Children with sickle cell disease (SCD) have an increased risk of sleep disordered breathing (SDB) compared with the general pediatric population. There has been a growing research interest on this field in recent years, yet many questions regarding risk factors and clinical implications of SDB remain unclear. The aim of this review is to provide a concise narrative and systematic synthesis of the available evidence on the epidemiology, clinical presentation, complications and management, of SDB in children with SCD. An electronic search was conducted on studies published from the 1st of January 2000 to the 31st of December 2020 in PubMed/Medline, Scopus and Cochrane databases. All studies focusing on SDB in children with SCD aged from 0 to 20 years were included. Studies were eligible for inclusion if available in the English language. A quantitative synthesis of the included studies was performed. Only studies focusing on specific treatment outcomes were included in a meta-analytic process. A total of 190 papers were initially identified. After screening the title and abstract, 112 articles were evaluated for eligibility. At the end of the selection process, 62 studies were included in the analysis. Sleep-disordered breathing is associated with worse neurological, neurocognitive and cardiological outcomes, whereas the association with frequency or severity of vaso-occlusive pain events and acute chest syndrome was not clarified. Therapeutic interventions like adenotonsillectomy or oxygen supply may result in a significant increase in mean nocturnal oxygen saturation but effective clinical implications remain still unclear.
Thoracic endovascular aortic repair (TEVAR) has quickly become the mainstay of treatment for acute aortic dissection, in particular cases of acute complicated Stanford Type B dissection (co-TBAD). Necessarily, TEVAR carries with it the risk of postoperative complications, including stroke and renal failure. As a result, the management of patients with uncomplicated type B aortic dissection (un-TBAD), which is generally accepted as being less severe, are safely managed via optimal medical therapy (OMT) alone. However, despite OMT, patients with un-TBAD are at substantial risk of severe disease progression requiring delayed intervention. The cost-benefit ratio associated with TEVAR for un-TBAD is therefore of key interest. Howard and colleagues produced a fascinating systematic review and meta-analysis investigating the clinical outcomes of TEVAR for complicated and uncomplicated TBAD. Their data suggests that there is no significant difference in in-hospital mortality or 5-year survival between TEVAR for un-TBAD and co-TBAD, although the 30-day mortality rate appeared to be higher in the co-TBAD cohort. Patients with co-TBAD appeared to also be at a higher risk of postoperative stroke and TEVAR endoleak, while un-TBAD patients were at a higher risk of postoperative renal failure. Further prospective research into these relationships are recommended to fully elucidate the comparative efficacies of TEVAR for un-TBAD and co-TBAD.
Letter to editor: “Vaginal Er:YAG laser application in the menopausal ewe model: a randomised estrogen and sham-controlled trial “Cheng-Yang Hsu1, Ching-Hu Wu1, Cheng-Yu Long1, 21 Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan2 Department of Obstetrics and Gynecology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanRunning head: Two prospective for this promising experimentWords Count: 315Corresponding Author:Dr. Cheng-Yu Long, MD, PhD, Department of Obstetrics and Gynaecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100, Shih-Chuan 1st Rd, Kaohsiung 80708, TaiwanE-mail: email@example.comDear Editor-in Chief:We read with great interest with recent publication in BJOG by Mackova et al. (1) This study describe effects of non-ablative erbium-doped: yttrium-aluminium-garnet (Er:YAG) laser on vaginal atrophy induced by iatrogenic menopause in the ewe. The ewes were randomized to three groups: vaginal Er:YAG laser application, estrogen replacement, and sham groups.In the estrogen replacement group of ewes, an estrogen implant was inserted under the skin in the inguinal region. The result showed increase in epithelia thickness in vaginal biopsies and it was significantly higher compared with the laser application and sham groups. In all groups, the lamina propria did not showed any significant differences. Also the autopsy showed the uterus of estrogen-exposed ewes weighted more.We would like to humbly comment the vaginal estrogen use and laser application in genitourinary syndrome of menopause.The vaginal estrogen application was given twice a week with the cream in currently practice of female who suffered from genitourinary syndrome of menopause (GSM). Firstly, the vaginal estrogen application was given twice a week with the cream in clinical practice of female who suffered from GSM. The administration showed improvement of the symptoms while no significant change in serum estrogen level. (2) The estrogen implant in the ewe experiment continues to release estrogen and caused sustained estrogen effect in the ewe and caused gaining weight of uterus, which was very different with our clinical practice of intermittent vaginal cream use.Second, the application in this study is Er:YAG laser, with the the lesser wave length: 2940 nm. While the CO2 laser had much longer wave length 10600 nm and had deeper effect in not only vaginal epithelium but also lamina propia. (3) Therefore the vascularization effects of lamina propia may be obvious noticeably.We thought these 2 flaws could be revised to make the ewe experiment more accurate and similar to current management in women with GSM.ReferencesMackova KA-OX, Mazzer AM, Mori Da Cunha MA-O, Hajkova Hympanova LA-O, Urbankova IA-O, Kastelein AA-O, et al. Vaginal Er:YAG laser application in the menopausal ewe model: a randomised estrogen and sham-controlled trial. BJOG . 2021 May;128(6):1087-1096.Long CY, Liu CM, Hsu SC, Wu CH, Wang CL, Tsai EM. A randomized comparative study of the effects of oral and topical estrogen therapy on the vaginal vascularization and sexual function in hysterectomized postmenopausal women. Menopause . Sep-Oct 2006;13(5):737-43.Bhide AA, Khullar V, Swift S, Digesu GA. The use of laser in urogynaecology. Int Urogynecol J . 2019 May;30(5):683-692.
BJOG-20-1830.R3: The levonorgestrel intrauterine system versus endometrial ablation: when the choice of treatment goes beyond its efficacy Author: Sarah Maheux-LacroixEndometrial ablation and levonorgestrel intra-uterine system (LNG-IUS) are two well-established treatment options for women with heavy menstrual bleeding (Bergeron C, Hum Reprod Update 2020;26(2):302-11) that have contributed to the important decrease in hysterectomies over the last decades (Bergeron AM et al. J Obstet Gynaecol Can 2020;42(12):1469-74). Van den Brick et al. present a cost-effectiveness analysis comparing the two options, in which a treatment strategy starting with the LNG-IUS is less costly than a strategy starting with endometrial ablation. Up to now, economic analyzes mostly relied on simulation modeling and conclusions could vary depending on assumptions for efficacy and discontinuation in each arm. This study was based on actual data from an RCT with a 2-year follow-up.Despite the 43% discontinuation rate for LNG-IUS, this method was cheaper at 2 years and this conclusion stood up to sensitivity analyzes. The LNG-IUS remained superior despite the assumption of an ambulatory setting for endometrial ablation, but this analysis needs to be interpreted with caution. Data was lacking on costs of the outpatient setting and saving of only \euro111 was estimated when comparing to the inpatient setting (\euro2,241 versus \euro2,352). In other studies, the outpatient hysteroscopy was associated with substantial savings, being 2 to 4 times cheaper (Bennett A et al. J Obstet Gynaecol Can 2019;41(7) :930-41). Indeed, costs are always subject to vary from region to region with possibly different conclusions in different settings, but clearly an outpatient procedure reduces the cost difference between the two methods.Beyond 2 years, data is lacking. The two methods have been compared in RCT at up to 5 years (Bergeron C, Hum Reprod Update 2020;26(2):302-11) and we do not know if one method is superior the other to prevent longer term failures and re-interventions. The LNG-IUS requires replacement every 5 years but seems to decrease the risk of eventually requiring a hysterectomy in younger patient (Bergeron C, Hum Reprod Update 2020;26(2):302-11). Both factors could have an impact in a longer-term cost-effectiveness analysis and underline that future research should investigate the modifying effect of age.At the end of the day, the choice of treatment needs to be individualized to the patient needs and preferences. Certain characteristics lead us to favor the LNG-IUS, such as need for contraception, wish to preserve fertility, risk of endometrial neoplasia or presence of concomitant gynecologic conditions such as adenomyosis. On the other hand, some women do not tolerate or refuse potential side effects of hormones. Let’s keep in mind that both methods are effective, minimally invasive and represent substantial savings compared to a hysterectomy, but when both options are adequate for a patient, the LNG-IUS is less costly for society.
Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer and is dosed according to a one-dose-fits-all paradigm. We aimed to identify a pharmacokinetically-guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic-pharmacodynamic model. Dosing strategies explored were the approved 180mg QD, the highest tolerable dose tested in clinical trials: 240mg QD, and two precision dosing strategies targeting the median trough concentrations following 180mg QD, and 240mg QD. We investigated the impact of alternative dosing regimens on progression-free survival (PFS), overall survival (OS), and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240mg dosing strategy, with only a minor increase in the probability of developing toxicity.
The flagellin epitope flg22, a pathogen-associated molecular pattern (PAMP), binds to the receptor-like kinase FLAGELLIN SENSING2 (FLS2), and triggers Ca2+ influx across the plasma membrane (PM). The flg22-induced increases in cytosolic Ca2+ concentration ([Ca2+]i) (FICA) play a crucial role in plant innate immunity. It’s well established that the receptor FLS2 and the key downstream component, reactive oxygen species (ROS) burst, undergoes sensitivity adaptation after flg22 stimulation, referred to as desensitization and resensitization, to prevent over responses to pathogens. However, whether FICA also mount adaptation mechanisms to ensure appropriate and efficient responses against pathogens remains poorly understood. Here, we carried out detailed analyses of [Ca2+]i increases upon two successive flg22 treatments, recorded and characterized, for the first time, rapid desensitization but slow resensitization of FICA in Arabidopsis thaliana. Pharmacological analyses showed that the rapid desensitization might be synergistically regulated by ligand-induced FLS2 endocytosis as well as the PM depolarization. The recovery of desensitized FICA might require to de novo FLS2 protein synthesis. FICA resensitization appeared significantly slower than FLS2 protein recovery, suggesting additional regulatory mechanisms of other components, such as flg22-related Ca2+ permeable channels. Taken together, we have carefully defined the FICA sensitivity adaptation, which will facilitate further molecular and genetic dissection of the Ca2+-mediated adaptive mechanisms in PAMP-triggered immunity.
Background: β-blockers are first-line therapy in patients with long QT syndrome (LQTS). However, β-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add-on therapy for LQT3 patients. However, the effect of sodium channel blockers in all LQT patients remains unknown. Methods: We conducted a systematic electronic search of PubMed, Embase and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc≥500 ms and QTc≤460 ms in LQTS patients. Results: Pooled analysis of 14 studies with 213 LQTS patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (MD -49.43, 95%CI -57.80 to -41.05, P<0.001), reduced the incidence of CEs (OR 0.12, 95%CI 0.04 to 0.32, P<0.001) and the proportion of QTc≥500 ms (OR 0.15, 95%CI 0.09 to 0.26, P<0.001), and increased the proportion of QTc≤460 ms (OR 18.00, 95%CI 7.49 to 43.26, P<0.001). Sodium channel blockers significantly shortened QTc both in LQT3 and non-LQT3 patients, while the QTc shortening effect in LQT3 was superior to that in non-LQT3 (57.39 ms vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 ms vs. 49.08 ms vs. 50.10 ms). Conclusions: sodium channel blockers can be useful both in LQT3 and non-LQT3 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best.
Role of activation of the coagulation system in the pathogenesis of urticariaTaro Yasuma,1 Corina N. D’Alessandro-Gabazza,1 Tetsu Kobayashi,2 John Morser,3 Esteban C Gabazza.1*1Department of Immunology,2Department of Pulmonary and Critical Care Medicine, Mie University Faculty and Graduate School of Medicine, and Mie University Hospital, Edobashi 2-174, Tsu, Mie 514-8507, Japan.3Division of Hematology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, United States*Correspondence: Esteban C Gabazza, MD, PhD, Department of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Postal Code 514-8507, Tsu-city, Mie, Japan. Tel.: +81 59 231 5017; fax: +81 59 231 5225.E-mail:firstname.lastname@example.orgWord count: 590
Introduction Type 2 diabetes mellitus (T2DM) frequently associates with increasing multi-morbidity/treatment complexity. Some headway has been made to identify genetic and non-genetic risk factors for T2DM. However longitudinal clinical histories of individuals both before and after diagnosis of T2DM are likely to provide additional insight into both diabetes aetiology/further complex trajectory of multi-morbidity. Methods This study utilised diabetes patients/controls enrolled in the DARE (Diabetes Alliance for Research in England) study where pre- and post-T2DM diagnosis longitudinal data was available for trajectory analysis. Longitudinal data of 281 individuals (T2DM n=237 vs matched non-T2DM controls n=44) were extracted, checked for errors and logical inconsistencies and then subjected to Trajectory Analysis over a period of up to 70 years based on calculations of the proportions of most prominent clinical conditions for each year. Results For individuals who eventually had a diagnosis of T2DM made, a number of clinical phenotypes were seen to increase consistently in the years leading up to diagnosis of T2DM. Of these documented phenotypes, the most striking were diagnosed hypertension (more than in the control group) and asthma. This trajectory over time was much less dramatic in the matched control group. Immediately prior to T2DM diagnosis a greater indication of ischaemic heart disease proportions was observed. Post-T2DM diagnosis, the proportions of T2DM patients exhibiting hypertension and infection continued to climb rapidly before plateauing. Ischaemic heart disease continued to increase in this group as well as retinopathy, impaired renal function and heart failure. Conclusion These observations provide an intriguing and novel insight into the onset and natural progression of T2DM. They suggest an early phase of potentially-related disease activity well before any clinical diagnosis of diabetes is made. Further studies on a larger cohort of DARE patients are underway to explore the utility of establishing predictive risk scores.
Abstract Aim: To investigate the health care utilization and drug consumption of patients with fibromyalgia (FM). Materials and Methods: This is a cross-sectional study using the Clalit Health Care database. Clalit is the largest HMO in Israel, serving more than 4.4 million enrollees. We identified FM patients and age and sex-matched controls. Indicators of healthcare utilization and drug consumption were extracted and analyzed for both groups. Results: The study included 14,296 FM patients and 71,324 controls. The mean age was 56 years, with a female predominance of 92%. The mean number of visits across of all healthcare services (hospitalizations, emergency department visit, general practitioner clinic visits, rheumatology clinic visits and pain clinic visits) and the mean difference (MD) were significantly higher for FM patients compared to controls (MD 0.66, p<0.001; MD 0.23, p<0.001; MD 7.49, p<0.001; MD 0.31, p<0.001; MD 0.13, p<0.001), respectively. Drug use was significantly and consistently higher among FM patients compared to controls; NSAIDs (non-steroidal anti-inflammatory drugs) OR 2.56, P<0.001; Opioids OR 4.23, P<0.001; TCA (tricyclic antidepressants) OR 8.21, P<0.001; Gabapentinoids OR 6.31, P<0.001; SSRI (selective serotonin reuptake inhibitors) OR 2.07, P<0.001; SNRI (serotonin-norepinephrine reuptake inhibitor) OR 7.43, P<0.001. Conclusion: Healthcare utilization and drug use are substantially higher among patients with fibromyalgia compared to controls
Leptospirosis is a zoonotic neglected disease of worldwide public health concern. Leptospira species can infect a wide range of wild and domestic mammals and can lead to a spectrum of disease, including severe and fatal forms. Herein, we report for the first time a fatal Leptospira interrogans infection in a free-ranging nonhuman primate (NHP), a black-tufted marmoset. Icterus, pulmonary hemorrhage, interstitial nephritis and hepatocellular dissociation were the main findings raising the suspicion of leptospirosis. Diagnostic confirmation was based on specific immunohistochemical and PCR assays for Leptospira species. Immunolocalization of leptospiral antigens and identification of pathogenic species ( L. interrogans species) were important for better understanding the pathogenesis of disease. One Health related implications of free-ranging NHPs in anthropized areas and transmission dynamics of human and animal leptospirosis are discussed.
Title Page: MinicommentaryThis is a minicommentary on Reid et al. “How common are complications following polypropylene mesh, biological xenograft 3 and native tissue surgery for pelvic organ prolapse? A secondary analysis from the PROSPECT trial”.Title: Understanding Risk: a substitute for Information?Author : Swati Jha (MD, FRCOG)Consultant Gynaecologist and Honorary Senior Clinical Lecturer, Sheffield University. Subspecialist in UrogynaecologyInstitute : Department of Urogynaecology, Sheffield Teaching Hospitals NHS Foundation TrustAddress : Sheffield Teaching Hospitals, Level 4, Jessop Wing, Tree Root Walk, Sheffield. S10 2SFSwati.Jha1@nhs.net0044 (0)114 2268568Fax : 0114 2268165
Dobhoff tubes, used for post-pyloric feedings, have a weighted metal end with a small diameter that enhances their flexibility to traverse the gastrointestinal tract. Unfortunately, the metal stylet can iatrogenically perforate surrounding structures in patients with diminished cough and gag (1); and extreme caution should be considered before its utilization.
Aim To describe the antiepileptic drug (AED) prescription pattern in pregnant women and women of childbearing age in the 2010-2019 period in the Lombardy region, Italy. Methods The Lombardy region administrative healthcare databases (2010-2019) were analysed. AEDs were classified as drugs belonging to the N03A subgroup of the Anatomical Therapeutic Chemical Classification System. Women 15-49 years old were considered as women of childbearing age, while exposure during pregnancy was estimated taking into account the 12 months before delivery (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM codes in the diagnosis record from 650 to 659). Results During 2019, 16,605 women of childbearing age (prevalence: 14.8‰) received at least one AED prescription. Pregabalin was the most widely used antiepileptic in women of childbearing age (22.3%), followed by valproic acid (20.0%). The prevalence of AED prescription in pregnant women was 3.8‰, and levetiracetam and lamotrigine (16.6%) were the most commonly prescribed drugs. The prevalence of AED prescription did not change from 2010 to 2019 in women of childbearing age or in pregnant women. Valproic acid was one of the most used AEDs in pregnancy until 2016, after which its prescription declined from 19% to 14% of AED users. Conclusions Despite the decrease in valproic acid prescription over time, this drug is still among the most used AEDs, in particular in women of childbearing age. Educational interventions for healthcare professionals and women are needed in order to reduce the risk of unplanned pregnancy.
Background: Concern exists regarding adequacy of visualization of stress echocardiograms performed without intravenous contrast in persons with Class III obesity (body mass index ≥ 40 kg/m2). Methods: Dobutamine stress echocardiography (DSE) was performed on 128 candidates for bariatric surgery with class III obesity without chest pain or pre-existent coronary artery disease (CAD). DSE without intravenous contrast was initially performed on 62 patients with class III obesity, then was subsequently was performed with intravenous contrast on 66 patients with class III obesity. Left ventricular (LV) regional wall motion was assessed at baseline and peak stress using the 16-segment model. Results: In the intravenous contrast group 1046 of 1056 LV segments studied (99.1%) were well-visualized and interpretable at baseline and 1044 of 1056 LV segments studied (98.9%) were well-visualized and interpretable at peak stress. In the non-contrast group 905 of 992 segments studied (91.2%) were well-visualized and interpretable at baseline and 886 of 992 segments studied (89.3%) were well-visualized and interpretable at peak stress. A significantly greater number of LV segments were well-visualized and interpretable in the intravenous contrast group than in the group compared to the non-contrast group, at baseline and at peak stress (p < 0.00001 for both). DSE was positive for ischemia in 1 patient. All patients underwent bariatric surgery without cardiovascular complications. Six months after surgery, all patients were alive; none developed cardiovascular events. Conclusion: The use of intravenous contrast during DSE significantly improves visualization and interpretability of LV segments in patients with class III obesity.