The current landscape of literature highlights that there is insufficient well‐powered and robust evidence to support the integration of intravenous methadone into current guidelines and frameworks in supporting the pain management of cancer patient with complex pain syndromes. However, there is preliminary evidence, both from the literature as well as this case study that highlights intravenous methadone may be efficaciously and safety used for the management of postoperative pain in cancer patients with chronic pain undergoing operative management. Further research is required to fully elucidate key considerations of integrating this medication into clinical practice including consideration into dosing, opioid conversion, tolerance, and safety.Methadone is a broad‐spectrum analgesic with long duration of effect. Its multimodal mechanism of action, such as through effects on mu‐opioid receptor and presynaptic N‐methyl‐D‐aspartate receptors, has led to its current use in the management of opioid dependence in the community and in palliative care. These properties however make methadone appealing in the management of postoperative pain, particularly for patients with complex analgesic requirements. We report on an interesting case whereby intravenous methadone was effectively used for postoperative analgesia in a 56‐year‐old female with complex chronic pain secondary to a mucinous pelvic neoplasm of unclear primary who underwent palliative resection. Further, we review the literature surrounding usage of methadone in this setting to understand current challenges and barriers to implementation of methadone as an analgesia option for chronic pain patients following surgery. To do this, a case report and literature review was conducted in accordance to the CARE case report guidelines. The patient provided written consent for the de‐identification and use of their medical information and data for the generation and publication of this case report. Our case report and literature review demonstrate there remains significant heterogeneity, unfamiliarity, and scarce use of intravenous methadone in the perioperative and postoperative space in the management of patients with complex pain regimens such as chronic cancer pain patients. Despite this, our case report and literature review highlight as a broad analgesic, intravenous methadone warrants consideration following more rigorous research and development of safe use guidelines into its use for this purpose. Timeline to peri‐operative methadone use for analgesia for a cancer patient with chronic pain undergoing palliative surgery. Further, we explore the current and relevant literature and frameworks evaluating the use of IV methadone in postoperative pain management.2A brief overview of events is summarized in the timeline depicted by Figure 2.1A 56‐year‐old female was pre‐emptively referred to the acute and persistent pain service 7 weeks prior to palliative oncological surgery for optimization of persisting pelvic pain. The planned operative procedure includes a total pelvic exenteration (TPE) with concurrent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS HIPEC) for mucinous pelvic neoplasm of unclear primary.2.2The patient has complex gastrointestinal medical and surgical history. The patient first underwent a proctocolectomy and end ileostomy formation at age 16 for juvenile polyposis and was then subsequently diagnosed with fistulizing perianal Crohn's disease in which over her lifetime has been treated with multiple immunomodulatory and immunosuppressive medications including azathioprine, ustekinumab, adalimumab, and infliximab. At the time of review, the patient was no longer receiving any maintenance therapy. Since 2020, the patient had undergone multiple examinations under anesthesia (EUA) for chronic vaginoperineal fistula with seton insertion. Specifically, the patient had a chronic pelvic mucinous cyst with discharge into the perineum and posterior left thigh. These occurred in early November 2020, mid November 2020, mid‐ to late June 2021. Histopathology specimens from these demonstrated non‐specific inflammation and were all benign. These admissions were complicated by perianal sepsis requiring multiple debridements and IV antibiotic therapy. The patient's case was discussed in a specialist multidisciplinary discussion around mid October 2021. During this discussion, a magnetic resonance image (MRI) from June 2021 of the pelvis that demonstrated no definitive evidence of malignancy, a computerized tomography (CT) of the abdomen/pelvis from July 2021 that demonstrated interval reduction in size of the known multiloculated trans‐spatial pelvic collection, and a positron emission tomography (PET) scan from October 2021 that demonstrated no FDG‐avid disease was reviewed. The consensus was that the imaging and pathology were indicative of Crohn's disease process.The patient was re‐referred to operative service in late April 2023 for a progressive pelvic mucinous mass with new ureteric compression and ongoing mucinous discharge from natal cleft and posterior left thigh. The patient proceeded to a repeat EUA of the anorectal region with subsequent pathology identifying a low‐grade mucinous neoplasm of unclear primary. After a further specialist multidisciplinary meeting and shared decision‐making with the patient, a decision was made to proceed to TPE, CRS HIPEC, and ileal conduit as a palliative procedure to improve pelvic pain, mucinous leakage, and quality of life for the patient.2.3The patient presented to the acute and persistent pain clinic approximately 7 weeks before her scheduled operation. At this time, the patient's pain history was clarified.She reported 12 months of persistent pelvic pain presumably secondary to the pelvic mass. The pain was described as a pressure‐like sensation which upon bearing down would change to a constant aching sensation. The patient also reported a burning‐type pain in the pelvis associated with urinary flow. There were no other typical neuropathic pain descriptors associated with any other areas. The patient reported her pain was exacerbated by multiple factors including urinary frequency (5–6 times per day on average) and performing usual activities of daily living. The pain limited the patient's ability to walk to a duration of only approximately 4–5 min and her tolerance for standing still was reduced to only 10 min at a time. Temporary reprieve was found only in the sitting position. Reports of anhedonia and low mood were largely attributed to pain with poor sleep also a factor.From a social perspective, the patient lives with her mother who is unwell with high care needs but is reasonably independent with personal activities of daily living. The patient has been financially dependent on a disability pension since the age of 16. She does not consume alcohol or smoke and has an allergy to penicillin (anaphylaxis). She rarely leaves the house due to pain.2.4At the time of her pain clinic review in July 2023, the patient was on an analgesia regimen consisting of oxycodone liquid as required (up to 40 mg per day) with additional temazepam 10 mg as needed for sleep. She was also prescribed 45 mg of mirtazapine at night. She had previously tried sustained‐release (SR) oxycodone‐naloxone as well as tapentadol SR and transdermal buprenorphine with poor effect. It was suspected that the low efficacy of oral formulations was due to poor absorption in the setting of ileostomy. Additionally, the patient did not tolerate buprenorphine which had caused a peri‐stomal rash. Methadone was discussed as an additional line of analgesia at this time; however, the patient opted to revisit this discussion at a later time given the negative connotations associated with the drug. She continued with her immediate‐release (IR) oxycodone in the interim.The patient re‐presented to the pain clinic 2 weeks following her review ongoing persistence of the aforementioned pelvic pain. She had now been taking up to 50 mg of oxycodone per day. Through a shared decision‐making process, the patient agreed to commence oral methadone at a dose of 5 mg twice a day with IR oxycodone to be used as a bridge for symptom control. Over the subsequent weeks leading up to her surgery date, the patient uptitrated methadone to an oral dose of 5 mg in the morning and 10 mg at night which allowed her symptoms to become more manageable. She had downtitrated her oxycodone liquid dose at the same time.2.5The patient proceeded to surgery with a planned two‐stage procedure. The first stage occurred on first day of admission where the patient underwent an open completion posterior exenteration with hysterectomy including resection of lateral and posterior wall of the vagina, bilateral oophorectomy, left nephrectomy and let adrenalectomy, insertion of bilateral ureteric catheters, and temporary closure of the abdomen. Postoperatively the patient was routinely managed in the intensive care unit (ICU) with analgesia regimen consisting of a fentanyl infusion (200mcg/h), IV paracetamol 1 g six hourly and breakthrough 5 mg IV methadone if required. This regimen was introduced given the unique short‐onset and long‐offset of the medication to provide more effective and longer‐lasting pain relief. This also has the additional benefit of reducing total opioid dose by reducing the amount of immediate‐release as required opioid medication. The patient developed a fever day 1 post‐op, and a septic screen was performed. The patient was managed with IV cefazolin however required vasopressor support for hemodynamic compromise. The patient returned for second‐stage surgery day 2 post first‐stage operation, consisting of resection of residual mucinous neoplasm from the left pelvic sidewall, right pelvic sidewall, posteromedial right thigh, distal pre‐sacral region, and through the left anterior table of the distal sacrum (S4) into the left gluteus maximus. HIPEC was not performed due to concerns about sepsis in ICU. This was followed immediately by a left pedicled anterolateral thigh flap reconstruction to the perineal defect. The patient returned to ICU for routine care. Postoperative analgesia consisted of paracetamol 1 g six hourly, fentanyl infusion (200 mcg/h), ketamine infusion (12 mg/h), epidural (ropivacaine 0.2%), and IV methadone (5 mg BD). The following day, the epidural was removed, and fentanyl infusion was transitioned to oxycodone patient‐controlled analgesia (PCA), and ketamine was increased to 16 mg/h with no changes to methadone and paracetamol dosing. The patient experienced episodes of breakthrough pain which was not relieved PCA and ketamine alone, with methadone dosing being reported by the patient to subjectively improve her pain including improved comfort when resting and with movement and reduced somatic symptoms of pain such as anxiety and distress. On the third day following the second‐stage operation, the patient was transferred from ICU to ward‐level care, continuing with PCA, ketamine, and IV methadone dosing as per the day prior with good analgesic effect. Upon arrival to the ward, the patient experienced breakthrough pelvic pain associated with distress. The patient's pain was not relieved with the baseline PCA and ketamine regimen. It was noted that the patient had missed her evening methadone dose due to ICU to ward transfer, and only upon receiving the methadone dose did her pain improve, indicating the effectiveness of methadone in supporting the patient's pain, physical distress, and discomfort in addition to her baseline analgesia. The patient underwent routine care on the ward with a plan to taper off analgesia back to the baseline pre‐admission regimen.3Opioid medications are used as main‐stay therapy for chronic cancer and non‐cancer pain.Despite these sentiments, mechanistically, methadone exhibits many desirable properties that may prompt its use in postoperative patients with complex analgesia requirements. Methadone is a highly potent mu‐opioid receptor agonist with affinity for central and peripheral kappa‐ and delta‐opioid receptors; it also exhibits NMDA receptor antagonism and is a presynaptic blocker of serotonin and noradrenaline.The mixed mechanism of action and complex pharmacology of methadone allow it to occupy a unique place in therapy for hard‐to‐treat pain syndromes which is highly relevant for cancer patients who often experience chronic pain secondary to the burden of their condition. However, methadone is often relegated to last‐line therapy or therapy reserved only for specialists in the field due to an overall unfamiliarity with the drug and a lack of consensus opinion on dose conversions from comparator opioids such as morphine.The side effect profile of methadone is another consideration. The primary concern is that of the implications on respiratory depression on the background of the medications' long, unpredictable, and dose‐dependent half‐life.Extending from this, clinicians and patients also need to consider the social implications of instituting methadone‐based regimens for postoperative analgesia. The stigma around methadone and its links to opioid addiction (including illicit substances such as heroin) were highlighted as a barrier clearly in this case and also reflected in the literature.In specialist settings, such as that of a tertiary hospital, the use of methadone is not limited to treatment of opioid dependence or chronic pain and has a growing body of evidence that supports intraoperative doses in a variety of surgeries to lessen postoperative pain scores and thus minimize postoperative opioid requirements.4At this point in time, there is insufficient robust evidence to suggest the evidence‐based incorporation of IV methadone into the regimen of postoperative care of patients, regardless of whether the patient has complex analgesia requirements or not. From a clinical perspective, stigma regarding the use of methadone should not, in the context of judicious pain management, be a significant barrier to the use of methadone. However, inexperience and poor characterization of methadone titration and effect pose an important barrier toward implementation. Despite this, evidence suggests that methadone may offer favorable analgesic effects in the postoperative period, with lower pain scores, improved patient satisfaction, and lower opioid consumption.Khang Duy Ricky Le: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; supervision; validation; visualization; writing – original draft; writing – review and editing. Jean Hua: Conceptualization; data curation; formal analysis; investigation; methodology; validation; writing – original draft; writing – review and editing.There are no conflicts of interest or disclaimers.There was financial and grant support.The case report generation process was discussed with the Peter MacCallum Cancer Centre ethics and governance team. No formal ethics approval was required following the discussions.The patient provided informed consent that was written and signed for generation and publication of this manuscript using their de‐identified medical information.


Limited studies report on the status of surgical closure patches for atrial septal defect (ASD) in the remote period. In our case, transthoracic echocardiography revealed a fistula of ASD patch before pulmonary vein isolation for atrial fibrillation. Preoperative Imaging examinations aid in evaluating the effect of the needle puncture around the artificial material of the atrial septum and catheter manipulation for patients with a history of ASD closure. A 72‐year‐old man was referred to our department due to palpitations secondary to paroxysmal atrial fibrillation. He had undergone surgical closure of an atrial septal defect (ASD) approximately 50 years prior. Electrocardiogram revealed paroxysmal atrial fibrillation (AF). Transthoracic echocardiography (TTE) revealed dilation of the left atrium and right ventricle Figure . The rig2 score; 2 points, CHA2DS2‐VASc score; 3 points). Prior to radiofrequency catheter ablation, preoperative cardiac imaging evaluation of the ASD closure patch was planned.According to the diagnosis of AF, edoxaban , bisoprolol (0.625 mg/day), and amiodarone (50 mg/day) were prescribed  revealed an atrial shunt Figure . TransesBased on the location of the slit identified by TEE prior to the ablation procedure, we aimed a sheath to the slit using the intracardiac echocardiography (ICE) AcuNav catheter (Biosense Webster Inc) and successfully passed a guidewire through to the left atrium without a needle puncture. To avoid increasing the leakage due to manipulation of a large‐diameter sheath, an 8.5‐Fr steerable sheath was only inserted into the left atrium through the slit followed by extensive encircling pulmonary vein isolation (PVI). PVI was performed with a fast anatomical mapping image Figure . Post‐abOver 6 months of follow‐up, this patient had no recurrence of AF nor any evidence of increased leakage.Surgical closure of atrial septal defects (ASDs) has been a standard modality of treatment for decades. Since the first reports of surgical ASD closure in 1948, more than 70 years of experience have resulted in a safe and effective surgery with minimal mortality and complications. However, prolonged follow‐up is rare for patients with a history of surgical treatment for ASD. Thus, to the best of our knowledge, limited studies report the long‐term status of the closure patch.Those studies that have reported the long‐term outcomes after surgical repair of ASD generally neglect to evaluate the status and material of the closure patch.In patients with surgically repaired ASDs, the transseptal puncture method can be performed via the neighboring native atrial septum tissue or the patch itself.Here, we reported a case of ASD, detected by preoperative TTE and cardiac CT, where a transseptal approach via minor peri‐closure patch leak was used. Imaging examinations provided important indications informing puncture sites. Evaluation of the status of the closure patch before using a transseptal puncture approach in patients with a history of treatment for ASD has been emphasized, although the follow‐up data of most patients with a history of surgical closure of ASD long time ago are often unavailable because of censored follow‐up. Thus, understanding the utility and benefits of preprocedural multi‐modality imaging to assess the ASD closure patch may improve the utility of the transseptal approach.This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.The authors have nothing to disclose.Approval was obtained from the local ethics committee.Written informed consent was obtained from the patient for the publication of this case report.Not applicable.Not applicable.N/A.Figure S3Click here for additional data file.Movie S1Click here for additional data file.Movie S2Click here for additional data file.


Physician burnout impacts all levels of medical education and has a relatively unknown impact on those responsible for medical student education, particularly in paediatrics. This study examines the prevalence of burnout among paediatric undergraduate medical educators and explores the impact of roles in medical education on medical educator burnout.This cross‐sectional mixed‐methods study utilised a binational survey of paediatricians involved in undergraduate medical education. Respondents answered demographics, standardised questions about burnout and attitudes towards students, and an open‐ended probe about interactions between medical student education and wellness.Of 445 possible, 120 (26.9%) responded to demographic and burnout questions. Of these, 23.3% endorsed burnout, 21.7% high emotional exhaustion (EE) and 10.8% high depersonalisation (DP). High levels of student‐related burnout symptoms were reported by fewer than 5% of respondents and were correlated with overall EE and DP. Content analysis revealed four emergent themes: positive effect of student‐related role, need to balance medical education and clinical roles, impact of protected time and medical education‐related autonomy on educator well‐being, and the burden of the administrative portion of educational roles.Participating paediatric educators had low rates of burnout compared with paediatricians as a whole in prior studies. The vast majority found working with students rewarding and described the overall positive impact of their medical education role on wellness.Physician involvement in rewarding non‐clinical activities may improve their overall well‐being. Providing dedicated time for these activities may ameliorate the difficulty that many medical educators described in balancing their clinical and educational roles. Future studies should continue to explore how we can better support medical educators and the impact of this support on burnout. Racism still impacts Asian physicians and physicians who self‐identify as ‘other’, even if they may not be specifically ‘under‐represented’ based on their proportion of the medical workforce compared with their proportion of the general population. Employment questions included specialisation, academic rank, role in UME , class size and percentage of employment allocated (FTE) to UME. Comparative demographic data are unavailable for the COMSEP membership as a whole at the time of the survey and, thus, we were unable to determine if the sample was fully representative of the broader membership. The study was deemed exempt by the University of Michigan IRB; there was no independent funding for this project. Notably, this survey was performed prior to the ongoing SARS‐COVID‐19 pandemic.This cross‐sectional study surveyed paediatricians involved in undergraduate medical education (UME). The study population was composed of members of COMSEP , the US and Canadian professional organisation for academic paediatricians who supervise medical student education. COMSEP performs an anonymous annual survey of members, which is electronically sent to all COMSEP members once and response is not required or compensated. The 2019 survey included questions designed to elicit information about individuals' demographics, employment status and levels of burnout. Demographic questions included gender, age, ethnicity and geographic region. Members who self‐identified as African‐American, Latinx, Asian or ‘other’ were classified as ‘non‐White’ for demographic purposes. Although the formal ‘Under‐represented in Medicine’ designation is more stringent than this, the survey team felt it was important to explore the impact of being ‘non‐White’ because in the current landscape of microaggressions, it often matters less about how one self‐identifies and more about how others never to every day; the question regarding reward working with students was reverse scored.Burnout questions in the survey included a validated two‐question scale originating in the Maslach inventory—an item for DP, ‘I have become more callous towards people since I took this job’, and an item for EE, ‘I feel burned out from my work’.Box 1Emotional exhaustion (EE): ‘I feel burned out from my work.’Depersonalisation (DP): ‘I have become more callous towards people since I took this job.’Emotional exhaustion towards students (EES): ‘Working with students directly puts too much stress on me.’Depersonalisation towards students (DPS): ‘I don't really care what happens to some of my students.’Feels guilty about students (FGS): ‘I feel guilty about my attitude at work towards students.’Finds working with students rewarding (WSR): ‘I find working with students rewarding.’When evaluating burnout literature, some studies report symptoms of burnout as either a logical conjunction (Venn ‘and’) of EE and DP or a logical disjunction (Venn ‘or’) of EE or DP.Respondents were also asked to expand on the role of medical students in their wellness through typed response to an open‐ended prompt, ‘How does your role in medical education affect your wellness? What is the impact of wellness, or lack thereof, on your professional role in medical education?’How does your role in medical education affect your wellness?Analysis of quantitative data was performed using SAS 9.4. We used the Spearman correlations to examine the correlations among the different burnout measures. When the demographic variable was continuous, Student's t‐test and the Mann–Whitney U‐test were used when appropriate for statistical comparison. When the demographic variable was categorical and the subgroups were large enough, we used a chi‐squared test for analysis, and when there were smaller cells , we used the Fisher exact test. We used the Spearman correlations to examine the correlation between dedicated educational FTE and the feelings of burnout.A thematic and sentiment analysis of responses to the single open‐ended question was performed by two authors  independently reading through the responses and assigning both codes and valences  to each statement. Responses were iteratively reviewed, and differences were reconciled through review and discussion. Themes were identified and member checking was conducted by sharing themes and example statements with a subset of the COMSEP membership attending a 2021 annual conference session on wellness. The 15 members who participated approved the themes as presented in the 30‐minute review and discussion. Given the anonymous nature of the survey, we cannot ascertain if the members participating in the member checking had also completed the survey.3Of 445 COMSEP members who received the 2019 annual survey, 120 completed both the demographic and the burnout sections (26.9% response rate). The majority of respondents (61%) identified as White/Non‐Hispanic; 67% identified as female .positive effect of student‐related role—most respondents found working with students rewarding, regardless of their own feelings of burnout;need to balance medical education and clinical roles—many respondents noted the pressure to balance multiple roles and the time and effort involved;impact of protected time and medical education‐related autonomy on educator well‐being—many respondents noted it was easier to balance these roles if they had dedicated educational time or administrative support; andthe burden of the administrative portion of educational roles—respondents with administrative support found it easier to balance their educational and clinical responsibilities.In content analysis, narrative response valences were coded as 50% positive, 28% neutral/mixed and 22% negative, with respect to medical education roles and their impact on wellness. Themes that emerged included Table positive1.positive effect of student‐related role;2.need to balance medical education and clinical roles;3.impact of protected time and medical education‐related autonomy; and4.the burden of the administrative portion of educational roles.Themes that emerged includedMember checking resulted in universal thematic approval and suggested no supplementary elements.4Paediatric medical educators in this study had a low rate of burnout (23.3%) in comparison with published studies for paediatricians as a whole .Paediatric medical educators in this study had a low rate of burnout (23.3%) in comparison with published studies for paediatricians as a whole . Respondents described the overall positive impact of their medical education role on their wellness and 95% found working with students rewarding.Decreased burnout has been documented among educators previously. Dyrbye et al. found that 46% of internal medicine CDs reported high EE and 41% had high DP, less than the 50% of internists who reported burnout.Educators noted the positive effect of the student‐related role and overwhelmingly found working with students rewarding.This echoes a Delphi‐method study in which a multispecialty group of clerkship educators deemed that critical resources, including dedicated time and administrative assistance, were necessary to perform the essential elements of medical education.Strong correlations emerged between the burnout questions and three of four questions regarding attitudes towards students: EE towards students, DP towards students and feelings of guilt related to working with students, which were all highly correlated with each other. In the prior study by Dyrbye et al., the questions about DP towards students and EE towards students were indicative of higher odds of EE or DPOur study is subject to several limitations, including a low response rate of 27% of possible respondents, affecting the quantitative portion of the study. People experiencing burnout may be less likely to complete surveys, and it is also possible that generalised burnout, or that related to students, may contribute to attrition in medical education roles, affecting the population of educators involved in education/COMSEP membership; both factors may contribute to lower rates of burnout in the study group. Because of the lack of accurate data on the overall membership of COMSEP, we are unable to determine if the present sample is representative of COMSEP membership or of all US/Canadian paediatric medical educators. Because burnout rates are known to be higher in physicians who are non‐White, the low diversity of respondents is also a limitation; if this lack of diversity is accurate, it demonstrates that we have work to do in improving the diversity of leadership in medical education as a means to widening the pathway and providing mentorship to students under‐represented in medicine.In 2017, 61% of the general adult working population reported satisfaction with work–life integration; however, only 40% of physicians did so and general paediatricians had approximately 50% satisfaction with work–life integration.5Paediatric medical educators report fewer burnout symptoms than their same‐specialty peers and other specialty educators. Working with students was rewarding and student‐related roles had positive impact, regardless of personal burnout symptomatology. Asking educators about EE towards students, feelings of DP towards students and feelings of guilt around working with students may help evaluate burnout. The positive, and perhaps protective, impact that working with students has on the wellness of the physician educators may support provision of protected time for physicians to dedicate to rewarding non‐clinical activities to improve their sense of autonomy and overall sense of well‐being. Respondents identified the difficulty in balancing their medical education and clinical roles and that achieving this was easier with dedicated educational time and administrative support. Similar to graduate medical education (GME) faculty, UME faculty would benefit from dedicated FTE and administrative support for their clerkship roles.UME faculty would benefit from dedicated FTE and administrative support for their clerkship roles.The authors have no conflict of interest to disclose.The study was deemed exempt by the University of Michigan IRB. All participants consent to the sharing and submission of their responses for publication when they complete the COMSEP annual survey.


Maternal parity, which is usually measured as the number of children born to a mother, has a substantial impact on the social and environmental factors around children and their development. This paper estimates the Early Childhood Development Index (ECDI) of 3‐ and 4‐year‐old children in Bangladesh and examines the relationship between maternal parity and early childhood development.The study analysed nationally representative data from the Bangladesh Multiple Indicator Cluster Survey 2019. The dataset had 9453 children aged from 36 to 59 months. The ECDI was computed following the UNICEF's approach involving psychometric computation of four domains of development: physical, literacy‐numeracy, learning and social–emotional. Since the dataset has a hierarchical structure, we used multilevel logistic regression.A quarter (25%) of the children were not on track in their early childhood development. Seventy‐one percent were not developmentally on track in the literacy‐numeracy domain, 27% were not in the social–emotional and smaller percentages were not in learning (9%) and physical (1%) domains. There was a significant negative association between maternal parity and ECDI . Attendance at early childhood education programmes was significantly associated with early childhood development . Also, female children, those who were not stunted, located in rural areas, received parental stimulation activities, lived in relatively wealthy households or had mothers who had received secondary or further education were more likely than others to be on track of early childhood development.Early childhood development is negatively correlated with maternal parity. The literacy‐numeracy domain constitutes the major developmental delay. Programmes for parental awareness should be widely expanded. A quarter (25%) of the children aged 36 to 59 months were not on track in their early childhood development.The literacy‐numeracy domain constitutes the major developmental delay.This study found a significant negative association between maternal parity and early childhood development.Early childhood education programmes, education for girls and the creation of parental awareness should be widely expanded.1There is growing evidence that early childhood is the most important developmental phase throughout the lifespan. Healthy early child development, which includes the physical, social–emotional and language‐cognitive domains of development, influences children's overall health and well‐being and establishes their developmental trajectories and life‐courses , which measures four areas of development: physical, literacy‐numeracy, learning and social–emotional. The resulting scores reflect whether children are developmentally on track in each of the four domains and overall. The ECDI reflects the population‐based normative distribution of developmental status  and these are then nested in the 64 administrative districts. Thus, we used multilevel logistic regression—both for overall ECDI and the four individual domains as outcome variables. We used a three‐level multilevel model: children (level 1), community (level 2) and districts (level 3). The main study factor, maternal parity, was included as a continuous variable in the regression models. Three models were developed. Model 1 was the null model and did not have any predictor variables, Model 2 examined the relationship between maternal parity and ECDI of their children and Model 3 was the final model that examined the relationship while being adjusted for other covariates.The general contextual effects have been estimated using the between‐neighbourhood variance and the median odds ratio . A quarter (25%) of the children were not on track in their ECDIs. Only 19% had ever attended early childhood education programmes. Table Univariate analysis with the ECDI and maternal parity shows a significant negative association. Figure p‐values of the likelihood ratio test were lower than 0.001 for all of these models, suggesting that the multilevel model is preferable to logistic regression. The random‐effects variance and median odds ratio indicate that the district‐level context has a substantial effect and is important for understanding children's ECDIs.Table The constant value of the intercept‐only model  is the estimated odds of early childhood development being on track for the children. The adjusted odds ratio (AOR) of Model 2 was 0.91 (95%CI: 0.87–0.94), which shows that maternal parity has a significant negative effect on the ECDI. The AOR in Model 3 shows that maternal parity is a significant factor in the ECDI. For every additional child, the odds ratio for a child being developmentally on track is reduced by 5%. In the final model, several other variables were found to have significant effects on children's ECDIs. Four‐year‐old children were significantly more likely than 3‐year‐old children to be on track in their early childhood development. Furthermore, female children  and those who had attended early childhood education programmes  were more likely than others to be developmentally on track. The higher the scores for parental stimulation activities in the previous 3 days, the more likely it was that the children were on track in their ECDIs . Children whose mothers had completed higher secondary or further education were also significantly more likely to be developmentally on track. There was a somewhat positive trend regarding household wealth status in terms of the ECDI, with AOR increasing gradually for the higher levels of wealth quintiles; however, the association was statistically significant only for children from the most affluent households. In addition, children living in rural areas were more likely to be developmentally on track than those in urban areas .Multilevel regression with the individual domains of the ECDI shows that the literacy‐numeracy and social–emotional domains were significantly negatively associated with higher maternal parity Table . Of thes4The findings of this study suggest that, overall, a quarter of the children were not on track in their early childhood development, which is much higher than is estimated in many other low‐ and middle‐income countries (Emerson et al., Our results suggest that literacy‐numeracy is the most challenging domain, which substantially delay children's development. McCoy et al.  argue thSeveral covariates in our study, including stunting, access to early childhood education, the household's wealth status, the mother's educational status and the location of the residence, have been consistently identified as important for early childhood development (Frongillo et al., While improving social conditions in low‐income countries takes time, at least some programmes can be established for parents from relatively low socioeconomic backgrounds, as they may not have the same access to health information as other families Begum, . Parenta2. We recommend further research to find causes for the association that was observed in our study. The expected benefit that would come from further research is important for Bangladesh and for similar countries.There could be several explanations for the negative association that was observed between the maternal parity and the ECDI. Since we had no information about the genetics of the children, and we examined only the psychosocial factors, one possible explanation is that of “resource dilution” Downey, , which rAn important finding of the multilevel regression is that the developmental scores of children living in rural areas were better than those in urban areas. This observation is quite the opposite of what has usually been observed in other settings (Gil et al., 5This study has several limitations. Firstly, this is a cross‐sectional study. Thus, the relationship between maternal parity and early childhood development is associational only. Secondly, although we adjusted the regression models for many potential confounders, it is not unlikely that some residual confoundings remain unadjusted. Future research should examine this relationship using a prospective cohort dataset. Lastly, the contemporary theoretical conceptualization of child development incorporates the biopsychosocial model of health, which puts importance on both nature and nurture. We were unable to account for the biological and genetic endowment of the children.6Our study found a negative association between maternal parity and early childhood development. Among the four domains of early childhood development, the performance in literacy‐numeracy was the worst. Several factors such as children's nutritional status, their attendance at early childhood education programmes, the parental stimulation activities they had, their mothers' education and their households' wealth status were significantly associated with early childhood development, and this highlights the importance of social determinants of health. While addressing all these factors may not be an achievable goal over the short term, particularly within the context of a developing country, ongoing efforts for early childhood education, education for girls and the creation of parental awareness should be widely expanded.Conceptualization: MMI; formal analysis: MMI; visualization: MMI; writing ‐ original draft: MMI; critical review: MMI, MNK.


The study reports a rare case of pelvic solitary fibrous tumor (SFT) that was initially considered as a peri‐anal gastrointestinal stromal tumor due to similar radiologic/pathologic features. SFT diagnosis can be challenging due to its rarity and wide range of diagnoses that must be ruled out precisely.Solitary fibrous tumors (SFTs) are rare tumors that can occur in any part of the body. Although usually benign, malignant SFTs have been reported, especially outside the lungs. Radiology can help with diagnosis, but immunohistochemistry is necessary to distinguish SFTs from other possible diagnoses such as gastrointestinal stromal tumors (GISTs). This study presents a rare case of pelvic SFT initially considered to be a peri‐anal GIST, highlighting the importance of accurate diagnosis given the rarity of SFTs and the need to rule out other potential diagnoses. Resected pelvic solitary fibrous tumor (SFT). The patient had no significant symptoms except slight generalized abdominal pain and peri‐anal discomfort and she did not state any previous experience of similar abdominal or pelvic pain and GI disorder in herself or her family members. All of the examinations including abdominal and rectal examinations were normal without any suspicious findings.All of the patient's medical data regarding CT scan, magnetic resonance imaging (MRI), sonographies, and angiography prior to angioembolization in addition to the final pathology and IHC results of the resected tumor, are provided in order in the following parts.First, a spiral thoraco‐abdomino‐pelvic CT scan with and without contrast was performed in which an infiltrative mass with the central necrotic components was found in the left peri‐anal region pressing the external anal sphincter. The mass had the size of about 96 × 66 × 48 mm growing to the perineal area causing superior displacement of levator ani on the left side; still, it had not shown any developments to the peri‐rectal region and is limited to the perineal region. Blood supply of the mass was provided by the left pudendal artery. No invasion to the muscles, bones, and other peripheral structures was mentioned and all other organs and structures were completely intact Figure . After tAfter complete tumor resection Figure , the pel3SFT is a spindle‐cell fibroblastic mesenchymal neoplasm that can affect almost all anatomic sites but most commonly occurs in visceral pleura.In addition to the rarity of this neoplasm, SFT has a wide range of differential diagnoses that make accurate SFT diagnosis more challenging. Indeed, imaging studies along with considering related clinical features may lead to SFT diagnosis; but a definite diagnosis should be confirmed through IHC evaluations in order to differentiate it from other mesenchymal tumors with similar sources.Complete resection is the choice treatment strategy for SFTs that is connected to patients' prognosis4SFT can be introduced as a rare and slow‐growing metastasizing fibroblastic mesenchymal neoplasm having a variety of differential diagnoses and can mimic other tumors' characteristics. Although its diagnostic processes may benefit from radiologic evaluations in the first steps, IHC studies have shown great importance in distinguishing it from other diagnoses due to diagnostic challenges.Seyed Amir Miratashi Yazdi: Conceptualization; writing – review and editing. Roudsari Payvand Parhizkar: Conceptualization; writing – original draft; writing – review and editing. Hadi Ahmadi Amoli: Conceptualization; supervision. Reza Hajebi: Conceptualization; writing – review and editing.This study received no funding or financial support.The authors declare that there is no conflict of interest.The study was performed regarding the ethics committee of Tehran University of Medical Sciences.The authors have confirmed that patient consent has been signed and collected in accordance with the journal's patient consent policy.


This case report describes a successful procedure involving pulmonary vein isolation (PVI) and left atrial appendage (LAA) closure with a watchman device in a 78‐year‐old male with atrial fibrillation and an interrupted inferior vena cava. Due to the vascular anomaly, a transhepatic approach was used, which proved successful. These instances include chronic venous occlusion, interrupted inferior vena cava (IVC), and venous heterotaxia syndrome, a rare congenital disease with the abnormal arrangement of thoracoabdominal organs across the left to the right axis.We reported a case series of three patients previously who had interrupted IVC and required left atrial ablation. We performed the ablations successfully through hepatic vein cannulation and reported the characteristics of that approach.2DS2‐VAScA 78‐year‐old Caucasian male with a known history of symptomatic paroxysmal atrial fibrillation (afib) and New York Heart Association (NYHA) class II congestive heart failure presented with exertional palpitations and associated fatigue. He had documented history of paroxysmal afib for 2 years with progression to persistent afib in the preceding 3 months. Amiodarone and direct current cardioversion (DCCV) twice failed to maintain sinus rhythm. The patient was therefore referred for pulmonary vein isolation (PVI). He was also a candidate for LAA closure due to CHADue to recurrent symptoms and inability to tolerate anticoagulation, it was decided to proceed with trans‐hepatic access for atrial fibrillation ablation and implantation of the watchman device simultaneously. Right internal jugular (IJ) access was obtained under ultrasound guidance. The coronary sinus (CS) catheter was inserted through the right IJ access and placed into the CS under fluoroscopy. Transhepatic venous access was obtained by interventional radiology (IR) under fluoroscopy as shown in the images. A 22‐gauge Chiba needle was used to target the right hepatic vein, and a 0.014‐inch wire was negotiated through the right hepatic vein into the IVC. A NEFF set (Cook) was then introduced through which the Swartz Braided SL Trans‐septal Guiding Introducer Sheath (SL1) guidewire was negotiated through the IVC and right atrium (RA) with its tip placed in the superior vena cava (SVC). SL1 sheath was then advanced over the guidewire that was placed by IR into the SVC. Transesophageal echocardiography (TEE) was used for guidance of transseptal access. A single transseptal puncture was performed after adequate anticoagulation with intravenous heparin. An almost horizontal and significant anterior projectory of the SL1 sheath placed in the right atrium necessitates rotating the sheath posteriorly, significantly beyond the level required during the conventional approach  was mapped, and CTI ablation was done in a standard fashion. Due to the almost 90‐degree angle between the catheter entrance projection and the CTI line, we had to use an exaggerated bend in the ablation catheter Figure .The transhepatic access was then closed by IR using two 8 mm Amplatzer Vascular Plugs type 4 (Abbott) which were deployed in the access tract through the access sheath, followed by Gelfoam injection under fluoroscopic guidance. Post‐embolization contrast injection revealed successful embolization of the tract through coils placement and injecting foam into the transhepatic access for hemostasis. The 14‐French venous sheath was then removed completely. The patient tolerated the procedure well and was discharged home after 3 days to allow for dofetilide loading without any complications.2Here we presented a PVI + Watchman implantation case with interrupted IVC, and we proceeded through transhepatic access to overcome this particular challenge. This has been described before for ablation purposes, but we here discuss using it for occlusion device placement and elaborate on some techniques that could help these patients. The first challenge in the case was proceeding with the transseptal access due to the difficult and unusual alignment of the transseptal access system and the usual human atrial septal anatomy. In this situation, after the initial septostomy with the needle and the dilator, pointing the dilator toward the right upper pulmonary vein can help pass the sheath through the transseptal access. The second important challenge in the case was the difficulty in the positioning of the watchman delivery system into the left atrial appendage. Here we described the use of the mapping catheter as a steerable body to guide the sheath into the left atrial appendage. After placing the sheath inside the LAA, the delivery of the watchman device was uneventful, possibly due to the dominant anterior wing, which was aligned with the projectory of the sheath.Based on our experience, we recommend using a short deflectable agilis or any other 8.5 French deflectable sheath when using this approach due to the proximity of transhepatic access to the point of entry of the catheter to the skin compared to the groin access. This will help leave less excessive length of the sheath outside the skin entrance and offers better maneuverability. In addition, for our next case, we may ablate the CTI line using a Swartz Right (SR) 3 or 4 prior to septostomy. As shown in (Figure Performing afib ablation combined with the placement of the Watchman device for LAA occlusion has been evaluated before, with results showing evidence of safety and ability to perform.Sameh Girgis: Writing – original draft. Negar Niknam: Writing – review and editing. Zabeer Bhatti: Writing – original draft. Jalal Mohsin: Data curation. Ahmed Kamel Abdel Aal: Resources; supervision. Ramesh Hariharan: Resources; supervision. Khashayar Hematpour: Project administration; supervision; writing – review and editing.None.All authors declare that they have no conflicts of interest.Written informed consent was obtained from patients to publish this report in accordance with the journal's patient consent policy.


Interference competition has the potential to alter avian assemblages at long‐lasting arid zone waterholes, particularly in a warming world, as more potentially aggressive species frequent these sites to drink. We used camera traps and observational surveys to investigate interference competition between terrestrial avian species at six long‐lasting waterholes across three sampling seasons (two summers and one winter) within the MacDonnell Ranges Bioregion in central Australia. The proportion of individuals drinking for each of four dietary classes  was modelled in relation to their abundance in the immediate waterhole habitat, which informed the potential for competition in each season. We then used the temporal overlap estimators to quantify the degree of competition between species at waterholes with species grouped into families . We found the proportion of individuals drinking at waterholes was greatest during hot and dry periods, suggesting the potential for interference competition is greatest during these times. This was particularly the case for nectarivores where, in hot and dry conditions, the proportion of drinking individuals increased significantly as their abundance also increased in the waterhole habitat. We predicted that subordinate species would alter their activity periods to avoid competitive interactions with meliphagids (honeyeaters), however, we found there was a high degree of temporal overlap between all families sampled across all seasons. These results suggest subordinate species are unlikely to be excluded from long‐lasting waterholes by potentially aggressive species, such as honeyeaters. However, some species may face trade‐offs between foraging and accessing waterholes to stay hydrated as they shift their activity to avoid the hottest parts of the day during the summer months. Under global warming, extended hot and dry periods will likely create conditions where balancing energy and hydration requirements becomes increasingly difficult and results in the loss of body condition. Interference competition has the potential to alter avian assemblages at long‐lasting arid zone waterholes. However, we found there was a high degree of temporal overlap between the species drinking at our study sites. Our results suggest subordinates are unlikely to be excluded from long‐lasting waterholes by aggressive honeyeaters. CompetiLong‐lasting waterholes in arid zone environments are areas where interspecific and competitive interactions can occur, particularly during hot and dry periods, when surface water in the surrounding landscape is scarce. Both population densities and the time individuals spend in these habitats can increase during periods of water scarcity  granivores under all seasonal weather conditions; and (b) nectarivores and omnivores as weather conditions became increasingly hotter and drier. We did not anticipate changes in insectivore drinking under any seasonal weather conditions because of the higher water content of their diet. Finally, we predicted that selected species of granivores, omnivores, and insectivores – the Estrildidae (finches), Ptilonorhynchidae (bowerbirds), and Rhipiduridae (wagtails) – would shift their temporal niches to avoid competitive interactions with aggressive nectarivores – the Meliphagidae (honeyeaters) – as the number of meliphagids drinking at waterholes increased during hot and/or dry periods.22.1The MacDonnell Ranges Bioregion contains the largest collective group of mountains in central Australia and includes several distinct range systems. The ranges are rugged and rise to elevations of 1531 m above sea level (Mount Zeil). The climate in this bioregion is considered arid, but the mountains are high enough to generate greater average annual rainfall  than experienced in the surrounding drylands and deserts  but long‐lasting waterholes. Here, we define long‐lasting as persisting for several years, even if minimal rainfall is received. Three sites were in the West MacDonnell Ranges, within the Tjoritja/West MacDonnell Ranges National Park and three were in the George Gill Range, within Watarrka National Park , winter 2018 (from July to the end of August), and summer 2019 (from January to the end of February). Four direct  surveys were conducted at each site within each sampling season; two surveys at the beginning of each sampling season and two at the end of the season, coinciding with the days that the cameras were either deployed or removed from the study sites. The two surveys (one morning survey between 7 am and 9 am and an afternoon survey between 3 pm and 5 pm) were conducted at times of the day when birds are known to be active at waterholes , were identified to species, along with the time at which they were sighted, the number of individuals, and their behaviours  were recorded. Species were identified from their appearance with reference to Pizzey et al.  or via tA 5‐min event window was applied to species observed via direct surveys. Once a particular species was recorded, a five‐minute window had to lapse before a record of the same species could be counted in the next independent sampling event (ISE). This enabled us to estimate the frequency of visits for a given species to the sampled waterhole sites and corresponded to analyses of camera data. Birds were classified into five dietary classes: insectivores, granivores, carnivores, insectivores or omnivores  triggered (Reconyx HyperFire HC600 and Ltl Acorn 5210A) camera traps were used to record the presence of avifauna at each site. Camera traps were set up in a systematic manner (between 10 and 20 m apart depending on the size of the waterhole) to cover as much of the perimeter of the waterhole as possible. A total of 39 cameras were deployed across the sampling sites during each sampling period. The number of cameras varied per site from four to nine, depending on the size of the waterhole. Of the 39 cameras deployed across the sampling sites, six were Reconyx and 33 were Ltl Acorn. Reconyx cameras were used at sites where there were not enough Ltl Acorn cameras to provide full coverage, and no more than two Reconyx cameras were used at any one site.Cameras were mounted on stakes and positioned approximately 1.5 m away from the water's edge and 30–40 cm above the ground. This distance and height were selected so that the cameras' PIR sensors were aligned parallel to the waterline, such that they were at the optimal position to detect both the small and large birds that accessed the study sites  and the method described by Hendry and Mann . A trap We were unable to test for differences in activity periods between seasons by combining species at the dietary class level. This was because the activity periods for species within a given dietary class were often different . Species within the same taxonomic family showed similar activity periods at waterholes. Therefore, select species from each dietary class were further sorted into their respective taxonomic families  where camera trap data were used to analyse temporal overlap Table .2.5Mean maximum temperature and rainfall data for the Watarrka and Tjoritja/West MacDonnell Subregions (TWMSR) were obtained from the Australian Bureau of Meteorology 015652 , 015667  and 015590  weather stations , and the jth dietary class  within the nth site . yijn follows a binomial distribution with mean np, and a variance of np1−p. The logit of pijn is modelled by a regression equation with βs as the intercept for the sth season , βh is the slope (regression coefficient) of the hth predictor (h = 1), xhijn is the is ith response of the jth avian dietary class within the nth site for the hth predictor. an is the site‐specific random effect, which is assumed to be normally distributed with mean 0 and variance σ2.For each dietary class, generalised linear mixed models (GLMMs) with binomial distributions were used to model the proportion of individuals drinking at waterholes in relation to those observed in the immediate waterhole habitat. Modelling was carried out following the method of Zuur et al.  and BrooResidual patterns and deviations from the expected binomial distributions were examined for each GLMM applied to our dataset using R package DHARMa  by GLMMs applied to avian dietary classes were determined following the methods of Nakagawa and Schielzeth  and ∆^4 (Dhat4). We used Dhat1 for smaller sample sizes (under 50) and Dhat4 for larger sample sizes (over 50).Camera trap data were used to estimate temporal overlap of the Meliphagidae in relation to members of Estrildidae, Ptilonorhynchidae, and Rhipiduridae. Temporal overlap was quantified using the R package, CamtrapR  were recorded from 144 hours of direct observational surveys, which resulted in 7544 ISEs being recorded across all study sites and seasons. Camera traps recorded 49 species (excluding waterbirds), which were captured by 39 camera traps deployed for a total of 98,280 camera trap hours. Camera traps recorded more than 185,000 images and 14,119 ITEs from the six study sites across three sampling seasons Table .The seasonal rates of species accumulation were similar at waterholes across the MacDonnell Ranges Bioregion, with higher rates occurring during the summer seasons. Of the two summer seasons, accumulation rates were slightly greater during the hotter and drier summer 2019 season, and approximately five additional species were recorded across most sites at this time. Rates of accumulation were generally higher at the Tjoritja/West MacDonnell National Park sites, particularly during the summer 2019 season. Most of the smoothed curves did not reach an asymptote, particularly within the summer 2019 season, where accumulation rates were still increasing at the end of the sampling periods Figures .The proportion of individuals drinking at sampled waterholes within each dietary class differed significantly between seasons (model intercepts). The proportion of individuals drinking at sampled waterholes was significantly greater for all dietary classes in the summer 2019 season compared to the summer 2018 season. The proportion of granivores and omnivores drinking was also significantly greater during the winter 2018 season compared with the summer 2018 season. Granivores were the only dietary class where the greatest proportion of individuals drinking was observed during the winter 2018 sampling season Table .While the proportions of individuals drinking at waterholes varied significantly between seasons relative to those present in the surrounding habitat (not drinking), the slopes of the relationships between these variables (within seasons) were not significant in most cases. The exception was that during the summer 2019 season the proportion of nectarivores drinking increased significantly relative to the number of individuals (ISEs) sampled within the waterhole habitat. The relationship was linear and the proportion of individuals drinking increased from 30% to 60% as sampling events approached 120 Figure .The family classes, as sampled by camera traps, within this study displayed varied activity patterns across seasons. Estrildid (finch) species showed consistently similar patterns of activity across all seasons, with activity peaking at around 12 pm. Species within Ptilonorhynchidae and Rhipiduridae displayed similar activity patterns where, in the summer seasons, their activity densities were bimodal and peaked in the mornings and afternoons. The activity densities of Meliphagids were also bimodal during the summer 2018 season, however, they did not retain this pattern across the remaining seasons, adopting unimodal density pattens that peaked around 12 pm and declined steadily across the afternoon. Activity densities were similar  for all sampled family classes, with their activity densities peaking around 12 pm Figure .The extent of overlap between estimated activity of the Meliphagidae and other families also varied across seasons. The greatest overlap between each family occurred during the winter season, where estimates ranged between 0.83 and 0.88. Activity overlap between Meliphagidae and Ptilonorhynchidae reduced in the summer seasons, with the summer 2019 season showing the greatest reduction in overlap as both families shifted to a bimodal activity distribution (overlap estimates 0.65 and 0.68). Meliphagidae overlap with the Estrildidae was consistently high across all sampling seasons, ranging from 0.78 to 0.83.4Our study examined surface water use and interference competition between avian species at arid zone waterholes under varying seasonal conditions. We found that the number of species present at waterholes was greatest in the second summer and of the individuals present, the proportion drinking was also greatest for most dietary classes at that time. These results were consistent with the increasing need for water under hot dry conditions. However, in many cases, as drinking activity increased, so did the degree of temporal overlap between family classes, indicating that interference competition may not be as important as originally predicted. This result was unexpected, particularly for nectarivores (Meliphagidae), which are known to display aggressive interactions with other species when foraging  suffered reductions in body condition in high temperatures, particularly under repeat exposure to daily maximum temperatures over 35°C. However, this decline was only found under low‐rainfall conditions when no rain had fallen for a period of 30 days or more.The exception in this study was nectarivores within the summer 2019 season. Our model had predicted that as the number of individuals increased within the immediate waterhole habitat, up to 60% would be drinking. These predictions were consistent with previous evidence that showed nectarivores increased their visitation to waterholes under similar conditions  and Brown Goshawks  or distributions skewed toward the early morning (Meliphagidae) in the hot summer months suggests the species in these families modify their behaviour to avoid activity during the hottest part of the day. Other studies have shown that avian foraging rates can decline as air temperatures become exceedingly hot  were present. Camels are particularly prevalent in arid Australia outside of managed national parks. As all the study sites sampled as a part of our study were within national parks, we did not detect any camels at the study sites. Raptors on the other hand were present at the waterholes at some times, and the frequency of their visits was highest during the hot and dry summer of 2019. The diel activity of ambush predators including the Brown Goshawk and Collared Sparrowhawk was highest during the middle of the afternoon ; formal analysis (lead); funding acquisition ; investigation (lead); methodology (lead); project administration (lead); writing – original draft (lead); writing – review and editing (lead). Christine Schlesinger: Conceptualization (supporting); formal analysis (supporting); funding acquisition (supporting); investigation (supporting); methodology (supporting); resources (supporting); supervision (supporting); writing – review and editing (supporting). Fiona Dyer: Conceptualization ; investigation (supporting); methodology (supporting); resources (supporting); supervision (supporting); writing – review and editing (supporting). Valerie Caron: Conceptualization (supporting); funding acquisition (supporting); methodology (supporting); supervision (supporting); writing – review and editing (supporting). Jenny Davis: Conceptualization ; formal analysis (supporting); funding acquisition ; investigation (supporting); methodology (supporting); resources (lead); supervision (lead); writing – review and editing (supporting).6This study was funded by an Australian Postgraduate Award and a generous donation from an anonymous donor (see acknowledgements). No external research grants were received for this study.Appendix S1Click here for additional data file.Figure S1.Click here for additional data file.Figure S2.Click here for additional data file.Figure S3.Click here for additional data file.Figure S4.Click here for additional data file.Figure S5.Click here for additional data file.


This case report offers support for treatment approaches in a historically rare and very difficult to treat CLL patient population with no established guidelines.Central nervous system involvement of chronic lymphocytic leukemia is a rare condition. Its diagnosis is often challenging, and treatment can be difficult with a lack of established guidelines. We describe a case of a 76‐year‐old male Caucasian with known chronic lymphocytic leukemia for more than 25 years, initially treated with chlorambucil. Upon first clinical relapse, cytogenetic analysis and fluorescence in situ hybridization combined showed three different abnormalities (complex karyotype), suggesting a poor prognosis. He was started on ibrutinib but developed an out‐of‐hospital cardiac arrest due to ventricular fibrillation 2 months later. Ibrutinib treatment was consequently discontinued. Due to the seriousness of the adverse event and the lack of apparent treatment indication after rapid improvement on ibrutinib, a watch‐and‐wait approach was maintained. Four years later, he developed progressive cognitive impairment, a balance disorder, and a peripheral facial nerve palsy. Anamnesis further revealed significant progressive weight loss. Routine blood tests did not show any abnormalities, but brain magnetic resonance imaging showed focal staining of cranial nerves and leptomeningeal staining. Cerebrospinal fluid analysis revealed the same monoclonal B‐cell lymphocytosis as that was already known to be present in the peripheral blood. Further analysis ruled out sample contamination or other conditions. PET‐CT scan revealed an increased uptake in the liver, and biopsy confirmed infiltration of chronic lymphocytic leukemia at the site. The patient was first started on treatment with intrathecal administration of dexamethasone, cytarabine, and methotrexate. This did not result in complete clearance in the cerebrospinal fluid. Next, oral venetoclax was initiated, resulting in rapid clearance and clinical resolution. Venetoclax, administered orally, was able to achieve clearance of the monoclonal B‐cell lymphocytosis from the cerebrospinal fluid as well as clinical response of neurological symptoms. Response was durable with persistent remission at 1 year of treatment. Brain MRI, transverse plane. Staining of multiple cranial nerves (arrow). He received chlorambucil at the time of diagnosis after which he stayed in a durable remission, occasionally needing intravenous immunoglobulins because of secondary hypogammaglobulinemia with respiratory infections. In 2005, a bone marrow examination was performed, revealing a complex fluorescence in situ hybridization (FISH) pattern with a trisomy 12 in 14/60 interphase nuclei, a deletion of 17p13.1 in 5/100 interphase nuclei and a deletion of 13q14, or monosomy 13, in 14 and 3/60 interphase nuclei. In 2017, he developed a rapidly progressive, symptomatic lymphadenopathy in his left groin. Peripheral blood counts stayed normal without lymphocytosis or cytopenia, but flow cytometry revealed a monoclonal B‐cell lymphocytosis compatible with CLL (Catovsky ≥ 4). Biopsy revealed an invasion of CLL with similar immunophenotype as peripheral blood without signs of transformation. Cytogenetics revealed trisomies 12 and 19, and FISH analysis showed a deletion of 13q14. The presence of three cytogenetic abnormalities (complex karyotype) is associated with poor prognosis.In 2021, at the age of 76, the patient presented at the emergency department with progressive cognitive impairment as well as a balance disorder and a peripheral facial nerve palsy of unclear onset and was hospitalized on the neurology ward for further investigations. Anamnesis revealed no recurrent fever or night sweats, but there was unintentional weight loss of 17 kg over the course of one and a half years . There were no apparent palpable lymphadenopathies or splenomegaly on clinical examination. Magnetic resonance imaging of the brain showed staining of multiple cranial nerves with focal leptomeningeal staining in the right sulcus callosus, suspect of leptomeningeal lymphoma deposits  CLL, a bruton kinase inhibitor would be the preferred treatment option for this 76‐year‐old patient with a CLL with poor cytogenetics with established CNS involvement.We report on a different treatment strategy used in this case consisting of venetoclax in combination with intrathecal dexamethasone (4 mg), methotrexate (15 mg), and cytarabine (40 mg). The patient was first started on intrathecal (IT) chemotherapy alone on a weekly basis because of his frailty profile. A total of six IT regimens were administered. Minimal residual disease was still detected by flow cytometry on the CSF before initiating the venetoclax ramp up to 400 mg once daily. After 1 month of (ramp‐up) venetoclax, the CSF was cleared. Because of a low‐symptomatic COVID‐19 infection, rituximab was not associated as per the initial plan. Over the next few months, the patient improved considerably with clear improvement of the neurologic symptoms and Montreal Cognitive Assessment, and he had a weight gain of 10 kg. Overall, the treatment regimen was very well tolerated. Repeated flow cytometry on the CSF showed a durable response almost 1 year after start of treatment. Follow‐up PET‐CT after 1 year showed no more aberrant uptake in the liver or anywhere else.3Our rationale for choosing the BCL‐2 inhibitor venetoclax as treatment strategy for our patient was based on a few reports in the literature. There is circumstantial evidence from studies in other hematologic malignancies that oral venetoclax administration can lead to penetrance through the BBB. Venetoclax is briefly discussed in Blood (2018) as an interesting agent for primary central nervous system lymphoma (PCNSL).Few other case reports mention the use of venetoclax in CNS involvement of CLL. One discusses a patient with CNS involvement of CLL treated with ibrutinib who experienced a relapse of neurological symptoms and the reappearance of a monoclonal B‐cell population in the CSF after 4 years. Venetoclax was added to ibrutinib, and this resulted in an ongoing, complete response.Currently, there are also two clinical trials running using venetoclax in combination with other treatment modalities in CNS lymphoma. The first trial evaluates venetoclax plus obinutuzumab for relapsed/refractory PCNSL (VENOBI‐CNS). This is a phase IB study to assess the pharmacokinetics in the CSF.4In this case report, the clinical response as well as the durable response in CSF clearance attribute to the potential importance of venetoclax in patients with CLL with associated symptomatic CNS involvement. It offers support for treatment approaches in this historically rare and very difficult‐to‐treat CLL patient population with no established guidelines. Further research is necessary in order to determine the role of venetoclax in CNS involvement by CLL more precisely. Since adequately powered interventional studies in this rare disease setting are difficult to achieve, observational studies, either prospective or retrospective, offer more approachable research potential. A multicenter prospective observational research trial on CLL patients with established CNS involvement receiving a venetoclax‐based regimen seems to be a feasible study design and is likely to give more answers.Rosina Dewaide: Conceptualization; investigation; writing – original draft; writing – review and editing. Kirsten Saevels: Supervision.The author(s) received no financial support for the research, authorship, and/or publication of this article.The author and co‐author state that they have no conflict of interest.Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.


ILD) following amiodarone treatment for variable lengths of time with different dosages. The presentations on computed tomographic images and in pulmonary pathology differed among the three patients. All three had immediate discontinuation of amiodarone and received treatment with systemic corticosteroids. One patient eventually died from ventilator‐associated pneumonia after an initial improvement. The other two patients recovered well but later experienced ILD recurrence following brief re‐exposure to amiodarone. Through this case series, we aim to demonstrate the variable features of amiodarone‐related ILD, and highlight the importance of timely amiodarone cessation and avoiding re‐exposure to prevent the progression and recurrence of ILD.Amiodarone is a commonly used antiarrhythmic agent but exhibits potential pulmonary toxicity. In this case series, we describe the clinical, radiographic, and histologic manifestations of three patients who developed interstitial lung disease ( Amiodarone‐related interstitial lung disease may exhibit variable clinical, radiographic, and histologic presentations. Prompt discontinuation and avoiding re‐exposure of the agent is important to prevent the progression and recurrence of the interstitial lung disease. Amiodarone is a commonly used antiarrhythmic agent, owing to its efficacy and the convenience in its administration and dosing titration. However, the agent exhibits potential toxicity to multiple organs including the lungs, and there have been reports of respiratory complications following treatment with amiodarone even at low doses.A 62‐year‐old man was transferred to our hospital in August 2020, presenting with rapidly progressive bilateral pneumonia and the associated acute respiratory failure. The initial thoracic computed tomography (CT) showed ground‐glass opacities and dense consolidations involving both lungs Figure  and diffA 72‐year‐old non‐smoking male had his first episode of amiodarone‐related ILD in May 2012, after 18 months of amiodarone therapy  for Af. His symptoms were relatively mild . Serological surveys reported negative results for CTD‐related autoantibodies. The thoracic CT revealed multiple scattering ground‐glass and alveolar‐consolidating opacities and ill‐defined nodules in bilateral lungs Figure . ClusterA 65‐year‐old non‐smoking male had been treated with amiodarone (100–200 mg/day) for paroxysmal Af since February 2019. In May 2020, he presented with a non‐productive cough, exertional dyspnea, and hypoxemia (with the pulse oximetry measuring 89%–92%) while breathing ambient air that had progressively aggravated over several weeks. He was afebrile and exhibited no symptoms, signs, or serological evidence of CTDs. The chest radiograph showed extensive ill‐defined opacities in both lung fields Figure , while tAmiodarone exhibits potential pulmonary toxicity, though the exact pathogenesis is still not fully elucidated. Proposed mechanisms of alveolar epithelial injury (which elicits subsequent inflammatory reactions) include intracellular oxidative stress relating to the iodine‐moiety of amiodarone, impaired organelle functions and phospholipid metabolism due to the amphophilic structure of amiodarone, dysregulated autophagy, and epithelial apoptosis possibly mediated by angiotensin‐2 associated pathways.The CT features of all three patients were compatible with that of organizing pneumonia with mixed patterns and multi‐lobe involvement. It has been reported recently that organizing pneumonia that manifests on CT images as mixed patterns and extensive involvement is more likely to be secondary than cryptogenic when compared to organizing pneumonia presenting solely with limited alveolar consolidation.Case 1 presented a rapid and severe form of ILD, whereas the ILDs in cases 2 and 3 exhibited a relatively subacute course. These differences demonstrate the wide variability in the severity and presentations of drug‐induced ILDs among different individuals. Moreover, case 2 and case 3 had a recurrence of the ILD after re‐exposure to amiodarone. Even though case 2 had already stopped taking amiodarone for more than 8 years, the re‐exposure quickly led to a recurrent ILD that appeared even more extensive than in the first episode. Furthermore, the recurrent ILD in case 3 quickly resolved after the mere discontinuation of amiodarone, even without corticosteroid treatment. These clinical features of our patients highlight the key point in managing drug‐induced ILD, which is the prompt removal of the triggering agent and the avoidance (as possible) of any subsequent re‐exposure.In conclusion, we describe in this case series the different clinical, CT, and histologic presentations of three cases of amiodarone‐related ILDs, which can be quite variable from patient to patient. Clinicians treating patients with amiodarone must be alert to the potential pulmonary toxicity of this agent regardless of the dosing regimen and involve amiodarone‐related ILD as a major differential diagnosis when the patients exhibit unexplained respiratory or radiographic abnormalities. For patients who develop ILD, timely discontinuation of amiodarone and the avoidance of future re‐exposure is critical.I‐Lin Tsai and Tang‐Hsiu Huang contributed to the concept, clinical data collection and review, and the drafting of the manuscript. Li‐Ting Huang contributed to the collection and curation of radiographic images and the editing of the pertinent descriptions. Yu‐Ting Yu and Chung‐Ta Lee contributed to the collection and curation of histological and electron microscopy images and the editing of pertinent descriptions. Tang‐Hsiu Huang contributed to the critical review of the manuscript and the correspondence.None declared.The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.Parts of the information described in this case series were presented in a thematic poster in the 2022 Annual Congress of Taiwan Society of Pulmonary and Critical Care Medicine.


To develop appropriate use criteria (AUC) for the treatment of basal cell and squamous cell carcinoma by superficial radiation therapy (SRT) technique.Delphi‐type discussion of the experts.Presented in Figure 1.These AUCs are in compliance both with the position statement of the American Academy of Dermatology (AAD) and the ASTRO Clinical Practice Guideline on this subject. It is further recommended that SRT will be only performed by either a dermatologist who is board certified in Mohs surgery (MDS) and who had adequate SRT training or by radiation oncologists. Hopefully, this publication will stimulate further discussion on this topic. Alexander Zemtsov is a board‐certified Mohs surgeon who has been using SRT since 1990 ; he is also one of the first physicians in the US to develop expertise in high‐frequency skin ultrasonography (HFUS).3When evaluating patients for SRT we use the criteria shown in Figure Optimally SRT should be administered only by either a board‐certified Mohs surgeon who had adequate SRT training or by radiation oncologists. Furthermore, appropriately trained physicians should work with medical physicists trained and experienced in SRT. SRT should be offered as a treatment option because of medical indications not because a physician lacks appropriate surgical skills. SRT training may be incorporated into both a dermatology residency curriculum as well as Mohs training. HFUS technique, originally developed by European dermatologists, is used for determining the tumor depth prior to initiation of radiation therapy and for monitoring cancer response to SRT,Further studies are needed to document the efficacy of SRT in the management of large, difficult‐to‐resect lentigo maligna/melanoma in situ tumors and the utility of SRT as a postoperative adjuvant therapy to minimize the chance of recurrence in these cancers. The optimal KeV for lentigo maligna is in the 10–20 range – this SRT regimen for this indication is widely used in Europe.Our final recommendations (not related to SRT AUC criteria).In summary, the authors provided their suggested guidelines for the appropriate use of SRT in the management of skin cancers. Hopefully, this manuscript will stimulate further research and discussion on this subject.


Chronic consumption of sodium in quantities exceeding recommendations has led to sodium being designated as a nutrient of health concern for overconsumption. As a result of the prevalence of sodium overconsumption, the Food and Drug Administration (FDA) released voluntary sodium reduction goals for a wide variety of products on both short‐ and long‐term timespans. As food palatability may decrease when sodium is reduced, flavor enhancers such as monosodium glutamate (MSG) may provide a promising solution to mitigate such palatability loss. The objective of this research was to investigate consumer acceptance of white and multigrain breads with either a 43% or 60% reduction in sodium content and with and without MSG as well as to investigate the influence of information on consumer acceptance of these breads under blind, informed, and informed with education conditions. Seventy‐eight frequent bread consumers participated in the evaluations. A significant difference was evidenced across breads with different levels of sodium content and MSG status, although no difference was seen across the different evaluation conditions. Consumer segmentation found multiple consumer clusters showing different liking patterns of the bread treatments for both white and multigrain breads. Breads with sodium content set at the FDA's long‐term goal with and without MSG were liked no differently in nearly all attributes evaluated than the full‐sodium bread demonstrating the feasibility of producing acceptable reduced‐sodium breads. Future research characterizing the predominant sensory attributes of full‐sodium and reduced‐sodium breads with and without MSG would be valuable for identifying the drivers of liking in such products.Practical Application: The findings of our study suggest that consumer liking of reduced sodium white and multigrain breads could be improved with the addition of monosodium glutamate. Increasing the acceptance of reduced sodium food products could help to reduce the risk of hypertension and subsequently heart attacks and stroke for the American population. In total, 78 panelists were recruited in this study . Females in this study were younger than males on average, with 78% of females between the ages of 18 and 25, and 53% of males between the ages of 26 and 35. This experimental protocol was reviewed and approved by the Institutional Review Board.2.2White bread and multigrain bread loaves were formulated to contain various levels of sodium chloride (NaCl) and MSG. For white bread, samples prepared included one treatment containing the average amount of sodium for bread, two breads with reduced sodium content adjusted for the FDA's 2.3oF water. The multigrain bread loaves were composed of all the ingredients used in producing the white bread loaves, with the addition of whole wheat flour  and 5 grain cereal . Ingredients were loaded into the bread pan by order of liquid ingredients, followed by dry ingredients, and lastly yeast.The white bread loaves were composed of bread flour , nonfat powdered dry milk , unsalted butter , MSG fine crystals , granulated sugar , vital wheat gluten , rapid rise yeast , vitamin C , and 95 Tables 2.4Consumer testing took place in a sensory lab on the University of Illinois at Urbana‐Champaign campus. Objective 1 was accomplished by conducting consumer evaluations of both multigrain bread and white bread under conventional blind tasting condition. Objective 2 was accomplished by conducting consumer evaluations of white bread under informed condition, followed by consumer evaluations of white bread under education condition. This experimental design is illustrated in Figure In the first session, acceptance was assessed in a conventional consumer test protocol of a blind condition. Panelists first evaluated the five white bread samples for overall acceptance on a 9‐point hedonic scale  has been recognized as safe for consumption for the general population by the United States Food and Drug Administration . Analysis of Variance (ANOVA) was used in analyzing the comparison of results among samples and conditions. A three‐way mixed model ANOVA was conducted with condition and sample as fixed factors and panelists as a random factor. The significance level was set at 0.05. Fisher's least significant difference was used for conducting the mean separation test with a 95% confidence interval. Panelists were then grouped according to their overall liking scores based on sample and condition for agglomerative cluster analysis.33.1F‐values across all conditions for white breads are shown in Table The consumer liking F‐values for multigrain breads are shown in Table The consumer liking 3.2Overall liking ratings within the informed and informed with education conditions are shown in Table Similar to the informed condition of the white breads, there was no condition×sample interaction found, and thus consumers were not significantly influenced by the information combined with education. As seen in the previous conditions, samples in the informed with education condition were found to have significant differences in liking. The moderately reduced sodium bread sample without flavor enhancement (LT) was found to be liked the most, followed by its MSG‐containing counterpart (LTMSG) and then the full sodium bread, although not significantly. The two samples with the greatest level of sodium reduction (XT and XT+MSG) were both liked significantly less than LT, although not differently compared to LTMSG or the full sodium bread Table . The lac3.3n = 35) or the informational flyer (n = 40) as their chosen mode of education, with the audio clip rarely selected (n = 3). Only samples evaluated under the flyer and video clip selections were found to be significant, although the small number of panelists who selected the audio clip likely limited any differences across the samples to become significant. Consumers who selected the flyer as their choice of education liked the moderately reduced sodium bread most, followed by the full sodium bread, although the difference in liking was not found to be significant. Although the moderately reduced sodium bread with MSG was liked less than its non‐MSG counterpart, it was liked no differently than the full sodium bread. Both breads with significant sodium reduction were liked significantly less than both the full sodium bread and the bread with a moderate level of sodium reduction and no MSG , panelists who rated all samples highly , and panelists who liked higher sodium  clusters emerged. Cluster 3 was the largest with over half of the panelists, followed by cluster 2, and last cluster 1.Panelists were clustered according to their overall liking ratings across conditions shown in Figure n = 46), panelists who liked higher sodium , and panelists who liked reduced sodium breads with or without MSG . After revealing ingredient information, the number of panelists who liked higher sodium  decreased indicating the influence of sample knowledge of sodium content on reducing the liking of full sodium samples. Additionally, more panelists fell into the cluster 1 (n = 46), which liked MSG samples the least, than in the blind condition, possibly indicating that the knowledge of MSG presence may negatively impact sample liking ratings. While analyzing the impact of information on sample liking was not significant when investigating all consumers at once leading to the theory that consumers are progressing away from valuing a clean label, by clustering consumers into groups based on their patterns of liking, it became evident that certain clusters of consumers are still influenced by their perception of clean label ingredients.In the informed condition of white bread, three clusters were identified: panelists who liked all samples but MSG‐containing samples least , panelists who disliked higher sodium and like reduced sodium breads with or without MSG , and panelists who like a moderate level of sodium reduction with or without MSG . The largest cluster consisted of panelists who liked all samples but liking of samples reduced as the sodium content was reduced. From the blind to the informed with education condition, while the number of panelists who preferred higher sodium increased, the number of panelists who liked reduced sodium breads also increased twofold .In the informed with education condition of white bread, clusters emerged include panelists who liked all samples but preferred higher sodium , panelists who rated LTMSG2 only as significantly less liked than the full sodium bread , and panelists who liked moderately reduced sodium breads with or without MSG and bread greatly reduced in sodium . Greater than half of the panelists were part of cluster 2, where nearly all reduced sodium breads with or without MSG were liked no different than the full sodium, indicating the largest consumer cluster of multigrain breads were accepting of reductions in sodium content at and greater than those set by the FDA as their long‐term 10‐year goal and more than twice that of the percent reduction goal detailed within the FDA's recently updated sodium reduction guidelines for bread.Multigrain bread consumers were clustered according to their overall liking ratings in Figure 4Consumer perception of reduced‐sodium flavor‐enhanced bread samples were varied with clusters such as those preferring higher‐sodium samples, those preferring reduced‐sodium breads with MSG, and those who rated all samples similarly. Despite the consumer segmentation, samples with a moderate level of sodium reduction both with and without flavor enhancement by MSG were generally liked similarly to the full sodium bread in regard to overall liking, saltiness liking, and savoriness liking. These results are promising for the feasibility of the FDA's voluntary sodium reduction guidelines, as reduction levels set at their long‐term 10‐year goal were frequently liked the same as a full sodium bread. Furthermore, breads with the largest level of sodium reduction were frequently liked significantly less than all other samples, although it is worth noting that the level of sodium reduction in those samples was more aggressive than the FDA's recommended reductions and could be considered a limitation of this study. These results indicate that breads with a reduced‐sodium content commensurate with the FDA's voluntary guidelines with or without MSG could find success in the market being liked similarly to full‐sodium bread. While consumer education has been previously found to be effective in improving consumer dietary selections and perceptions of flavor additives, no clear impact of information or education on such was evident in our findings. Despite such lack of significance, consumers had a clear preference for receiving education through video clips or flyers over audio clips. This study was limited in the fact that many participants were tied to the university conducting the research, whether by attending as a student or working as staff, and thus the impact of education on the subject may have been minimized had the research included more consumers without higher education. A series of pre‐ and post‐test questionnaires designed to assess participant's knowledge of human nutrition and food additives may have proven useful in determining the extent of this limitation. Further investigation into specific attribute intensities through descriptive analysis would be beneficial in characterizing specific differences across samples and in identifying attributes considered drivers of liking for bread.Dunteman Aubrey: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Visualization; Writing – original draft; Writing – review & editing. Soo‐Yeun Lee: Conceptualization; Funding acquisition; Project administration; Resources; Supervision; Writing – review & editing.The authors declare no conflict of interest.