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Department of CardiologyThe Prince Charles HospitalRode RdChermside Qld 4032AustraliaAuthor NoteConflicts of Interest: Institution received research funding for EV FIH study from Medtronic.Funding: NilORCID Number: 0000-0003-4819-6922Removal of EVICD leads are specialized tools required?Implantable Cardiac Defibrillators (ICDs) have improved the survival of patients at risk of sudden death and are widely indicated1]. Up until recently ICDs have been implanted transvenously and unfortunately been associated with a relatively high rate of lead complications during follow up 2. This often requires lead extraction which incurs some risk and is only available at specialized centers3. To overcome some of the limitations of the transvenous lead, Extravascular ICD (EVICD) systems have been developed over the last 15 years. First with a lead placed in the subcutaneous tissues above the sternum4and more recently in the retrosternal extravascular space above the pericardium 5 . Like all implantable cardiac devices these systems do fail and may require removal usually for either infection or lead related issues. Given the limited experience and the unique location of the EVICD lead in the retrosternal space the optimal management and risks associated with removal are still well defined.Sagi et al 6recently reported the largest clinical experience to date with removal of the EVICD lead from the retrosternal space. In 347 patients enrolled in three pre-market approval studies, lead removal was performed in twenty-nine patients at a mean of 12.6 months post implant. The overall success rate was 93.1%. (27/29). Leads with a dwell time of less than one year had a 100% success rate of removal (19/19) and required only simple traction in all cases. Leads with a dwell time of greater than 12 months had a lower success rate of 80% (8/10). Simple traction failed in six cases and extraction tools (laser or mechanical) were used in five cases with a success rate of 80%. One lead was abandoned. The longest dwell time for a successfully removed lead was 36.8 months. Importantly there were no procedural related complications.The paper by Sagi suggests that early removal of the EVICD lead within 12 months of implant is a safe and simple procedure requiring no more that simple traction. For leads longer than 12 months, however the optimal technique is still not clear and simple traction alone was not always successful. Delving into the reasons for failure of simple traction and the use of extraction tools, all appear to be related to the presence of dense adhesions at the sub xiphiod incision or diaphragmatic insertion area rather than the retro sternal space. This suggests that extensive dissection along the lead body to the level of the diaphragmatic insertion may be required before an extraction tool is used. Furthermore, if an extraction tool is used it is likely to be particularly important that the lead and tool be always kept coaxially. The angulation often seen as the lead passes under the sternum may result in the extraction tool damaging the outer insulation, which will cause significant weakening of the tensile strength of the lead which may result in it breaking and failure of removal. In the series by Sagi et al the longest dwell time was 58 months, and this lead was not successfully removed. The premature use of both a laser sheath and mechanical tool to assist the removal procedure, prior to adequate dissection of the sub diaphragmatic space resulted in disruption of the outer insulation, loss of tensile strength and subsequent breaking of the lead which left 6.4 cm remaining in situ. It should be noted the EVICD lead, unlike traditional transvenous leads, is lumenless and hence a locking stylet cannot be used to create a rail and assist with use of extraction tools.In this issue of the journal two case reports from Chauhan7 and de Veld [8] extended the dwell times of EVICD leads successfully removed to 43 and 49 months, respectively. In both reports, the leads were removed with simple traction after the suture sleeve was released and dissection was performed along the lead towards the sub diaphragmatic surface. Both these cases highlight the importance of adequate dissection in the sub diaphragmatic space as most adhesions associated with this lead appear in this region rather than the retrosternal space. It may be best to avoid the use of extraction tools which are not design for the lumenless EVICD lead until adequate dissection has been performed The premature use of the tools prior to adequate dissection of the sub diaphragmatic space may in fact hinder the removal of the lead due to disruption of the outer insulation and loss of tensile strengthThese reports add to the evidence suggesting these leads can be removed safely with simple techniques at a medium term follow up of 4 years, while this is reassuring it must be remembered the experience with removal of these leads is still small and with short dwell times. It is reassuring that the site of all adhesions to date appear to be in the sub xiphiod and sub diaphragmatic space rather than the retrosternal space. Hopefully, this means potentially more serious complications related to cardiac injury during lead removal from adhesions related to the pericardium remain rare. The optimal personnel to perform this procedure (electrophysiologist or cardiac surgeon), location (EP lab or operating room) and even the need for pre removal imaging if any is still not clear. Will leads with dwell times of 10 years or more be as easy to remove. These are all unknowns at present and the answers will only become clearer as the experience grows. For the time being the removal of these leads, especially if older than 12 months, should probably continue to be undertaken, by cardiac teams experienced in implanting the device with a good understanding of the sub diaphragmatic space. With adequate dissection of the lead, transvenous lead extraction tools may be rarely required. To date there continues to be no procedural complications reported with removal of the EVICD lead and with time this may prove to be yet another advantage of the EVICD over traditional transvenous ICD even when implanted in the novel retrosternal space.References1. Zeppenfeld K, Tfelt-Hansen J, De Riva M, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J . 2022;43(40). doi:10.1093/eurheartj/ehac2622. Koneru JN, Jones PW, Hammill EF, Wold N, Ellenbogen KA. Risk factors and temporal trends of complications associated with transvenous implantable cardiac defibrillator leads. J Am Heart Assoc . 2018;7(10). doi:10.1161/JAHA.117.0076913. Bongiorni MG, Kennergren C, Butter C, et al. The European Lead Extraction ConTRolled (ELECTRa) study: A European Heart Rhythm Association (EHRA) Registry of Transvenous Lead Extraction Outcomes.Eur Heart J . Published online 2017. doi:10.1093/eurheartj/ehx0804. Bardy GH, Smith WM, Hood MA, et al. An Entirely Subcutaneous Implantable Cardioverter–Defibrillator. New England Journal of Medicine . Published online 2010. doi:10.1056/NEJMoa09095455. Friedman P, Murgatroyd F, Boersma LVA, et al. Efficacy and Safety of an Extravascular Implantable Cardioverter–Defibrillator. New England Journal of Medicine . 2022;387(14). doi:10.1056/nejmoa22064856. Sagi V, Murgatroyd F, Boersma LVA, et al. Comprehensive analysis of substernal lead removal: experience from EV ICD Pilot, Pivotal, and Continued Access Studies. Europace . Published online August 30, 2024. doi:10.1093/europace/euae2257. Chauhan K, Royse A, Goh I, Crozier I, Wynn G. Oldest-in-Human Successful Extraction Experience of a Novel Substernal Extravascular Defibrillator. J Cardiovasc Electrophysiol . Published online November 22, 2024. doi:10.1111/jce.165118. de Veld J, Kooiman K, Knops. Uncomplicated extravascular implantable cardioverter extraction after four years dwell time: a case report. J Cardiovasc Electrophysiol

TITLE: Clinical Improvement without Increased Platelet Count with Eltrombopag in X-Linked ThrombocytopeniaAuthors:Mahmut Yasar Çeliker (Corresponding author)Director of Pediatric Oncology ProgramDivision of Pediatric Hematology and Oncology Department of Pediatrics Maimonides Children’s Hospital 977 48th Street, Brooklyn, NY, 11219Phone: +1 718-283-6652Fax: +1 718-635-5973Email: [email protected] Odurowaa YeboahDepartment of Pediatrics Maimonides Children’s Hospital 977 48th Street, Brooklyn, NY, 11219Ludovico GuariniPediatric Hematology and Oncology Division of Pediatric Hematology and Oncology Department of Pediatrics Maimonides Children’s Hospital 977 48th Street, Brooklyn, NY, 11219

Integrating mapping and 4D ultrasound – is this the dawn of a new ICE age?Rachel M. Kaplan, MD, MS, FHRSIntracardiac echocardiography (ICE) is routinely used by electrophysiologists in the United States for numerous procedures. ICE provides visualization of anatomic structures and can be used to guide ablation lesions. Integration with mapping expands the utility of ICE to also facilitate acquisition of anatomic geometry and aid in identifying structures of interest such as coronary arteries.In the past few years, multiple companies have developed 4D ICE catheters which have elevated the range of imaging obtainable with ICE to be more similar to modern transesophageal echocardiography (TEE). These catheters can obtain multiplanar imaging which enables 3D views in real time and can reduce the need for ICE catheter manipulation to obtain multiple views1.The use of 4D ICE is increasingly described for LAAO, primarily because it can substitute for TEE. Multiple studies have shown comparable outcomes between ICE guided and TEE guided LAAO, though some have shown higher rates of pericardial effusions with ICE2-4. Reduced need for catheter manipulation in the left atrium with 4D ICE catheters may help mitigate this risk. The benefit of utilizing 4D ICE in ablation procedures is less clear. Beyond the technologic intrigue, multiplanar and 3D imaging is not typically required in ablations5. However, integration with mapping has the potential to utilize these additional imaging features for benefit in ablation procedures.In this issue of JCE, Blumenthal et al . describe a pre-clinical study of the use of a 4D ICE catheter with mapping integration in swine models6. The NuVision 4D ICE catheter (Biosense Webster) provides real-time 3D ultrasound imaging and integrates with CARTO anatomic mapping (CARTOSOUND, Biosense Webster). They demonstrated rapid acquisition of geometry by using CARTOSOUND with the 4D ICE catheter where multiplane imaging acquires two 2D images with each position. Furthermore, 360-degree imaging can be obtained without moving the catheter itself. Additionally, ICE provides real time visualization during cardiac motion which can show the operator how the ablation catheter is moving on a structure such as the papillary muscles, therefore improving catheter stability.There are a few drawbacks to 4D ICE. The catheters are slightly larger which then require larger bore vascular access and higher risk of vascular complications. The biggest concern, however, is cost. These catheters cost significantly more than standard 2D ICE catheters. Cost-effectiveness of 2D ICE has been described for LAAO procedures where it has been shown to be comparable to TEE for overall costs (counting both equipment and professional services)7. However, studies comparing 4D to 2D ICE for LAAO have shown that the 3D images are more comparable to TEE with regards to sizing of the LAAO device8. Demonstrating cost-effectiveness of 4D ICE for ablation procedures will be more complex. Future studies will need to investigate effects on procedure duration, risk of complications, or even procedure efficacy (perhaps for papillary muscle premature ventricular contractions where stability can be difficult). Unfortunately, until cost effectiveness demonstrates tangible benefits to 4D ICE in ablations, these catheters may be relegated to selective and investigational use in most hospitals.One niche area for a mapping-integrated 4D ICE catheter may be concomitant atrial fibrillation ablation with LAAO because ICE is typically used in the United States for atrial fibrillation ablation. Use of 4D ICE can enable the entire case to be performed without needing to use TEE for the LAAO part. This also avoids the requirement for a TEE trained imaging physician to be available for the procedure. An example of an LAAO device implant under 4D ICE guidance with the NuVision catheter is shown in the Figure. In this case, the patient underwent pulmonary vein isolation with the ICE catheter in the right atrium, then the NuVision ICE was advanced into the left atrium to guide the implantation of a Watchman device (Boston Scientific). In such cases, the added cost of a 4D ICE catheter compared to a 2D ICE catheter can be offset by not needing the expense of TEE or TEE trained physicians. Imaging with 4D ICE catheters requires advanced knowledge of the imaging console which is often provided by representatives from the ICE catheter company. However, such costs are borne by the whole healthcare industry rather than attributed to an individual procedure by the hospital.Mapping integrated 4D ICE is a technologically exciting forward step though its utility in ablation procedures has yet to be established. Cost concerns will likely limit its broad adoption but it may provide benefits in specific complex ablation cases or perhaps in concomitant ablations with LAAO.1. Adams A, Mahmood R, Balaji N, Dixit P, Chandra S, Weisman D. Real-world experience utilizing the nuvision 4D intracardiac echocardiography catheter for left atrial appendage closure. Sci Rep. 2024;14(1):11937.2. Ferro EG, Alkhouli M, Nair DG, et al. Intracardiac vs Transesophageal Echocardiography for Left Atrial Appendage Occlusion With Watchman FLX in the U.S. JACC Clin Electrophysiol. 2023;9(12):2587-2599.3. Serpa F, Rivera A, Fernandes JM, et al. Intracardiac vs transesophageal echocardiography for left atrial appendage occlusion: An updated systematic review and meta-analysis. Heart Rhythm. 2024.4. Diaz JC, Bastidas O, Duque M, et al. Impact of intracardiac echocardiography versus transesophageal echocardiography guidance on left atrial appendage occlusion procedures: A meta-analysis. J Cardiovasc Electrophysiol. 2024;35(1):44-57.5. Kaplan RM, Narang A, Gay H, et al. Use of a novel 4D intracardiac echocardiography catheter to guide interventional electrophysiology procedures. J Cardiovasc Electrophysiol. 2021;32(12):3117-3124.6. Blumenthal C, Hsue W, Chen T, Zhang D, Brem E, Garcia F, Callans DJ, Marchlinski FE, Santageli P, Tschabrunn CM. Pre-Clinical Experience using 4D ICE to Guide Ablation and Structural Procedures of Complex Intracavitary Structures. Journal of Cardiovascular Electrophysiology. 2024.7. Alkhouli M, Chaker Z, Alqahtani F, Raslan S, Raybuck B. Outcomes of Routine Intracardiac Echocardiography to Guide Left Atrial Appendage Occlusion. JACC Clin Electrophysiol. 2020;6(4):393-400.8. Della Rocca DG, Magnocavallo M, Gianni C, et al. Three-dimensional intracardiac echocardiography for left atrial appendage sizing and percutaneous occlusion guidance. Europace. 2023;26(1).Figure

High myopia stands as the primary cause of blindness globally, with cataract emerging as one of the most prevalent complications. However, the underlying mechanism of high myopic cataract remains unknown. The lens capsule is the basement membrane enclosing the lens. In this study, we hypothesized lens capsule tissue-derived EVs (Ti-EVs) play a vital role in the formation of cataract. Ti-EVs were collected from the lens capsule of high myopic and age-related cataract patients during cataract surgery, and isolated by ExoDisc. Then we performed proximity barcoding assay (PBA) for single EV analysis, which enabled us to identify the alteration of Ti-EV subpopulations associated with high myopic cataract. Our findings revealed a predominant immunity cluster within cataracts, characterized by a significantly higher abundance of macrophage-derived EVs in high myopic cataracts, which strongly correlated with the AQP1 cluster, suggesting a potential interaction between these two components in the progression of high myopic cataract. It was also observed that the eye morphogenesis cluster may also work in concert with AQP1, potentially driving the progression of high myopic cataracts through this pathway. These findings not only shed new light on the underlying mechanisms of high myopic cataract, but also pave the way for the development of novel therapeutic strategies to prevent or treat this devastating condition.

The healthcare industry is widely regarded as a key driver of economic growth and social development in the 21st century. This study employs multi-source data alongside hybrid analytical techniques, including Principal Component Analysis (PCA), hotspot analysis, and clustering analysis, to explore the development factors and spatial patterns of the ethnic medicine and healthcare industry (EMH) in Yunnan Province, China. The results indicate that the first five principal components account for 79.80% of the total variance, providing significant insights into the industry’s competitive drivers. Using the Porter Diamond Model, spatial clustering of the EMH sector across Yunnan reveals a distinct pattern of ”one ring, two points, three areas, and multiple clusters.” The analysis further shows that industrial competitiveness is closely linked to the spatial distribution of regional factors, suggesting the need for a targeted development strategy: ”central innovation, western optimization, eastern enhancement, northern strengthening, and southern expansion.” These findings provide valuable recommendations for policymakers aiming to enhance the EMH sector’s contribution to regional economic development and healthcare modernization.

Reply to Wang et al.To the Editor,We sincerely appreciate the thoughtful response from Wang et al.1, regarding our recent study2. We are grateful for the effort the authors put into expressing potential limitations of our work, as such comments enrich the dialogue in the emerging intersection of pediatric healthcare and health geography. In this interdisciplinary field, constructive discourse is essential to refining methodologies and fostering collaborations that drive innovative solutions. We welcome the opportunity to address their concerns and engage further in this important conversation.Firstly, we acknowledge that a more diverse study sample would have been beneficial. The overall patient population in our health system are diverse across race, ethnicity, language, illness, environmental exposures, and geography. However, the nature of this single center study, as Wang et al. correctly point out, is that our patient study population are less diverse, particularly, in overall geographic composite index measures such as the Social Vulnerability Index (SVI) and Child Opportunity Index (COI). Notably, our study sample represents a group with particularly high scores on SVI and lower scores on COI. That said, a multicenter study involving patients from other health systems would indeed help us further understand the association between SVI or COI and the risk for pediatric intensive care unit (PICU) admission for status asthmaticus. Scaling out to a multicenter study using patient addresses and spatially granular data can be challenging due to the need to protect patient privacy3. Establishing the partnerships, information sharing infrastructure, and processes necessary to conduct a more comprehensive multicenter study is an ongoing area of focus for our team. We are committed to advancing this critical work.Secondly, we acknowledge that a large percentage of patients at the time of our study have reported race and ethnicity values of “other” or “unknown.” Unfortunately, this can be common across health systems with diverse patient populations. Despite the Meaningful Use mandate by the Centers for Medicare and Medicaid Services requiring the collection of race and ethnicity values in electronic health records (EHR), many health systems lack comprehensive race and ethnicity data for their patient populations4. While sub-optimal, there are multiple reasons for responses of “other” and “unknown.” For one, EHRs were traditionally designed with limited race and ethnicity options for patients to choose from, leading to an oversimplification of race and ethnicity categories. Limited options and discrete choices may not always reflect the identity of patients4. Not to mention, directly asking patients how they identify is difficult because the conversation can be uncomfortable for all those involved4. Also, the value of race and ethnicity data for research may not always be fully understood by healthcare professionals and patients leading to subpar data collection4. Still, it is worth noting that since our study was completed, our health system has conducted a large systemic effort to improve the collection of race and ethnicity data. For instance, patients are given more options to self-identify their race and ethnicity with better processes in place during clinic appointments to facilitate data collection. Efforts to minimize missing race and ethnicity data for health disparities research and other health system applications continues to be an important work for all healthcare systems.Thirdly, we concur that other factors, including the residential environment, air pollution, and indoor allergens are important considerations in pediatric healthcare and respiratory diseases. The exposome encompasses a wide array of factors that are associated with asthma5. As we work toward improving our understanding of addressing pediatric health, future work will integrate the physical, social, and environment as key drivers of health. A more holistic approach to understanding this extended environment as it relates to patient health can unlock a better understanding of health and open opportunities to create meaningful and effective interventions. Linking individual environmental factor data remains a key focus for this team.We are thankful for the insightful comments provided by Wang et al. Response to research work provides us all with the opportunity to engage in thoughtful discourse amongst our colleagues to drive research and healthcare forward. Our study of PICU admissions for status asthmaticus is ongoing and a part of a growing work in progress. We share the same ideals Wang et al. express, but more importantly, we share the same desire to advance the health of children everywhere through research.Alicia Adiwidjaja, BS1,2Justin Jones, MD1Patrick Ross, MD1,3Matthew Keefer, MD1,3Margaret J Klein, MS1Jonathan M. Tan, MD MPH MBI1,2,31Children’s Hospital Los Angeles, Los Angeles, California, USA2University of Southern California Spatial Sciences Institute, Los Angeles, California, USA3University of Southern California Keck School of Medicine, Los Angeles, California, USAConflicts of InterestJonathan Tan receives research grant funding from the Anesthesia Patient Safety Foundation, Foundation for Anesthesia Education and Research, and the Southern California Environmental Health Sciences Center. Jonathan Tan is a consultant for GE HealthCare, Edwards Lifesciences, and Medtronic. Jonathan Tan is on the Board of Directors for the Society for Pediatric Anesthesia.ReferencesWang C, Tian H, Shang J. Comment on Justin Jones et al.Pediatric Allergy and Immunology. 2024.Jones J, Klein MJ, Adiwidjaja A, Ross P, Keefer M, Tan JM. The association between composite measures of social vulnerability and PICU admission for status asthmaticus. Pediatric Allergy and Immunology. 2024;35(11). doi:https://doi.org/10.1111/pai.14278. PMID: 39526837. U.S. Department of Health and Human Services. Summary of the HIPAA Privacy Rule. 2003.Diallo MS, Tan JM, Heitmiller ES, Vetter TR. Achieving Greater Health Equity: An Opportunity for Anesthesiology. Anesth Analg. 2022 Jun 1;134(6):1175-1184. doi: 10.1213/ANE.0000000000005937. Epub 2022 Feb 2. PMID: 35110516.Guillien, A., Cadiou, S., Slama, R., & Siroux, V. (2021). The Exposome Approach to Decipher the Role of Multiple Environmental and Lifestyle Determinants in Asthma. International Journal of Environmental Research and Public Health, 18(3), 1138. https://doi.org/10.3390/ijerph18031138

Environmental DNA (eDNA) analysis has become a popular conservation tool for detecting rare and elusive species. eDNA assays typically target mitochondrial DNA (mtDNA) due to its high copy number per cell and its ability to persist in the environment longer than nuclear DNA. Consequently, the development of eDNA assays has relied on mitochondrial reference sequences available in online databases, or in cases where such data are unavailable, de novo DNA extraction and sequencing of mtDNA. In this study, we designed eDNA primers for the critically endangered Bellinger River turtle (Myuchelys georgesi) using a bioinformatically assembled mitochondrial genome (mitogenome) derived from a reference genome. We confirmed the accuracy of this assembled mitogenome by comparing it to a Sanger-sequenced mitogenome of the same species, and no base pair mismatches were detected. Using the bioinformatically extracted mitogenome, we designed two 20 bp primers that target a 152-base-pair-long fragment of the cytochrome oxidase 1 (CO1) gene and a 186-base-pair-long fragment of the cytochrome B (CytB) gene. Both primers were successfully validated in silico, in vitro, and in situ.

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not-yet-known not-yet-known not-yet-known unknown A 57-year-old woman with frequent palpitations was referred for radiofrequency ablation. The baseline 12-lead electrocardiogram and echocardiography were normal. The baseline atrio-His (AH) and His-ventricular (HV) intervals were 70 and 35 ms, respectively. Dual atrioventricular (AV) nodal physiology was not observed during programmed atrial stimulation. Ventriculoatrial conduction showed a decremental and concentric pattern, with the earliest atrial activation recorded in the His bundle region. There was no evidence of a jump-up phenomenon during programmed ventricular stimulation. Supraventricular tachycardia (SVT) with variable AH and His-atrial (HA) intervals was induced by extra atrial stimulation without any jump-up in the AH interval. The earliest atrial activation during SVT was recorded at the coronary sinus (CS) 7,8 region, corresponding to the CS ostium, which differed from the atrial activation sequence during ventricular pacing. The atrial-atrial (AA) intervals demonstrated variability exceeding 50 ms without any alteration in the atrial activation sequence (Figure 1A). Ventricular entrainment pacing was performed during SVT (Figure 1B). Transient 2:1 AV conduction was observed during SVT (Figure 1C). Based on these findings, what is the mechanism of the variability in the AA, AH, and HA intervals during tachycardia?

Reply to the Letter to the Editor by Kember et al, Regarding Wilson et al., “A Position Modification Device for the Prevention of Supine Sleep During Pregnancy: A Randomised Crossover Trial” Published in the British Journal of Obstetrics & Gynaecology on 16 September 2024.Danielle L. Wilson, MSc., PhD1,2,3; Carley Whenn1; Maree Barnes, MBBS1,4; Susan P. Walker, MBBS, MD, FRANZCOG, DDU, CMFM2,5; Mark E Howard, MBBS, FRACP, GDEB, PhD1,41Institute for Breathing and Sleep, Austin Health, Heidelberg, Victoria, Australia;2Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia.3School of Electrical Engineering and Computer Science, The University of Queensland, St Lucia, Queensland, Australia.4Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.5Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia.Address correspondence to: Danielle L. Wilson, Institute for Breathing and Sleep, Level 5 Harold Stokes Building, Austin Health, Heidelberg, Victoria, Australia. Tel: 613 9496 3517; Fax: 613 9496 5124; e-mail: [email protected] Prof. Aris Papageorghiou,We thank Dr. Kember and his colleagues1 for their interest in our recently published article2. Firstly, we acknowledge the recent publication by Coleman et al3 regarding the benefits of the Prenabelt on foetal growth, as revealed through re-analysis of their data using Bayesian methods. Unfortunately, this paper3 was published after our initial submission. Interestingly, while the frequentist analysis approach just fell short of significance, a Bayesian approach shows promise for supine sleep position interventions, by throwing an interesting light on the likelihood of a benefit depending on prior clinical beliefs. It remains that the mechanisms of action need further exploration however, given that supplemental data from the original publication4 suggests that objectively measured supine sleep in a subset of women did not differ between those using Prenabelt v sham.Secondly, we recognise our study was constrained by the measurement device used. The Night Shift Sleep Positioner (Night Shift) with neck placement was initially chosen, however, during our study a chest belt was introduced by the manufacturer. We performed a sub-study with N=20 of the participants wearing the device at both neck and abdominal placements for one night. An epoch-by-epoch comparison revealed substantial agreement between the two devices for all sleep positions with 88% concordance overall (unweighted κ = .797 [SE .006], p<.001). Regrettably, we neglected to include these data within the original publication.Despite the limitations of our measurement device, we believe that distinguishing between neck and pelvic position would not have substantially impacted our conclusions, given the high concordance between neck and abdominal devices revealed above, and particularly given that the intervention showed a nonsignificant increase in the proportion of supine sleep overnight. As Dr. Kember’s team have demonstrated, sleep positions where the thorax and pelvis are discordant (e.g., supine thorax with left pelvis tilt) are infrequent, occurring in less than 6% of “real-world” sleeping positions during pregnancy.5We agree that the Night Shift lacked sufficient resolution to fully appreciate the complex interplay between maternal positioning and foetal haemodynamics, as mentioned in the limitations section of our paper. Indeed, measurement limitations persist with all position sensing methodologies including infra-red video monitoring, with Dr. Kember’s recent paper5 demonstrating that while the most commonly occurring sleeping positions (left-lateral, right-lateral and supine) were well-recognised by modelling, the twisted/hybrid positions had intermediate performance, with the modelling particularly challenged by left or right tilted positions. To address the limitations of the Night Shift, we have recently completed data collection on a subsequent study using tri-axial accelerometry at abdominal level to characterise maternal sleep position in degrees of roll around the axial plane, with an aim to capture the subtleties of maternal position on uteroplacental haemodynamics and foetal growth.As mentioned, this is an understudied area. Dr. Kember and his team share our drive to gather objective evidence of a causal pathway between supine sleep position and foetal wellbeing, which we believe is particularly important given current guidelines regarding safe sleeping position in late pregnancy are based on retrospective cohort studies of self-reported “going-to-sleep” position. Our team congratulates Dr. Kember and his colleagues for their excellent work in the sleep position during pregnancy space, and we look forward to the outcomes from their upcoming DOSAGE Study.Disclosure of Interests:The authors have no financial disclosures or conflicts of interest.Contributions of Authorship:Dr. Wilson, Prof. Walker and Prof. Howard drafted and revised the manuscript, Ms. Whenn and Dr. Barnes critically revised the manuscript.Details of Ethics Approval:Additional analyses comparing device location were approved under an amendment to the original approval by the Mercy Hospital for Women Human Research Ethics Committee project number 2020-015, on 3rd June 2021.References:https://doi.org/10.1111/1471-0528.179521. Kember A. Placeholder for Letter to the Editor for BJOG.2. Wilson Danielle L, Whenn C, Barnes M, Walker Susan P, Howard Mark E. A position modification device for the prevention of supine sleep during pregnancy: A randomised crossover trial. BJOG: An International Journal of Obstetrics & Gynaecology. 2024; .3. Coleman J, Grewal S, Warland J, Hobson S, Liu K, Kember A. Maternal positional therapy for fetal growth and customised birth weight centile benefit in a Bayesian reanalysis of a double-blind, sham-controlled, randomised clinical trial. BMJ Open. 2024; 14 (4): e078315.4. Coleman J, Okere M, Seffah J, et al. The Ghana PrenaBelt trial: a double-blind, sham-controlled, randomised clinical trial to evaluate the effect of maternal positional therapy during third-trimester sleep on birth weight. BMJ Open. 2019; 9 (4): e022981.5. Kember AJ, Zia H, Elangainesan P, et al. Transitioning sleeping position detection in late pregnancy using computer vision from controlled to real-world settings: an observational study. Sci Rep. 2024; 14 (1): 17380.

Re: “Necessity the mother of invention”-wider significance of novel mid-urethral rectus fascial sling. Petros, Peter. Response letter.Author: Abdalla Fayyad.Centre of Urogynaecology and Advanced Laparoscopic Surgery. 12 Khalidi Street, Amman, Jordan 11180.E mail: [email protected] Dr Aris Papageorghiou,We thank Professor Petros for the letter to the editor titled “Necessity is the mother of invention”-wider significance of novel mid-urethral rectus fascial sling1 and the interest shown in our novel technique of laparoscopic mid-urethral autologous fascial sling (LMAFS)2. In his letter to the editor, Professor Petros supports our novel approach of using the autologous rectus fascia as mid-urethral sling inserted laparoscopically. We are honored to have our technique endorsed by the discoverer of the integral theory (IT), and the co-developer of the mid-urethral sling (MUS).We agree with Professor Petros that restoring vaginal support does improve pelvic floor symptoms related to prolapse, lower urinary tract symptoms and obstructive daefecation3. We are currently examining the feasibility of using autologous rectus fascia laparoscopically to restore apical support as a non-mesh option. We agree that the potentials of using the rectus fascia laparoscopically can be numerous, but does indeed need further evaluation.It is important, however, to emphasize that surgical interventions for pelvic floor dysfunction should be considered after conservative measures have failed to improve patient’s bothersome symptoms. Regarding the symptoms of overactive bladder (OAB), e.g. urgency and urgency incontinence, we agree with Professor Petros that many patients with OAB do improve following corrective reconstruction of the support of the bladder base and trigone, as the stretch receptors in the bladder are no longer activated at low bladder volumes3. However, it is important to recognise that OAB is a nonspecific, complex and multifactorial symptom syndrome frequent in the general population, and among men as well4,5. There appear to be several distinct subtypes of OAB with different pathophysiology, with overlapping underlying factors including metabolic syndrome, affective disorders, gastrointestinal disorders, hormonal deficiency, and subclinical autonomic nervous dysfunction5. Surgery for prolapse does not necessarily address these potential underlying causes. The mainstay of managing this sub group of patients with OAB, is through conservative measures and medical treatment.In conclusion, we thank Professor Petros for his letter, and agree that understanding the IT provides an important insight into majority of pelvic floor dysfunction symptoms. We used the principles of the IT when we developed the technique of LMAFS1. We are certainly looking for further uses of laparoscopic rectus fascial sling in pelvic floor reconstruction.Word count: 368Conflict of interest: NoneFunding information: None

In this paper, we investigate the long-term stability of classical solution to 3D one-fluid Euler-Poisson system of electrons with non-zero vorticity. It is shown that the classical solution is well-posed for a lifesapn Tδ at least εδ, where ε>0 is the size of the initial perturbed density and velocity, δ>0 is the size of the initial vorticity. This implies that the lifespan Tδ only essentially depends on the size δ of the initial vorticity.

Biopsychosocial approaches to treat female chronic pelvic painJim Thornton, Emeritus professor obstetrics & gynaecology, university of Nottingham, UKNick Brown, Department of Psychology, Linnaeus University, Växjö, SwedenCorresponding author: [email protected] Dr. Aris Papageorghiou,We read the recent systematic review of biopsychosocial approaches to treat female chronic pelvic pain (October 2024) [1] with interest. The fact that three included studies had been conducted by the same research group, and differed only in the type and focus of goal setting [2, 3, 4], inspired us to read them carefully.All three studies contain multiple reported mean values, for variables which are normally reported as integers, which appear to be impossible: so-called GRIM inconsistencies [5]. We have posted our concerns on the peer review website PubPeer.com,https://pubpeer.com/publications/A182FA06122C1D2C38E819415EC155\#1, https://pubpeer.com/publications/16A4EA3222C67B2E38AD0790F38E43 and https://pubpeer.com/publications/7B0A50B193748DEF5196E10529FC76\#1 and asked the editors of Maturitas and Archives of Physical Medicine and Rehabilitation to investigate.Although such inconsistencies can be due to typos, or other minor data errors, the occurrence of so many, in three different randomised controlled trials by the same investigator group, raises serious questions about the integrity of the data and, hence, the validity of the results in these articles.We suggest that readers interpret the reliability of these three studies, and hence also the systematic review, which is partly based on them, with caution unless the respective journal investigations indicate no cause for concern. We also think it essential that the authors should provide their data for reanalysis, to determine the origin of these inconsistencies.Jim Thornton, Emeritus professor obstetrics & gynaecology, iniversity of Nottingham, UKNick Brown, Department of Psychology, Linnaeus University, Växjö, SwedenJohnson, S., Bradshaw, A., Bresnahan, R., Evans, E., Herron, K. and Hapangama, D. (2024), Biopsychosocial Approaches for the Management of Female Chronic Pelvic Pain: A Systematic Review. BJOG. https://doi.org/10.1111/1471-0528.17987Ariza-Mateos MJ, Cabrera-Martos I, Ortiz-Rubio A, Torres-Sánchez I, Rodríguez-Torres J, Valenza MC. Effects of a Patient-Centered Graded Exposure Intervention Added to Manual Therapy for Women With Chronic Pelvic Pain: A Randomized Controlled Trial. Arch Phys Med Rehabil. 2019 Jan;100(1):9-16. doi: 10.1016/j.apmr.2018.08.188. Epub 2018 Oct 9. PMID: 30312595.Rodríguez-Torres J, López-López L, Cabrera-Martos I, Prados-Román E, Granados-Santiago M, Valenza MC. Effects of an Individualized Comprehensive Rehabilitation Program on Impaired Postural Control in Women With Chronic Pelvic Pain: A Randomized Controlled Trial. Arch Phys Med Rehabil. 2020 Aug;101(8):1304-1312. doi: 10.1016/j.apmr.2020.02.019. Epub 2020 Apr 20. PMID: 32325162.Ariza-Mateos MJ, Cabrera-Martos I, López-López L, Rodríguez-Torres J, Torres-Sánchez I, Valenza MC. Effects of a patient-centered program including the cumulative-complexity model in women with chronic pelvic pain: a randomized controlled trial. Maturitas. 2020 Jul;137:18-23. doi: 10.1016/j.maturitas.2020.04.005. Epub 2020 Apr 25. PMID: 32498932.Brown, N. J. L., & Heathers, J. A. J. (2017). The GRIM Test: A Simple Technique Detects Numerous Anomalies in the Reporting of Results in Psychology. Social Psychological and Personality Science, 8(4), 363-369. https://doi.org/10.1177/1948550616673876

A document by Mohanaraj Ramachandran. Click on the document to view its contents.

On October 7, 2024 the Nobel Assembly of the Karolinska Institute awarded this year’s Nobel Prize in Physiology or Medicine to Victor Ambrose and Gary Ruvkun “for the discovery of microRNA and its role in post-transcriptional gene regulation” (https://www.nobelprize.org/prizes/medicine/2024/press-release/). The prize-winning research was published in back-to-back 1993 papers in Cell demonstrating in the nematode worm C. elegans that the lin-4 microRNA regulates the translation and degradation of lin-14 mRNA post-transcriptionally in the cytoplasm during transition from the first to the second stage of larval developments by base-pairing to the target mRNA. When Ruvkun and colleagues later identified and characterized the more evolutionarily conserved let-7 microRNA to play a similar post-transcriptional regulatory role during the transition from late larval to adult stages in animals from mollusks to vertebrates (but not in plants, yeast, bacteria, jellyfish or sponges), the scientific community began to accept microRNAs as part of the canonical developmental regulatory machinery of multicellular organisms [1].

Title: Potential arrival pathway for Highly Pathogenic Avian Influenza H5N1 to Oceania

Low-Dose Amitriptyline: A Potential Therapeutic Option for Chronic Pain in Older PeopleTakayuki Suga, DDS, PhD1; Trang Thi Huyen Tu, DDS, PhD1,2; Motoko Watanabe, DDS, PhD1; Takahiko Nagamine MD, PhD1,3; and Akira Toyofuku, DDS, PhD11 Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo2 Department of Basic Dental Sciences, Faculty of Odonto- stomatology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam3 Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, Yamaguchi, Japan.Word count:798Acknowledgements: noneConflict of interest statement: There are no conflicts of interest to declare.Keywords: psychopharmacology, safety Pharmacology, chronic pain, antidepressive agents, older adultCorrespondence to:Takayuki Suga, DDS, PhD1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.Phone number: +81358035898; Fax: +81358035898; Email: [email protected] use of antidepressants in older adults with chronic pain is controversial. We found Dr. Narayan et al.’s article, titled “Efficacy and Safety of Antidepressants for Pain in Older Adults: A Systematic Review and Meta-Analysis,” on the use of antidepressants in older people with chronic pain to be highly engaging. (Narayan et al., 2024) They conducted a systematic review and meta-analysis on the efficacy and safety of antidepressants for chronic pain in older people. Due to various limitations, they concluded that the benefits and harms of antidepressant medicines for most types of chronic pain, especially knee OA, are unclear.Conducting clinical research with older adults poses challenges, often excluding them due to pre-existing conditions. Randomized controlled trials (RCTs) in this population are particularly difficult for several reasons:1. Comorbidities and Polypharmacy: older people often have multiple chronic conditions and take various medications, complicating group allocation, the isolation of the intervention’s effects and increasing the risk of drug interactions.2. Heterogeneity and Follow-up Challenges: Due to mobility impairments and other factors, it is difficult for older people to make regular visits to hospitals conducting RCTs, leading to high dropout rates.3. Ethical Considerations: The older people are often regarded as a vulnerable population, requiring ethical considerations when involving them in risk-related interventions.Despite these challenges, studies using real-world data suggest that, when used carefully, antidepressants might help manage chronic pain in older adults, particularly for conditions like burning mouth syndrome (BMS).BMS, a common type of chronic orofacial pain affecting mainly postmenopausal women, has uncertain pathophysiology.We previously reported that low doses of amitriptyline are effective in managing pain in older people with BMS. (Suga et al., 2019) Furthermore, even in patients over 80 years old, amitriptyline demonstrates efficacy when used in low doses with careful administration. (Watanabe et al., 2022) Regarding common side effects, managing these side effects in elderly patients will be effective through regular visits and examination. (Suga et al., 2019; Watanabe et al., 2022) Hence, it is crucial to monitor for anticholinergic side effects such as drowsiness, dry mouth, and constipation, as well as potential falls due to dizziness and any changes in cognitive function in clinical assessment.A therapeutic window exists for the dosages of amitriptyline that are effective in managing chronic pain, indicating that its efficacy is not dose-dependent. (Nagamine, 2024) In contrast to the doses used in psychiatry for depression (typically 100 mg/day or more), amitriptyline is effective at doses of 5-20 mg/day in the treatment of BMS. The use of amitriptyline at this dosage is considerably lower than the doses employed in the RCTs included in the authors’ study, suggesting a reduced risk of side effects and withdrawal symptoms.The challenges of administering antidepressants to older people with chronic pain are not limited to concerns about side effects but also encompass issues related to their overall efficacy in this population. Serotonin’s role in pain modulation is complex, as it can either exacerbate or alleviate pain depending on the receptor subtype activated. This bidirectional effect is attributed to the distinct pathways involved in serotonin-mediated pain processing, with some receptors promoting analgesia and others enhancing nociception. (Bannister & Dickenson, 2016) Additionally, the elevation of serotonin levels might disrupt the delicate equilibrium with dopamine, thus hindering pain inhibition via the reward pathway. Therefore, increasing serotonin levels alone may exacerbate pain rather than produce therapeutic benefits.Moreover, chronic pain modulation involves not only serotonin but also other monoamines, such as dopamine and noradrenaline. Consequently, antidepressants that modulate serotonergic, noradrenergic, or dopaminergic pathways may exhibit therapeutic potential in managing chronic pain. (Bannister & Dickenson, 2016) This is also reflected in the study by Narayan et al., which demonstrated the efficacy of duloxetine, a dual serotonin and noradrenaline reuptake inhibitor, albeit with a modest effect size. Amitriptyline, which similarly targets both serotonin and noradrenaline, and to some dopamine transporters, may offer superior efficacy compared to other antidepressants. However, as previously mentioned, its therapeutic effect does not appear to be dose-dependent, suggesting that there may be an optimal therapeutic window at lower doses. Although not specifically in older people, other reports have also demonstrated the effectiveness of low-dose amitriptyline (5-25 mg/day) in managing conditions such as lower back pain, chronic neck pain, and chest pain. (Maarrawi et al., 2018; Park et al., 2013; Urquhart et al., 2018) Given the above, it is conceivable that low doses of certain antidepressants, such as amitriptyline, may be effective and safe for patients with other types of chronic pain. Research on the use of antidepressants for chronic pain in older people is still limited; therefore, as the authors have pointed out, there is a need for more prospective studies and numerous real-world investigations. In conclusion, careful clinical management and the accumulation of treatment data are essential for the effective treatment of chronic pain in older people using antidepressants.ReferencesBannister, K., & Dickenson, A. H. (2016). What do monoamines do in pain modulation? Curr Opin Support Palliat Care , 10 (2), 143-148. https://doi.org/10.1097/SPC.0000000000000207Maarrawi, J., Abdel Hay, J., Kobaiter-Maarrawi, S., Tabet, P., Peyron, R., & Garcia-Larrea, L. (2018). Randomized double-blind controlled study of bedtime low-dose amitriptyline in chronic neck pain. Eur J Pain , 22 (6), 1180-1187. https://doi.org/10.1002/ejp.1206Nagamine, T. (2024). Amitriptyline at low dose for burning mouth syndrome. Oral Diseases , 30 (7), 4650-4652. https://doi.org/10.1111/odi.14966Narayan, S. W., Naganathan, V., Vizza, L., Underwood, M., Ivers, R., McLachlan, A. J., Zhou, L., Singh, R., Tao, S., Xi, X., & Abdel Shaheed, C. (2024). Efficacy and safety of antidepressants for pain in older adults: A systematic review and meta-analysis. Br J Clin Pharmacol . https://doi.org/10.1111/bcp.16234Park, S. W., Lee, H., Lee, H. J., Park, J. C., Shin, S. K., Lee, S. K., Lee, Y. C., & Kim, J. E. (2013). Low-dose amitriptyline combined with proton pump inhibitor for functional chest pain. World J Gastroenterol , 19 (30), 4958-4965. https://doi.org/10.3748/wjg.v19.i30.4958Suga, T., Takenoshita, M., Watanabe, T., Tu, T. T. H., Mikuzuki, L., Hong, C., Miura, K., Yoshikawa, T., Nagamine, T., & Toyofuku, A. (2019). Therapeutic Dose of Amitriptyline for Older Patients with Burning Mouth Syndrome. Neuropsychiatric Disease and Treatment ,Volume 15 , 3599-3607. https://doi.org/10.2147/ndt.S235669Urquhart, D. M., Wluka, A. E., van Tulder, M., Heritier, S., Forbes, A., Fong, C., Wang, Y., Sim, M. R., Gibson, S. J., Arnold, C., & Cicuttini, F. M. (2018). Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain: A Randomized Clinical Trial. JAMA Intern Med ,178 (11), 1474-1481. https://doi.org/10.1001/jamainternmed.2018.4222Watanabe, M., Takao, C., Liu, Z., Nayanar, G., Suga, T., Hong, C., Tu, T. T. H., Yoshikawa, T., Takenoshita, M., Motomura, H., Nagamine, T., & Toyofuku, A. (2022). The Effectiveness and Adverse Events of Amitriptyline and Aripiprazole in Very Elderly Patients With BMS.Frontiers in Pain Research , 3 . https://doi.org/10.3389/fpain.2022.809207