current data on mindfulness-based stress reduction during pregnancy. Most of the related research to date lacks methodologically rigorous trials with a randomized-controlled approach -32. A rePregnant women engage regularly with digital health technology and they were found to be willing to participate in web-supported perinatal interventions . Indeed,The aim of our study was to investigate the effectiveness of a brief electronic 1-week course of mindfulness on prenatal depression and anxiety in a setting of hospitalized patients with high-risk pregnancies. We hypothesized that attending a 1-week eMBI course can alleviate the symptoms of depression and anxiety during the hospital stay.mindmom app, which is currently being examined in a prospective randomized trial . The RCT aims to examine the clinical effectiveness and cost-effectiveness of an eMBI in a sample of pregnant women during the third trimester of pregnancy who were screened positive for emotional distress according to the Edinburgh Postnatal Depression Scale (EPDS). The screening is administered while attending ambulatory prenatal care either with a registered gynecologist or at one of the study centers. The participants were randomized in 1:1 into the intervention (eMBI) or control  group.This pilot study was conducted at the University Women’s Hospital in Heidelberg, a perinatal center of the highest level, performing over 2300 deliveries per year. Pregnant women hospitalized due to high-risk pregnancies were asked to participate in the study. The criteria for eligibility included age of 18 years or older, fluency in the German language, a gestational age of ≥24 and ≤34 weeks, and the ability to access to the internet. Women were not eligible to participate if they were expecting multiples. In total, 90 inpatients were asked to participate, of whom 68 women agreed. The reasons for not participating included lack of interest, scheduling conflicts (clash of dates due to lack of time), or severe pregnancy complications. After enrolling in the study, every participant was provided with a tablet and free wireless internet service and access to the eMBI course . The appThe original intervention was used prenatally in an established concept of 8 weekly 45-min sessions . In thisThrough mediation of psychoeducational content and cognitive behavioral therapy-related approaches, the app teaches participants how to deal with stress, pregnancy-related anxiety, and symptoms of depression. Thus, it promotes the autonomy of the mother-to-be regarding the upcoming birth and during the initial days and weeks with the newborn. The app contains instructional videos and audio files, interactive worksheets, and a personal “skills box” to collect exercises, videos, and texts, which the participants found helpful. After the 1-week course, participants had the opportunity to continue accessing the exercises. All the participants received scientifically validated information about pregnancy and birth via a pregnancy counselor. The main topics were the physical changes in pregnancy, the birth process, pain relief during birth, bonding between parents and child, breastfeeding, and tips on the formalities related to birth. No financial compensation was offered to the participants. All questionnaires were completed digitally prior to and after the 1-week course. In addition, we gathered medical and sociodemographic data that were double-checked against the hospital records . Data weTo assess the psychometric data on depression and symptoms of anxiety, the following instruments were used: EPDS, State-Trait Anxiety Inventory (STAI), and Pregnancy-Related Anxiety Questionnaire (PRAQ).The EPDS is a 10-item self-rating scale that assesses the depressive symptoms during the peripartum period. It was originally developed by Cox et al in 1987  and tranSymptoms of anxiety are assessed with the STAI. The STAI was developed by Spielberger et al  and tranPregnancy-related anxiety is assessed with the PRAQ. The questionnaire was originally developed by van den Bergh  and abriP>.18 in Kolmogorov-Smirnov-test), we chose a parametric analysis strategy for the parametric variables. Due to scale-specific amounts of the missing values, the number of valid cases varies between the analyses. We considered sociodemographic data , medical data , and the self-report data  for this procedure. The missing completely at random test results were not significant , indicating that missing values were at random and that subpopulations were representative for the total sample ) and low app engagement (8.30 [SD 4.05]) regarding EPDS scores at the second assessment . If participants completed more than 50% of all the modules, they had significantly lower PRAQ-R scores (18.74 [SD 4.49]) than those with low app engagement (22.54 [SD 6.90]) at the second assessment. Overall, 7.4% (ω²=0.074) of the PRAQ-R score variance at the second assessment can be explained by the group variable “high vs low app engagement.”However, a significant, medium-sized difference regarding PRAQ-R scores was observed at the second assessment  of the study participants achieved EPDS scores above the cutoff value for a minor/major depression and 66% 45/68) of the women had high levels of anxiety as measured with the STAI-S. Thereforeulations . In our ulations . Regardi/68 of thulations . The stuWhen compared to recently published studies with inpatient samples, we found similar tendencies for anxiety and depression levels during pregnancy. Regarding antenatal depression assessed via the EPDS, a study in Singapore found that the rate of major depression in a sample of high-risk pregnancies (11%) was higher than that in an unspecified obstetric risk cohort (4.3%) . DagklisIn direct comparison, it becomes clear that hospitalized pregnant women represent a vulnerable group, showing rates of anxiety and depression more than three times greater than those reported in nonclinical samples. Despite the high rates of anxiety and depressive symptoms, a surprisingly low number of participants were receiving mental health treatment. In inpatient obstetric settings, where access to individual psychotherapy is often extremely limited, eMBIs could provide an easily accessible support option. Incorporating low-threshold eMBIs not only in hospital care but also in outpatient practices could minimize the stigma of starting mental health treatment.For our sample, we decided to choose a cutoff value of >40 for STAI and a cutoff value >9 for EPDS, which is in line with that reported in recent studies on the use of EPDS and STAI as valid screening tools for depression and anxiety during pregnancy. Tendais et al found optimal cutoffs for STAI-S as 40 and EPDS as 9 during pregnancy . RegardiThe latest reviews about eMBI during pregnancy suggest that web-based interventions targeted at improving mental health may be beneficial during the peripartum period. However, the findings and their generalizability are limited both by the heterogeneity of the interventions and study designs and by methodological limitations. Pooled results of non-RCTs reporting outcomes on anxiety, depression, and perceived stress showed a significant benefit for the mindfulness group, but this review found no differences between the mindfulness intervention and control groups in RCTs . AnotherP<.03). Recent studies including other MBIs during pregnancy found similar effects with significantly lower STAI scores (P<.001) after interventions such as yoga, music therapy, or progressive muscle relaxation [In our pilot study without a comparison group, a significant reduction in the mean state anxiety levels was found after completing the 1-week eMBI . Concerning engagement with the app, participants who completed more than 50% of all the 3 modules showed lower scores for the PRAQ-R at the second assessment (P<.05). Our sample population showed an overall completion rate of 57% (39/68). We decided to consider an individual completion rate of more than 50% of the overall module in at least 2 of 3 course modules as compliant, as similar cutoffs have been used before. For instance, previous studies on mindfulness-based programs have considered participants who completed at least 50% of sessions as having fulfilled an adequate minimum amount of the course [As one of our key results, we found a small, yet significant reduction in the mean state anxiety levels after completing the 1-week electronic course of mindfulness (e course . Hence, e course ,63. Regae of 57% /68. We de course .As our pilot study design is not an RCT, the changes in the mean state anxiety levels after the 1-week course of mindfulness cannot be clearly attributed to the eMBI. Urech et al  assessedPeripartum anxiety and depression are highly relevant health issues in hospitalized pregnant patients. Despite high prevalence rates and the patients’ need for regular mental health support, only a very small proportion receives adequate treatment. In this pilot study, we could show that our 1-week course of mindfulness may be an effective brief intervention that could have the potential to positively influence childbirth anxiety and pregnancy-related stress among high-risk patients. eMBIs may provide an easily accessible and effective means to support pregnant women in managing anxiety and stress during their inpatient stay and beyond. RCTs with confirmatory analyses in larger samples are needed to confirm the effectiveness of mindfulness in promoting perinatal mental health and to study the potential for harm in mindfulness-based programs.


Chronic or acute insults to the myocardium are responsible for the onset of cardiomyopathy and heart failure. Due to the poor regenerative ability of the human adult heart, the survival of cardiomyocytes is a prerequisite to support heart function. Chaperone proteins, by regulating sarcomeric protein folding, function, and turnover in the challenging environment of the beating heart, play a fundamental role in myocardial physiology. Nevertheless, a number of evidences indicate that, under stress conditions or during cell damage, myocardial cells release chaperone proteins that, from the extracellular milieu, play a detrimental function, by perpetuating inflammation and inducing cardiomyocyte apoptosis. Blocking the activity of extracellular chaperones has been proven to have beneficial effects on heart function in preclinical models of myocardial infarction and cardiomyopathy. The application of this approach in combination with tissue engineering strategies may represent a future innovation in cardiac regenerative medicine. An efficient quality control mechanism is essential for sarcomere maintenance and dynamic adaptation to new physiological conditions  plays crucial roles in cardiomyocytes by inhibiting apoptosis and promoting unfolded protein degradation through macroautophagy. Indeed, mutations in the BAG3 coding gene are associated with dilated cardiomyopathy . BesidesHSP90 is an essential and ubiquitous chaperone that exerts multiple roles inside the cells, ranging from protein folding, buffering protein denaturation, and assisting signal transduction protein conformational changes . HSP90 iHSP60 is a chaperone protein located both in mitochondria and in the cytosol, responsible for the folding of mitochondrial-imported proteins . In mitoIn vivo coronary artery ligation followed by reperfusion induces the activation of the interleukin receptor-associated kinase-1 (IRAK-1), a kinase critical for TLR signaling. The treatment of mice with anti-HSP60 antibodies, prior to the ligation, significantly attenuates IRAK-1 activation (The translocation of HSP60 to the plasma membrane and its secretion induce the release of Bax that can move to mitochondria and activate the apoptotic cascade . In additivation . The abstivation . eHSP60 tivation .2–, the induction of TNF-α and IL-6 and the overexpression of IL-12 and IL-15 (In endothelial cells, HSP60 elicits the expression of E-selectin, ICAM-1, and VCAM-1, favoring the leukocyte trafficking within the vascular wall . In macrnd IL-15 . HSP60 hnd IL-15 . In addind IL-15 , causingnd IL-15 .HSP27 is a widely expressed chaperone protein belonging to the small HSP family, exerting a number of protective function in cardiomyocytes . Human aAll the evidence discussed above indicate that chaperones are actively secreted from stressed cells or released from damaged cells during chronic and acute cardiac insults or during clinical procedures like coronary artery bypass graft . Of noteAll authors wrote the manuscript and approved the contents for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Evidence for the use of lung ultrasound scan (LUS) examinations in coronavirus 2019 pneumonia is rapidly growing. The safe and non-ionizing nature of LUS drew attention, particularly for pregnant women. This study aimed to contribute to the interpretation of LUS findings in pregnant women for the obstetricians.LUS was performed to pregnant women suspected of or diagnosed as having Severe Acute Respiratory syndrome coronavirus-2 (SARS-CoV-2) in the first 24 hours of admission. Fourteen areas  were scanned per patient for at least 10 seconds along the indicated anatomical landmarks. The scan was performed in supine, right-sided and left-sided positions, respectively. Each area was given a score between 0 and 3 according to the specific pattern.In this study, 21 still images and 21 videoclips that enabled dynamic and real-time evaluation were provided. Pleural line assessment, physiologic A-lines, pathologic B-lines, light beam pattern, white lung pattern, and specific patterns for quick recognition and evaluation are described.The potential advantages and limitations of LUS and its areas of use for obstetricians are discussed. LUS is a promising supplementary imaging tool during the SARS-CoV-2 pandemic. It is easy to perform and may be feasible in the hands of obstetricians after a brief didactic course. It may be a firstline imaging modality for pregnant women. PRECIS: Lung ultrasound is feasible and relatively easy to perform for obstetricians to be used during the COVID-19 pandemic.,2. However, CT is relatively expensive, not feasible for monitoring and patients admitted to the intensive care unit, has an ionizing radiation nature and carries the risk of transmission during transportation.Chest computed tomography (CT) is the gold standard in the diagnosis of coronavirus diseases-2019 (COVID-19) pneumonia. The prominent features of COVID-19 are subpleural, ground-glass consolidative pulmonary opacities,3,4,5. Its interpretation is accepted as relatively easy because it is mainly based on pattern recognition and provides real-time dynamic images,6. LUS has been traditionally used by non-radiologists as an adjunctive imaging tool. Pulmonologists, emergency medicine physicians, thoracic and cardiac surgeons often benefit from LUS in the management of traumatic conditions and intraoperative situations. Obstetricians also use ultrasound liberally in their routine clinical practice. Practically, the examination of the maternal lungs immediately after obstetric sonographic evaluation could be feasible for obstetricians, basically to ascertain the presence or absence of normality and specific patterns, and thus to determine the need for further multidisciplinary management.By contrast, lung ultrasound scanning (LUS) is easy to perform, has a non-ionizing nature, and has the advantages of bed-side application and thus is well suited for monitoring patients. Changes in the lung parenchyma following COVID-19 pneumonia begin in the distal regions and progress proximally. Lesions are mostly located in the posterior and inferior fields of both lungs. This feature makes LUS non-inferior to CT in the pandemic setting compared with other respiratory disorders. The pathologic progression of pneumonia of COVID-19 provides credibility to a surface imaging modality such as LUS. Herein, it was aimed to provide a didactical, pictorial review to assist obstetricians in the multidisciplinary management of pregnant women suspected or diagnosed as haing COVID-19 infection.The attenuation of sound waves by the lung and bone tissues limits the use of LUS in the diagnosis of central lung diseases; therefore, LUS mainly targets artifacts that originate from peri-pulmonary lesions to reach a diagnosisIn this educational, non-systematic pictorial review, all lung images and videoclips were obtained with a dedicated machine  for use in pregnant women with suspicion or diagnosis of COVID-19. A 1-8-MHz convex transducer was used on the regular obstetric preset.. The scan was performed in supine, right-sided and left-sided positions, respectively  were scanned per patient for at least 10 seconds along the indicated anatomical landmarksectively . Where a. The pattern with a continuous and regular pleural line and horizontal artifacts, referred to as A-lines, was classified as score 0. The pattern with an indented pleural line and sporadic vertical white areas below the point of discontinuity in the pleural line, referred to as sporadic B-lines, was classified as score 1. The pattern with a broken pleura, small consolidated areas below the discontinuity, and multiple vertical white areas that reached the bottom of the field of view, referred to as multiple B-lines, was classified as score 2. The pattern with a severely broken pleura and a dense and largely extended white lung pattern with or without larger consolidations was classified as score 3. At the end of the procedure, the highest score obtained for each area was noted .Each area was given a score between 0 and 3 according to the specific patternLocal Instutional Ethical Board and National Scientific Research Board approved the study. Written consent was obtained from all patients underwent lung ultrasound.Video 1, 2, 3), five figures and three videos for score 1 , 5 figures and seven videos for score 2 , four figures and four videos for score 3  were provided and explained in detail. In addition, four featured videos were added showing pleural effusion, the co-existence of scores 0 and 1, and perihepatic and pericardial effusions . The clinical characteristics and outcomes of the patients were not in the scope of this study and were therefore not presented.In this study, six figures and three videos for score 0  of pleural line and subpleural effusion, if they exist.. The sliding sign is absent in some clinical conditions such as pneumothorax.The visceral and parietal parts of pleura slide over each other in backward and forward directions with respiratory movements called the normal sliding signThe subpleural consolidations appear as an irregular hypoechoic area. Small patchy, strip or nodule consolidations can often be observed as a subpleural lesion..In the COVID-19 infection, pleural thickening and subpleural effusion were found to be about 1-2 mm and 2-3 mm, respectively, which can change as the disease progressesA-lines: These represent repetitive reverberation artifacts and commonly appear as horizontal, parallel lines at regular intervals. These lines represent a normal inflated peripheral lung when combined with a normal pleural sliding sign.B-lines: These lines are well-defined vertical hyperechoic artifacts arising from the pleural line and reach the bottom of the screen. These lines move with the pleural line during respiration and may erase A-lines. Sporadic/coalescent or multiple B-lines can be seen and the density and combination of the pathologic signs may be correlated with the probability of disease.,10. However, possible false-positive cases should also be approached with great caution in the pandemic settings and should be considered as a possible pathologic condition until proven otherwise.Sometimes, fewer than three B-lines between two adjacent ribs may be seen in 30% of normal lungsThere are also false vertical lines including C-, E- and Z-lines, which can commonly be mistaken for B-lines. However, for obstetricians working in the COVID-19 pandemic setting, discriminating those from pathologic B-lines may not be clinically relevant because they refer to specialist’s (such as radiologist and pulmonologist) considerations to differentiate from underlying diseases. In addition, they are mainly differentiated with B-lines concerning their synchronous movements with inspiration and expiration. Basically, an obstetrician should pay attention to the synchronized vertical lines that move with respiration.Light beam pattern: A specific pattern that consists of a shining band-form artifact spreading down from a large portion of a regular pleural line and often has an on-off effect with respiration that may also have normal A-lines visible in the background. This pattern was proposed to reflect the acute phase of ground-glass opacities during the early spread of the active COVID-19 pneumonia.White lung pattern: This pattern corresponds to the increased density of the lung parenchyma in which physiologic A-lines and other vertical artifacts including B-lines are erased..Pleural effusions and air bronchograms, which are the reflection of air-filled bronchus in the context of opacity are rarely seen in COVID-19 infections and should lead physicians to superinfections or other differential diagnoses and should be ready for the second wave or the next epidemics or pandemics caused by other viruses. The use of LUS for pregnant women in the hands of obstetricians can make a difference during such exceptional and critical situations. This pictorial study can be used for the training of obstetricians in the pandemic setting and encourage the liberal use of LUS.Obstetricians should be responsive during the Severe Acute Respiratory syndrome coronavirus-2 pandemic because they are the frontline physicians for the pregnant population,5,8. The sensitivity and specificity of LUS in several clinical conditions range between 81% and 97%, and between 95% and 100%, respectively,15. Authors postulate that LUS should be the first choice of imaging method in pregnant women suspected of having COVID-19 infection. However, LUS findings should be evaluated with the patient’s background because they are not always specifically attributable. More importantly, mild LUS findings (score 1) in an asymptomatic woman should be approached cautiously. For example, A-lines that are known as physiologic artifacts can represent abnormal signs in atelectasis, asthma, chronic obstructive pulmonary disease, and pneumothorax. Similarly, B-lines can represent normal signs in healthy patients when they are fewer than three and do not reach the bottom of the screen.LUS cannot be a substitute for chest CT; however, it has certain advantages over CT as an adjunctive method in the diagnosis and management of respiratory involvement of COVID-19 infection, particularly for pregnant women. As physicians without formal radiology residency training, we organized a brief course that consisted of a didactic lecture and hands-on ultrasound examinations supervised by experts. This approach has been previously tested and found that LUS is feasible following theoretical training combined with still images taken from pregnant women infected with COVID-19,18. The interobserver agreement between obstetricians with different levels of experience on still-images and videoclips of LUS was found as good.We have previously shared our clinical experience in eight cases showing that the use of LUS immediately after the fetal assessment can positively affect the clinical management of pregnant women infected with COVID-19LUS is a promising non-invasive, safe, and easily learned and performed imaging tool that can be used in pregnant women suspected of having COVID-19 pneumonia following an initial fetal assessment. This technical pictorial study can encourage the reasonable learning of LUS for obstetricians in the pandemic setting.


Premotor predictions facilitate vocal interactions. Here, we study such mechanisms in the forebrain nucleus HVC (proper name), a cortex-like sensorimotor area of songbirds, otherwise known for being essential for singing in zebra finches. To study the role of the HVC in calling interactions between male and female mates, we used wireless telemetric systems for simultaneous measurement of neuronal activity of male zebra finches and vocalizations of males and females that freely interact with each other. In a non-social context, male HVC neurons displayed stereotypic premotor activity in relation to active calling and showed auditory-evoked activity to hearing of played-back female calls. In a social context, HVC neurons displayed auditory-evoked activity to hearing of female calls only if that neuron showed activity preceding the upcoming female calls. We hypothesize that this activity preceding the auditory-evoked activity in the male HVC represents a neural correlate of behavioral anticipation, predictive activity that helps to coordinate vocal communication between social partners.SIGNIFICANCE STATEMENT Most social-living vertebrates produce large numbers of calls per day, and the calls have prominent roles in social interactions. Here, we show neuronal mechanisms that are active during call-based vocal communication of zebra finches, a highly social songbird species. HVC, a forebrain nucleus known for its importance in control of learned vocalizations of songbirds, displays predictive activity that may enable the male to adjust his own calling pattern to produce very fast sequences of male female call exchanges. Many group-living species, such as zebra finches, use a large numbers of calls to interact within their social group and, in particular, with their mates . During To study the neural mechanisms of stimulus-response (sensorimotor) prediction underlying vocal interactions in a social context, we employed telemetric devices that enabled the continuous synchronized monitoring of vocal activity and of neurophysiological activity in HVC (proper name), a sensorimotor cortex-like nucleus known for its control of song pattern . HVC is Animal experiments were conducted according to the regulations of the government of Upper Bavaria (Az. 55.2-1-54-231-25-09). Experimental zebra finches were obtained from our breeding facility. Male and female zebra finches (>100 d post hatch) were used for the audiotelemetry and neurotelemetry experiments. Zebra finch pairs were kept in custom-made, sound-attenuated chambers. Each sound-attenuated chamber was equipped with a microphone , a speaker  and a telescopic antenna for wireless recordings. Zebra finches were kept in a 14/10 h light/dark cycle (fluorescent lamps), 24°C, and 60–70% humidity.Custom-made wireless microphones  were used for wireless sound recording . The wirPlayback experiments were performed in cohabitation  and in isolation . Recorded stack calls of the female mates were played back by a speaker . Female stack calls used for playbacks were recorded by the in-box microphone  before the experiments. The intervals between played-back calls were uniformly randomized between 1 and 30 s.2/min). During anesthesia, the animals were kept warm on a constant temperature pad  and wrapped in a thin gauze blanket. Some feathers of the head were removed, the skin was disinfected, opened and treated with lidocaine . After a window on the skull was opened, the bifurcation of the mid-sagittal sinus served as a reference coordinate. A 2-MΩ tungsten electrode (FHC) was lowered into HVC using a micromanipulator (Luigs and Neumann). After verifying the signals of HVC by playing back birds-own-song (BOS), conspecific songs and noise  and with one backpack microphone mounted on the male and another backpack microphone mounted on the female. All events recorded by the central microphone during a 4-h period were compared with those recorded by the backpacks at that time. In all cases, the backpack microphones mounted on the female or male, respectively, recorded the calls emitted by the microphone carriers. The sound levels of calls were estimated by calibrating between the central microphone and the sound meter .x, μ, and σ are call counts, mean, and standard deviation (SD) of call counts, respectively.Vocal data were recorded continuously at 22,050-Hz sampling rate and written to WAV files. Vocalizations were extracted from audio files by using custom-written software (sound explorer). The vocalizations of zebra finches were clustered by analyzing their sound features . The perx, μ, and σ are spike counts, mean, and SD of spike counts, respectively. The Z-score is used for indicating a significant increase or decrease in activity with the critical value ±1.645 (α = 0.05). The signal-to-noise ratio (SNR) was calculated as: F test to compare the neuronal activity patterns. We compared the neuronal activity in relation to associated female calls during cohabitation (coh-aF) against spontaneous female calls during cohabitation (coh-sF), associated female calls during separation (sep-aF), and spontaneous female calls during separation (sep-sF). In the context of separation, we separated female and male mates into two distant boxes with acoustic interconnections. The sum of the squared distances between the mean curves of coh-aF and individual curves of respective groups were calculated separately. The null hypothesis is that the difference (D0) between the mean curves of coh-aF and the individual curves of coh-aF yields the same variability as the difference (Dtest) between the mean curves of coh-aF and the individual curves of coh-sF, sep-aF, and sep-sF, respectively. The F-ratio between the sum of squared differences between D0 and Dtest and the sum of squared difference within D0 and Dtest was calculated. The degrees of freedom for between-groups and within-groups are bdf and wdf, respectively. The p value for the test is given by: x denotes F-ratio.The neurotelemetric signals were received and amplified with communication receivers . The signals were digitized  and recorded with custom-made software or registered on a DASH8X data recorder (Astro-Med). We used the same sampling rate  to record the neurophysiological data simultaneously with vocalizations of female and male zebra finches. Spike sorting was conducted offline by using Spike2 (CED). A template matching algorithm was applied for spike sorting in 300- to 10,000-Hz bandpass filtered recordings. Principal component analysis  confirmed isolated units, and we obtained two to three units from each animal (eight birds). We selected one single-unit for each bird for further analysis that showed premotor activity associated with call production. The raster plots and the PSTHs indicate the times at which HVC neurons fired in relation to the onset of vocal events (bin width: 10 ms). Z-scores were calculated as: post). The maximal Z-score within the time window  and isolation  as compared with cohabitation , while the RT during isolation were longer than the RT during separation .To test the impact of social context on the stack calling dynamic, we separated male and female mates into two distant boxes with acoustic interconnections and compared the RT between the contexts of cohabitation and separation in male zebra finches. Because the distribution of the calling intervals in zebra finches is scale free  and onlyFig. 1n = 8 birds) with wireless telemetric device simultaneously with his own vocalizations and with those of his female mate. We show example of neurotelemetric recordings from the HVC of one male zebra finch during male-female vocal interactions . We obtained two to three HVC single-units from each bird including one single-unit per recording site that showed premotor activity associated with productions of stack calls. We also recorded bursting activity associated with one specific type of syllables in the same animal (C). The stack call-related HVC units  recovered faster than did a bursting unit that did not show stack call-related activity . The waveform widths of stack call-related units at 25% peak amplitude were 0.22 ± 0.03 ms, which are comparable in spike width to those obtained with putative interneurons <0.3 ms (n = 8 birds). In this study, we focused on stack call-related HVC units of males during female-male calling interactions.We recorded the neuronal activity of the male HVC  but also associated with the female's stack calls during call-based vocal interactions . The female call-related activity in male HVC included two peaks, one following the female's calls and one preceding the female's calls by ∼200 ms . The excitatory activity preceding the female calls was always followed by activity suppression that lasted ∼200 ms .In addition to what has been previously reported , we founFig. 2G, the Z-score of one HVC single-unit), both the HVC activity preceding and following the occurrence of the female's stack calls remained present for the coh-sF class . Further, because of the definition of coh-sF calls, male calling was not related to these female calls.Since males produced different types of vocalizations , including stack calls in association with the occurrence of the female stack calls, these associated calls could be the reason for the preceding activity, thus either being premotor or auditory evoked. If so, the spiking patterns of male HVC neurons related to spontaneous female calls  should be different from the pattern related to the female calls associated with other calls of the male or female. Therefore, we compared the neuronal correlation of the associated female calls (coh-aF) with the neuronal correlation of the spontaneous female calls in the context of cohabitation (coh-sF). As similar as for the coh-aF , the backpack microphone recorded all sounds that were recorded by a calibrated standard microphone placed in the cage. Further, visual inspection of the sonograms of all coh-sF events confirmed the lack of low-amplitude female calls occurring briefly before the coh-sF. We were able to exclude the occurrence of very low-amplitude calls of the males uttered before the coh-sF since the backpack microphone recorded all calls.I,J, n = 8). Since the male HVC activity that preceded the female stack calling in the social setting was neither premotor nor auditory-evoked, we named this activity “predictive activity.” We discuss this term in relation to possible explanations such as repressed premotor activity in the discussion.During call production, HVC single-unit did not show auditory-evoked activity for female calls that occurred within 500-ms time window before (FM-) and after male calls . This increased activity preceding the female calls corresponded to the predictive activity shown in post) and the predictive activity (max Z-scorepre) in relation to female calls. The female calls were sorted into 10 quantiles according to the percentage of spikes occurring half a second before the female calls . We only found nine (out of 80) cases with significant auditory-evoked activity (max Z-scorepost) after Benjamini–Hochberg corrections, in which seven cases of significant auditory-evoked activity were found to be contingent on there also being activity preceding the female calls . These results suggest that, in the social context, a transient increase in predictive HVC activity is required for the auditory-evoked activity to occur in HVC.We tested the relationship between the predictive activity and the auditory-evoked activity . We found significant auditory-evoked activity only in calling events, in which the activity increased transiently before the onset of the females' calls A. This iA,C) and social context (E). In the isolated situation, the played-back calls would occasionally fall within the 500-ms criterion before and after a male call. We named these cases as iso-aPb (A). If the playback calls did not fall within 500-ms criterion, we named these cases as iso-sPb (B). In ∼60% of the playbacks , the male did not respond to the playbacks with calling and HVC neurons showed activity, which was auditory evoked . In this isolated context, there was no HVC activity preceding the hearing of the played-back female calls . This result remained even if we split the analysis of the playbacks into associated and “spontaneous” events; the auditory-evoked activity was significant in both cases , while there was no predictive activity preceding the hearing of the playbacks. The average latency of the auditory-evoked activity  to the playbacks during isolation is shorter than the average latency  in relation to hearing of female calls in the social context .Next, we isolated the male from his female mate and played back her stack calls to him. The male HVC neurons showed the calling-related premotor activity in both isolated A,C and s context E. In the iso-aPb A. If the iso-sPb B. In ∼60y evoked B,D. In tA; see Fig. 2F, coh-sF vs coh-aF, F = 2.21, p = 0.16, n = 8 pairs). To test the importance of sensory cues further, we separated the female and male mates into two distant boxes with acoustic interconnections. Visual isolation alone had little impact on the predictive activity, which was similar to that of the cohabitation context  = 3.66, p = 0.08, n = 6 pairs). However, if the vocal cue was not available during visual isolation, when the female calls occurred unexpectedly without temporal association with either vocal or visual cues for half a second, the males no longer exhibited significant predictive activity or auditory-evoked activity in response to female calls  = 9.11, p = 0.01, n = 6 pairs). When we played back female calls while the male and the female were cohabitating in the same aviary, the male HVC did not show auditory-evoked activity in relation to the played-back female calls  = 8.22, p = 0.02, n = 3). The playbacks were identical to those used in the isolated setting reported above . In the social context, the HVC single-units showed predictive activity preceding the hearing of female calls in all males. The auditory-evoked activity occurred only subsequently to the predictive activity but not subsequently to premotor activity in the social context of all males . Despite constrained interactions in the context of separation, the HVC single-units displayed predictive activity and auditory-evoked activity . The playbacks of female calls did not evoke auditory activity in male HVC during cohabitation . When the playbacks became the only communication channel in the isolated context, HVC single-units displayed auditory-evoked activity in relation to hearing female calls but no predictive activity . Thus, in the social context, the males produce predictive activity that helps to gate auditory response that evokes HVC activity for calls of the social partner.In summary, for all studied males and HVC single-units, we found the following patterns of task-dependent and social context-dependent activity in HVC neurons of male zebra finches : HVC sinFig. 6Zebra finches, like most other group-living songbirds, communicate using large numbers of acoustically invariant calls in addition to songs . SensoriThe stack call-related premotor activity of HVC interneurons is corroborated by recent results . For sinH), also other mechanisms could extract information of female's previous behaviors to generate predictive/fictive activity. In that case, the synchronized activity of a small fraction of HVC interneurons might not be sufficient to excite RA-projecting neurons, i.e., will not result in a motor output. The predictive/fictive activity might reflect the evolutionary history of HVC and the song control system in general as a network that evolved originally to control the timing of vocalizations such as innate calls. Only later during evolution, this auditory-vocal flexibility that originally concerned the time domain was extended to the spectral domain enabling vocal learning. Since the terms fictive or predictive matter only from an evolutionary perspective . We currently do not know whether Avalanche neurons excite HVC interneurons directly. In case of contingent excitation because of well-timed predictive activity and female calling, the excitatory input of Avalanche would result in auditory evoked activity in HVC interneurons. These complex computations would explain the delays of HVC activity when hearing female calls in a social context compared with the playback of her calls in a non-social context.The predictive premotor HVC activity was contingent on the activity of the same HVC interneuron activated by hearing the female call. During antiphonal callings, HVC interneurons seem to determine narrow time windows in which call processing in HVC is possible. Unlike motor performance, which can provide external feedback, the predictive activity may generate a feed-forward signal to auditory areas such as nucleus Avalanche [and caudomedial nidopallium (NCM) and caudal mesopallium (CM) interconnected with Avalanche] that respond to the incoming calls of the female mate, similar to an efferent copy of motor activity. Comparison of the timing of the male's predicting feed-forward signal, and of the timing of the female calls in the auditory areas, would result in an expectation error that measures the discrepancy between the predicted and the actual timing of female's calls. Neurons that detect errors in auditory feedback related to singing are present in CM . Since AFig. 5D), the males seem to be able to extract information from the previous calling activity of females to predict future calling events during vocal interactions. Such auditory and visual information about the mate might reach HVC via Uva, which exerts synaptic influence on HVC interneurons and those projecting to RA and area X (How might the perception of context affect HVC activity? The predictive HVC activity was still produced when we excluded all visual information or all short-term auditory information that preceded female calls. Since stack calling of zebra finch mates is steady  and follFig. 1d area X . Uva obtd area X , visual d area X , and attd area X . VNLL and area X . This spd area X  and are d area X . Howeverd area X .An ability to predict allows animals to avoid surprise and to minimize energy cost in sensory sampling and processing . Alterna


Purpose: This study aimed to compare the risk of orthodontic mini-implant (OMI) failure between maxilla and mandible. A critical analysis of finite-element studies was used to explain the contradiction of the greatest clinical success for OMIs placed in the maxilla, despite the higher quality bone of mandible. Materials and Methods: Four tridimensional FE models were built, simulating an OMI inserted in a low-dense maxilla, control maxilla, control mandible, and high-dense mandible. A horizontal force was applied to simulate an anterior retraction of 2 N  and 10 N (overloading condition). The intra-bone OMI displacement and the major principal bone strains were used to evaluate the risk of failure due to insufficient primary stability or peri-implant bone resorption. Results: The OMI displacement was far below the 50–100 µm threshold, suggesting that the primary stability would be sufficient in all models. However, the maxilla was more prone to lose its stability due to overload conditions, especially in the low-dense condition, in which major principal bone strains surpassed the pathologic bone resorption threshold of 3000 µstrain. Conclusions: The differences in orthodontic mini-implant failures cannot be explained by maxilla and mandible bone quality in finite-element analysis that does not incorporate the residual stress due to OMI insertion. Mini-implants have become a routine component of the contemporary orthodontists’ anchorage armamentarium . The posAn umbrella review recently evaluated the effectiveness of TADs, and a high success rate (≥90%) was reported for most analyzed studies . FailureSince the beginning of implant therapy, bone quality has gained attention because it was thought to be related directly to the procedure's success. Specifically to OMIs, it is believed that in low-density bones, the OMI installation may fail because it does not achieve sufficient primary stability, which is essential for the mini-implant activation. Still, high primary stability is associated with a zone of dead and dying osteocytes, along with microfractures that lead to a more significant peri-implant bone resorption . TherefoThe selection of the OMI insertion site is also an important criterion for the clinician . A higheThe Finite-Element (FE) Method is a powerful tool to predict and prevent biomechanical failures during treatment planning, including those associated with OMI use ,13–18. SConcerning the nature of bone–OMI contact, it is essential to highlight that, different from what is desired for a dental implant, OMI osseointegration is not necessary, nor even desirable, because when it occurs, it hinders the device removal and increases the risk of OMI fracture. Regarding the failure criteria, it is already established that the strain is the mechanical stimuli that drive the bone-remodeling process. It was postulated that when strain increases over 3000 µstrains, pathological changes in bone start to present as bone resorption . Frost's1 corresponds to the maximum tensile strain), the bone resorption risk is restricted to the tension areas. The risk at the compression areas cannot be assessed, although the chances of resorption in these areas are even higher. Therefore, the analysis of the minimum principal strain  is also crucial. When the major principal strain is used, simultaneous analysis of the compressive and tensile risk areas is performed, which is a considerable benefit.Nevertheless, due to the chosen failure criterion, most OMI-FE articles limit the analysis to critical tension values ,14 or crTherefore, this finite-element study was aimed at assessing the influence of bone density on the risk of OMI loss of primary stability  and peri-implant bone resorption  in the posterior region of the maxilla and the mandible. In addition, a critical analysis of finite-element (FE) studies was used to explain the contradiction of the greatest clinical success for OMIs placed in the maxilla, despite the higher quality bone of mandible.Four tridimensional (3 D) finite-element (FE) models of an anatomical maxilla and mandible were built according to four bone densities conditions: low-dense maxilla (LD-Mx), control maxilla (C-Mx), control mandible (C-Md), and high-dense mandible (HD-Md). The bone density differences were simulated by varying the cortical thickness and the trabecular elastic modulus .The sagittal external contours of maxilla and mandible bone were based on a CT scan of a 32-year-old man. The use of the patient DICOM file in this research project was approved by the ethics committee of São Paulo University School of Dentistry (registration number 4.251.051). The geometric modeling was performed using Rhino3D , and the mesh generation with Apex . After a mesh convergence test, the maxilla FE model consisted of 5,92,325 four-node tetrahedral elements and the mandible FE model of 5,76,384 four-node tetrahedral elements. The four 3 D FE models represented a posterior jaw region with a titanium orthodontic mini-implant (9.5 length and 1.4 diameter) inserted in the cortical and trabecular bone of the maxilla (LD-Mx and C-Mx) or mandible (C-Md and HD-Md). The material properties are presented in An orthodontic force was applied to the head of the OMI  in a horM) were analyzed to predict the risk of peri-implant bone resorption. The εM value corresponds to the maximum tensile strain or the maximum compressive strain, according to the following criterion:3 corresponds to the minimum principal strain. It was assumed that either a tensile or a compressive strain above 3000 µstrain would increase peri-implant bone resorption risk.The numerical analyses were performed with MSC.Marc . The intra-bone OMI peak of displacement was analyzed to predict the risk of primary stability failure, while compressive and tensile bone major principal strains  and mobility level have been used as the main parameters to evaluate the primary stability and to assess OMIs success rates in longitudinal clinical studies . In FE sThe observed peak displacement values were compatible with previous FE studies designed with similar loading regime and bone-OMI interface representation ,16,18. AThe intra-bone OMI peak displacement obtained in the present study was far below the 50–100 µm threshold, suggesting that the primary stability would be sufficient even in the overloaded low-dense maxilla scenario. Therefore, clinical failures due to insufficient OMI stability immediately after its insertion could not be confirmed in this study. The low-dense maxilla FE model probably could not represent the critical clinical scenario in which the OMI insertion region presents an ample bone marrow space. Nevertheless, when an excessive load is applied, initially stable mini-implants can become extraordinarily mobile and eventually fail . The strversus 80.4% for the mandible) [versus 12% for the maxilla) [Based on the maxilla bone quality , it could be expected that OMIs placed in the mandible would present higher success rates compared with the ones placed in the maxilla. Yet, robust evidence supports the greatest clinical success for OMIs when placed in the maxilla ,9,10,26.t >2 mm) may not guarantee higher OMIs stability [According to the present results, the maxilla is more prone to lose its stability due to overload conditions, especially in the low-dense condition, in which both tensile and compressive strains surpassed the 3000 µstrain limit. Still, initial high loads should be avoided for all insertion sites, since all FE models exceeded the compressive strain failure criteria under the overloading condition. The compressive strain limit was also reached in the 2 N model of the low-dense maxilla, reinforcing this poor bone quality scenario's vulnerability. It explains why the lack of initial stability is often observed in the case of cortical bone thickness lower than 1 mm . The pretability . NeitherThe understanding of this apparent contradiction is crucial for clinical decisions in OMI therapies. Although high insertion torque contributes to the implant's immediate stability, it also increases the risk of damaging the interfacial bone during insertion, thus compromising the maintenance of OMI stability . ExperimThe clinical implication of these findings is that for a low-dense maxilla, a higher insertion torque is desirable to guarantee OMI initial stability, while for a dense mandible high insertion torque must be avoided. Therefore, there may be some benefit to predrilling in areas of thick, dense cortical bone, such as the mandible , since tin vivo molecular, cellular, and histologic evidence approaching the high OMI insertion torque issues. High bone strains were linked with constriction in blood flow, microfractures in peri-implant bone, and extensive osteocyte death. Although the complex biological responses of the bone due to the OMI insertion were not fully represented in these simulations, it is well defined that the simulation of the strains generated due to implant insertion is crucial for the prediction of the higher risk of failure in high dense mandible by the finite-element method [Even though the finite element analysis is a powerful tool to study biomechanical failures, a critical analysis of the loading conditions is crucial for the accuracy of the results. As most published OMI FE studies, the present study was not designed to predict the higher bone resorption vulnerability of the mandible related to the residual strain or the thermal necrosis: our aim was to calculate the strains generated only from the orthodontic forces. As far as we know, only three FE studies simulated the OMI insertion procedure ,31,32. At method .Other simplifying assumptions used in this study could have affected the accuracy of the FE outcomes. First, the limitation of considering cortical and trabecular bones as a homogeneous material might affect the translation of the FE results to the clinical findings because it has already been shown that homogeneous models presented substantially different strain distributions and magnitudes . Second,The intra-bone OMI peak displacement obtained in the present study was far below the 50-100 µm threshold, which suggests that the primary stability would be sufficient even in the overloaded low-dense maxilla scenario.The maxilla is more prone to lose its initial stability due to orthodontic overloading, especially in the low-dense condition, in which both tensile and compressive strain surpassed the pathologic bone resorption threshold.The differences in orthodontic mini-implant failures cannot be explained by maxilla and mandible bone quality in finite-element analysis that does not incorporate the residual stress due to OMI insertion.


The management of musculoskeletal tumours is complex and requires a multi-disciplinary approach. Preoperative embolisation can be often employed to reduce intra-operative blood loss and complication rates from surgery. We report our experience with the safety, technical success and efficacy of pre-operative embolisation in musculoskeletal tumours.Thirteen consecutive patients who underwent pre-operative embolisation of a musculoskeletal tumour followed by surgical intervention at our institution from May 2012 to January 2016 were enrolled into the study. Patient demographics, tumour characteristics, embolisation techniques and type of surgery were recorded. Technical success of embolisation, amount of blood loss during surgery and transfusion requirements were estimated.There were five female and eight male patients who underwent pre-operative embolisation during the study period. The age ranged between 16 to 68 years, and the median age was 54. Technical success was achieved in all patients. Mean intra-operative blood loss was 1403ml, with a range of 150ml to 6900ml. Eight patients (62%) required intra-operative blood products of packed red blood cells and fresh frozen plasma. No major complications occurred during embolisation.Pre-operative trans-arterial embolisation is feasible and safe for a variety of large and hypervascular musculoskeletal tumours. Our small series suggests that preoperative embolisation could contribute to the reduction of the intra-operative and post-operative blood product transfusion. It should be considered as a pre-operative adjunct for major tumour resections with a high risk of bleeding. The use of the haemoglobin gap complemented the assessment of perioperative blood loss. Its role in the treatment of musculoskeletal tumours had become increasingly important with the use of arterial embolisation as a neoadjuvant therapy before surgical resection7.The management of musculoskeletal tumours is complex and often involves the multiple specialties of orthopaedic surgery, radiology, general surgery, neurosurgery and oncology. Trans-arterial embolisation was first reported by Dr Frieda Feldman in 1975 as a useful adjunct in the management of selective bone tumours9. The main aim of pre-operative embolisation was to achieve devascularisation of the tumour before surgical resection, with reduction of intra-operative blood loss and complication rates11. Early resection was preferred following embolisation, as revascularisation was seen at six weeks in some series5.The procedure of pre-operative embolisation itself was complex and various techniques and embolic agents had been described14. However, data was limited on the outcomes of preoperative embolisation of musculoskeletal tumours. In this retrospective study, we aimed to report on our experience and add onto the knowledge of safety, technical success and efficacy of pre-operative embolisation in musculoskeletal tumours. In our series, all embolisations were performed with either polyvinyl alcohol (PVA) particles alone or in combination with other embolic agents such as gelfoam slurry or micro coils.There are several studies on embolisation of musculoskeletal tumours for neoadjuvant, therapeutic and palliative therapyThis study was approved by our institutional review board, and the requirement for informed consent was waived. A total of 13 consecutive patients who were planned for pre-operative embolisation from May 2012 to January 2016 were enrolled in the study. The indications for pre-operative embolisation were discussed at a multidisciplinary tumour board, considering tumour size, histology and location, vascularity and estimated blood loss from surgery. Larger tumours, anatomically challenging locations for resection and tumours with hypervascularity and neovascularity on CT angiography were considered and a collective decision made for pre-operative embolisation at the tumour board meeting with the orthopaedic surgeon, interventional radiologist, diagnostic radiologist, medical oncologist and pathologist.Histological diagnosis of the tumour was confirmed by either open or core needle biopsy before definitive surgery. Location of the tumour was determined by pre-operative imaging with plain radiographs, computed tomography (CT) or magnetic resonance imaging (MRI). Size of the tumour was quantified by measuring the anterior-posterior, craniocaudal and transverse length on CT or MRI scans before embolisation.15. All procedures were carried out by a single procedurist. The embolic agent was at the discretion of the performing interventional radiologist, with PVA being the preferred embolic agent as it was used for distal tumour microvasculature penetration. Gelfoam was used to occlude proximal medium to larger vessels following deeper embolisation with PVA, reducing the risk of permanent non-target embolisation. Microcoils were similarly used to accurately complete the embolisation following PVA use to avoid recanalisation of the feeding vessel. Occasionally coils were used to embolise and protect non-target vessels originating proximally, which could not be navigated beyond to get closer to tumour feeders, thereby avoiding riskier distal non-target embolisation by PVA.All embolisation procedures were performed while the patient was under conscious sedation induced by intravenous fentanyl and midazolam. Vascular access was obtained via the common femoral artery, and a 5F or 6F vascular sheath was used. The appropriate 4F or 5F pre-shaped catheters were used for the diagnostic angiography. All embolisations were done using a micro-catheter system coaxially introduced through the 4F or 5F catheter with selective catheterisation of the tumour feeders. The embolisation procedural endpoint was reached when stasis was observed in the feeding arteries along with the significant reduction in tumour blush. A completion angiogram was performed to evaluate overall devascularisation of the tumour. The musculoskeletal interventional radiologist retrospectively reviewed the images obtained before and after an embolisation. The effect of pre-operative embolisation on obliterating the tumour blush was based on a comparison of the pre- and post-embolisation angiograms on the PACS monitors. The criteria for technical success included catheterisation of the significant afferent tumour-supplying vessels and total interruption of the blood supply to the tumour by 70% or more as in the post-embolisation angiographyOperative records were reviewed to determine the period from embolisation to surgery and the type of surgery performed. In our institution, all tumour cases undergoing pre-operative embolisation would have a definitive surgical procedure done within a week. The interval between embolisation and surgery varied and depended on the availability of the embolisation suite and the operating theatre list. Intra-operative blood loss and amount of blood products administered during the surgical procedure by anesthesiologist were recorded. Allogeneic and autologous red blood cells from cell salvage were combined to give the total red blood cells transfused intra-operatively. If the surgery was in two stages, the sum of the intra-operative blood loss (IBL) and the packed red blood cells (PRBC) units transfused for each stage were added together and the total used for the analysis.Pre, immediate, post-operative and subsequent haemoglobin levels were obtained from the online medical records and any transfusion within the week following surgery was determined from online records of blood products ordered. Descriptive data were presented as medians and means with ranges, if appropriate; categorical data were presented as percentages.A total of 13 patients, of which five were females and eight were males, underwent pre-operative embolisation during the study period . The ageAll embolisations were performed with either PVA alone or in combination with other embolic agents such as gel foam slurry or micro coils . The sizThe majority of the surgical interventions were either a resection or excision of the tumour in nine patients . Two cases underwent internal hemipelvectomy (15%) and two had a curettage (15%). There were two patients with thyroid metastases, Cases 6 and 7; one patient had an endoprosthesis inserted after the resection of the left proximal femur and the other patient had the diaphysis of the femur plated after a curettage of the tumour. A patient with a T9 spinal metastasis, Case 8, required a laminectomy with further posterior instrumentation of T7-11 vertebrae. Case 10 was a patient with a large giant cell tumour of the hemipelvis and required a curettage of the lesion, with subsequent monthly Denosumab as an adjuvant therapy with the medical oncologist. Of the three patients with sacral chordoma, two required an abdominal perineal resection as the tumour had extended into the lower rectum, another patient required a concurrent Hartmann’s procedure as the tumour had extended into the recto-sigmoid junction. One of the 3 patients, case number 13, required internal iliac vessels mobilisation and ligation as the tumour was found to be encasing the vessels; this resulted in significant blood loss (6900mls).Mean intra-operative blood loss was 1403ml with a range of 150ml to 6900ml, in nine patients (n=11). Eight patients  required intra-operative packed red blood cells (PRBC). The mean volume of PRBC given during surgery was 939ml (55ml - 4921ml) for the eight patients who had intra-operative blood products. Seven patients (54%) required further transfusion post-operatively due to persistent low haemoglobin. In the group of patients who received an intra-operative transfusion, four patients went on to receive further transfusion post-operatively. The mean post-operative blood transfusion units required by patients was 2.1 units.Haemoglobin parameters are summarised in 18. Selected case examples of successful embolisation are shown in In our series, pre-operative embolisation was successfully performed in all patients following the criteria of technical success with the catheterisation of the tumour-supplying arteries and the obliteration of >70% of the tumour staining mass19, improve visualisation intra-operatively and thus completeness of the resection margins. This was particularly important in large tumours in which challenging en-block resections were contemplated, with risks of life-threatening haemorrhage6. In a large series of 51 patients, Barton et al16 reported intra-operative blood loss of 500 - 1,500ml in patients who had undergone pre-operative embolisation of bone tumours; patients who had not undergone any embolotherapy had an intra-operative blood loss of 2,000 - 18,500ml. Manke et al20 reported significantly reduced intra-operative haemorrhage in patients with spinal metastases from renal cancer, following pre-operative embolisation with PVA particles compared to patients treated surgically without pre-operative embolisation. Kickuth et al21 reported a median intra-operative blood loss of 600ml with a range of 200 – 4,000ml for patients who have had undergone pre-operative devascularisation of bone tumours. Earlier studies on preoperative embolisation of musculoskeletal tumours had demonstrated its efficacy in reducing intra-operative blood loss and these results provided a baseline for comparison.Studies have shown that successful embolisation of musculoskeletal tumours could reduce intra-operative blood lossIn our study, we found our intra-operative blood loss to range from 150ml to 6,900ml with a mean of 1173ml and a median of 500ml, which was comparable to the literature. The mean blood loss calculated in this series was skewed by Case number 13, with a sacral chordoma resection where intra-operative blood loss was noted to be at 6900ml.et al’s case-control study22 where the group of patients with pre-operative embolisation had a significantly lower haemoglobin drop post-operatively compared to the control group. Some authors also believe that estimated blood loss, being a semiquantitative variable with a potential source of bias, could sometimes be inaccurate23. Hence, the haemoglobin gap could provide a clearer peri-operative blood loss profile.There were two patients Case number 4 and 5, where intra-operative blood losses were not documented. Blood losses in these two cases were then approximated from the change in haemoglobin post-operatively which were -4 and -4.2 for patient number 4 and 5, respectively. These suggested a significant but not an extensive amount of blood loss. Coupled with a minimal amount of blood products transfused post-operatively, we could then gauge the intra-operative blood loss. In Case number 12 where the intra-operative blood products given were not known, we could postulate that significant blood product was given as there was a large positive increase in the haemoglobin gap (+5.3) post-operatively. In our case series, the use of the hemoglobin gap serves as a useful adjunct to assess intra-operative blood loss as well as blood products given. The use of haemoglobin gap in postulating blood loss/blood products given was also supported by Bapuraj Post-operative transfusion requirement beyond the immediate peri-operative period was not often documented in published embolisation studies. In our series, postoperative transfusion requirement within one week of postoperative period averaged 2.1 units. The indication for transfusion beyond the immediate peri-operative period was based on clinical evaluation of the post-operative haemoglobin trend, symptoms related to anaemia as well as surgical drain output. No patient developed massive postoperative haemorrhage with hemodynamic instability requiring escalation of care, ionotropic support or further intervention such as angioembolisation or surgical exploration. Our case series suggests that a combination of pre-operative musculoskeletal tumour embolisation with major surgery could reduce the risk of severe delayed secondary haemorrhage, despite the many potential confounding factors including surgical technique, tumour type and location, and even concurrent resection of bowel.24 and reducing tumour volume25 or combined with ablation and cementoplasty9. Major complications arising from pre-operative tumour embolisation were uncommon26 with a non-target embolisation and the post embolisation syndrome being the most frequently encountered28. We experienced a small tumour-feeding artery dissection, supplying 5% - 10% of the tumour, arising from the anterior branch of the internal iliac artery during cannulation attempts in Case number 9. Technical success was achieved in that patient and there was no requirement for post-procedure blood transfusion. No other significant complications relating to the pre-operative embolisation were recorded in our retrospective case series. The overall complication rate from pre-operative embolisation was 7% (n=1) which was encouraging compared to the other studies in literature where the overall complication rate ranges from 3.1% to 28.6%30.Apart from reducing peri-operative bleeding, embolisation for musculoskeletal tumours could also reduce the amount of viable tumour, by inhibiting tumour growth and decreasing required doses of radiotherapy and chemotherapy. It could also be performed as a stand-alone in the palliative setting for pain relief32. Secondly, our study population was not homogeneous with regards to tumour types and the type of surgery performed. However, this reflected the clinical setting of primary and metastatic tumours, both referred simultaneously to the interventional radiologists for preoperative embolisations and subsequent operation by a single musculoskeletal tumour surgeon. A prospective randomised trial would be beneficial for defining the exact value of preoperative embolisation compared with surgery without preoperative embolisation. Such a trial would be difficult to design and not likely to be feasible.There were several limitations to our study. Firstly, data collection was retrospective, and comparison with a non-embolisation group was not available. However, by cross-referencing with multiple studies from the literature, we aimed to provide a fair depiction of pre-operative embolisation as an adjunct to orthopaedic tumour surgery. In our series, the median blood loss calculated at 500ml is comparable, if not lower than that was reported in most studiesPre-operative embolisation for musculoskeletal tumours is feasible and safe before surgical intervention for a variety of large and hypervascular musculoskeletal tumours. Our small series suggests that pre-operative embolisation could also contribute to reducing the intra-operative as well as postoperative blood product transfusion requirement and should be considered as an adjunct for major resections with a high risk of bleeding. The use of haemoglobin gap complemented an assessment of peri-operative blood loss.


Case Presentation. Here, we present the clinical course of a patient with IgG4 ophthalmic disease who achieved a favorable response from radiotherapy. Our patient initially presented with a history of recurrent painful flares of orbital inflammation, a pathologic diagnosis follicular lymphoid hyperplasia from a right lacrimal gland biopsy, and MRI imaging noting expansion of the lateral rectus muscle of the right eye. Initial treatment with dacryoadenectomy and multiple courses of corticosteroids failed to keep his symptoms at bay. Further evaluation revealed florid IgG4 staining. In this context, he was evaluated for image-guided intensity-modulated radiotherapy (IG-IMRT) to the orbit to 20 Gy in 10 fractions. His ophthalmic symptoms resolved.  IgG4-related ophthalmic disease is a rare, newly recognized entity with high failure rates on first-line therapy of systemic corticosteroids and no other proven management options.  This treatment experience suggests radiotherapy may be a favorable option for symptom relief in patients with IgG4-related ophthalmic disease not controlled by corticosteroids. IgG4-related ophthalmic disease (IgG4-ROD) is a relatively recently recognized ocular inflammatory entity characterized by the infiltration of IgG4-positive plasma cells into tissues, typically ocular muscles. The etiology and pathogenesis of this process is currently unknown , 2. IgG4Current treatments for IgG4-ROD limited to the orbit are guided by systemic agents used to address extraorbital multifocal disease. First-line therapy is often systemic corticosteroids, but retrospective data suggests progression/relapse rates as high as 72% . Other sHere, we describe the clinical course of a patient found to have IgG4-ROD, treated with image-guided intensity-modulated radiation therapy (IG-IMRT) who had an excellent and rapid clinical response at 3-month follow-up.The 39-year old patient initially presented in 2017 for recurrent episodes of dry, painful, swelling of the right eye . ComputeThe patient received dozens of courses of oral steroids over the course of the two years prior to presenting to radiation oncology. The steroid courses were of varying doses and duration and were not well tolerated due to medical comorbidities, mainly malignant hypertension. In 2019, he began to experience increased severity of symptoms during flares, rating pain 10/10 with no response to systemic steroids. Symptoms included new onset diplopia, severe ocular pain, and worsening upper and lower palpebral edema described by the patient as intermittently “so bad I can't open my eye at all.” His physical exam was significant for mild right proptosis, right-ptosis, evoked diplopia with inability to fully medialize the right globe, and incomplete conjugate gaze at the far medial and lateral fields without appreciable impairment of visual acuity. The patient was referred to radiation oncology, where his constellation of findings prompted consideration of the possibility of IgG4-ROD and a request for IgG4 staining of tissue from his 2017 orbitotomy was sent and shown to be 100 per high-powered field . A numbeTreatment options were reviewed. In the context of his comorbidities and polypharmacy, radiotherapy was selected as the preferred treatment approach by the patient over other second-line immunomodulators that have been described for use in IgG4-ROD to avoid the addition of another systemic therapy. We discussed that IgG4-ROD is one of a number of benign inflammatory conditions of the orbit including graves ophthalmopathy, orbital pseudotumor, and precursor lymphoproliferative process  lymphomas). We discussed that low-dose radiotherapy can be given to address the symptoms in the context of these other orbital processes and discussed the risks and benefits of a course of IG-IMRT with the goal of symptom control. After informed consent was obtained, the patient underwent IG-IMRT of 20 gray (Gy) in 10 fractions to the right orbit with attention to sparing the brain and lens.Although he experienced an inflammatory flare during the first week of radiotherapy, he subsequently had an impressive clinical response . In the The patient was immobilized with a short aquaplast mask and underwent a CT simulation without IV contrast and an orbital MRI with gadolinium. The treatment field was defined as the bony orbit. An intensity-modulated radiotherapy plan with volumetric modulated arc radiotherapy (V-MAT) using 6 MV photos was created with two arcs delivered with the couch at 0 degrees and one arc delivered with the couch at 280 degrees. The quality of the plan was assessed for conformality and homogeneity. Daily image-guidance with cone beam CT was undertaken with a match to the bone. The dose was 20 Gy in 10 fractions.IgG4-ROD typically presents with fibro-inflammation of the orbit and symptoms of unilateral or bilateral proptosis, eyelid swelling, ocular pain, and impaired ocular movement , 10. OthTherapeutic options are important for this cohort of patients as recurrent symptoms are common and long-term steroids do not always produce the desired clinical relief. Additionally, inadequate steroid dose can lead to insufficient immunosuppression, and as was seen in this case, steroids could not be tolerated due to a history of malignant hyperthermia treated with multiple antihypertensives. Even when steroids do provide relief, long-term corticosteroid use is associated with many negative side effects including osteoporosis, hyperlipidemia, hyperglycemia, and adrenal insufficiency . When stGiven the variety of clinical scenarios in which radiotherapy has been used, as well as variable reported efficacy, this case report provides an important and unique perspective , 12. ThiWhile there have been case reports of the use of radiotherapy in IgG4-ROD, the toxicities are often not described in the context of clinical decision-making in these cases. One of the most common side effects of radiotherapy to the orbit is dry eye syndrome. In this case, the patient had previously had a dacryoadenectomy in the affected eye that was to be treated with radiotherapy, which helped guide decision-making as the patient already had iatrogenically induced dry eye syndrome due to previous surgery. Radiation is often reserved as a second line therapy due to the increased risk of secondary malignancy following radiation.Additionally, this case demonstrates a diagnosis of IgG4-ROD two years after initial presentation. In the time between initial surgery in 2017 and definitive diagnosis, the patient continued to receive many courses of oral steroids and experienced adverse effects until steroids were no longer tolerable. As a relatively new pathology, it is expected that more cases of IgG4-ROD will be diagnosed after several therapies have been initiated. Understanding the role that radiotherapy can play in these cases provides a valuable addition to the literature and provides treatment experience that may apply to patients diagnosed under similar circumstances.Without available prospective data, case reports are an important way to prompt our colleagues to consider IgG4-ROD when evaluating patients with inflammatory orbital disease. As with all newly described entities, given a tool to assess for IgG4 staining, the number of patients who can be assessed as having IgG4-ROD will rise and, with it, a desire for data related to treatment options. This case report provides an important perspective in that the diagnosis of IgG4-ROD was made several years after initial evaluation and attempted disease management with steroids that were not well tolerated. Consideration of low-dose radiotherapy may be reasonable in the right clinical circumstance.