COVID-19 vaccination and pregnancy: getting the word outVictoria Male, Senior Lecturer in Reproductive Immunology, Imperial College LondonPregnancy is a risk factor for severe COVID-19, doubling the likelihood that an unvaccinated individual requires intensive care, invasive ventilation, or ECMO. Between March 2020 and December 2021 in the UK, COVID-19 emerged as the leading cause of death during pregnancy: among the 33 women who succumbed to the virus, none had been fully vaccinated (Knight et al, ISBN: 978-1-7392619-4-8). Furthermore, in unvaccinated individuals, SARS-CoV-2 during pregnancy can adversely affect infants, increasing the odds of preterm birth by 1.5-fold and those of stillbirth or neonatal death by approximately 3-fold (Male, Nat Rev Immunol, 2022, 22:277-82).In the face of these concerning statistics, COVID-19 vaccination in pregnancy seems a sensible precaution. Clinical trials and subsequent observational studies demonstrated that COVID-19 vaccination is safe and effective in the general population, but expectant parents naturally have an important additional question: is it safe for my baby?In the clinical trials of the COVID-19 vaccines, pregnancy was an exclusion criterion but nonetheless 102 participants became pregnant during mRNA vaccine trials, with miscarriage rates no different between the vaccinated and control groups. Early observational studies focussed on outcomes at birth which, during the pandemic, have been somewhat better in vaccinated individuals, particularly with respect to outcomes influenced by SARS-CoV2 infection (Prasad, Nat Comms, 2022, 13:2412*). A population-based cohort study published in this issue of BJOG (please add reference) is the latest in a mounting number of observational studies that examine the risk of early pregnancy loss following COVID-19 vaccination, controlling for gestational age and relevant medical and social confounders. This is the first to formally consider termination of pregnancy at the patient’s request as a competing risk, but whether or not this was including in the analysis, the authors found no increased risk of miscarriage associated with COVID-19 vaccination either during or before pregnancy.The evidence is now clear: COVID-19 vaccination is safe in pregnancy, but infection is not. Despite this, COVID-19 booster uptake among those eligible due to pregnancy remains low, peaking at 19% in the 2022-23 booster season. Some people are not aware their pregnancy makes them eligible for a booster and, among those who are, not all are informed of the extensive evidence on the safety and benefits of COVID-19 vaccination in pregnancy. Others believe their primary course of vaccination, or a previous infection, is sufficient to protect them. Although a primary course of vaccination continues to protect against severe disease, evidence on how long protection lasts, particularly in the face of new variants, is not yet available: as time elapses the benefit of a booster is expected to increase. Pertinently, people continue to die of flu during and shortly after pregnancy, despite having been exposed to the virus throughout their lives. In the UK, two women recently died this way: neither had received the recommended flu booster during pregnancy (Knight et al, ISBN: 978-1-7392619-4-8).While ongoing research remains important for confirming the safety of COVID-19 vaccination during pregnancy, it is unlikely that any new study will overturn the wealth of evidence we have already amassed. The challenge now is to get the word out.* For a regularly updated list of studies concerning the safety of COVID-19 vaccination in pregnancy, please see http://bit.ly/pregnancysafety
Herein we report an asymmetric two-component alkenyl Catellani reaction for the construction of C–N axial chirality through a pal-ladium/chiral norbornene cooperative catalysis and an axial-to-axial chirality transfer process. Various partially aromatic iodinated 2-pyridones, quinolones, coumarin and uracil substrates react with 2,6-disubstituted aryl bromides with a tethered amide group, to afford a wide variety of polycyclic C–N atropisomers (38 examples, up to 97% e.e.). The obtained C–N axial chirality is originated from the preformed transient C–C axial chirality with high fidelity. The synthetic utility of this chemistry is demonstrated by facile preparation of complex quinoline and pyridine based C–N atropisomers through a N-deprotection and aromatization sequence. In addition, a remote axial-to-central diastereoinduction process dictated by C–N axial chirality is observed with excellent diastere-ocontrol.
Background & Aims: Intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in HBV infection, cellular responses, antiviral and immunomodulator responses. Methods: 12 ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterised using histology, confocal and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma derived HBV (genotype B & C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT-PCR (RNA, cccDNA, extracellular DNA) and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon-stimulated genes (ISG)) to interferon-α and viral mimic (PolyI:C) were assessed. Results: ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well-differentiated ICOs using spinoculation, with time and donor dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg and HBsAg. Donor dependent drug-responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon-α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Conclusions: Human ICOs support HBV infection and replication with donor dependent variation in viral dynamics and cellular responses. These features can be utilised for development of personalised drug testing platform for antivirals.
EVE Clinical CommentaryThe case report by describes an interesting case of rib fracture in a race horse with an attributable hindlimb lameness. This case is the first to suggest that caudal rib fractures are a cause of hindlimb lameness and peri regional diagnostic analgesia of a rib fracture can be used to alleviate hindlimb lameness.A recent retrospective study reported 73 horses diagnosed with a rib fracture of which 56% (41/73) presented due to poor performance with a fewer number of horses presenting with lameness as a primary complaint (21/73). Undoubtedly rib fractures are painful in the acute stages of injury, with the most common site for rib fracture in a horse being dorsally (5-15cm from the costovertebral junction) on the 18th rib (Hall et. al. 2022). In this study, not all horses with caudal rib fractures were found to have lameness those that were lame had a variable pattern of lameness. All of the horses which underwent diagnostic analgesia were found to have lameness independent to the rib fracture. However only a small percentage of horses underwent diagnostic analgesia, a limitation of a retrospective study.An alternative retrospective case series of 50 rib fractures reported 5 fractures of the first rib which all occurred in racing thoroughbreds (age 2-7 years with a median age of 3), all of which had ipsilateral forelimb lameness. In the absence of a traumatic incident the authors suggested that fractures of the 1st rib may represent fatigue fracture pathology associated with training. A similar aetiology is possible for caudal rib fractures but is considered unlikely as this injury is not over represented in racing Thoroughbreds compared with a general population of horses and trauma remains the most likely cause.Ribs can be imaged in detail with nuclear scintigraphy given the relatively small amount of overlying soft tissue. Orthogonal images (lateral, dorsal and oblique) should be used to localise region, extent, pattern and origin of increased radiopharmaceutical uptake. Nuclear scintigraphy is highly sensitive in identifying osteoblastic activity but has low specificity for identifying the nature of the pathological process. Fractures show increased radiopharmaceutical uptake within 24-72 hours post injury, making nuclear scintigraphy highly sensitive in the acute stage of disease verses radiographic signs which may not be seen for around 7-10 days unless the fracture is displaced. The appearance of a fracture on nuclear scintigraphy includes 5-7 days of diffuse intense uptake, 1-4 weeks of focal intense uptake (figure 1.) and then a gradual decrease of radiopharmaceutical uptake over the next 6-12 months. This prolonged visibility on scintigraphy means that is difficult to age a fracture based on scintigraphy alone. Ultrasonography is potentially more suitable to monitor fracture healing and identify those cases which are non-healing and requiring intervention. Costochondral junctions normally have a moderate increased radiopharmaceutical uptake on nuclear scintigraphy and should not be mistaken for a rib fracture (figure 1.). The caudal ribs overly the kidney (figure 1.) but in most instances have a mild to moderate diffuse region of increased radiopharmaceutical uptake. The use of furosemide one hour before imaging has been advocated to improve soft tissue clearance and improve image count to background ratio. This was evaluated in a recent study where 1mg/kg furosemides was administered intravenously 1 h post 99m Tc-HDP administration and the image quality was assessed subjectively and semi-quantitively. There was no significant difference in image quality or radiation dose rate to handler, with a minimum distance of 30cm distance having the most effect on reducing handler dose rate by 65% .Ultrasonographic examination is highly sensitive and specific in identifying rib fractures (Hall et. al. 2022). If a rib fracture is suspected in the initial stages of examination, then survey ultrasonographic examination of the ribs is recommended, especially the caudal ribs. However, rib fractures rarely result in focal localising pain on palpation and so even a detailed clinical examination may be unrewarding. Ultrasonography of the ribs is a simple technique; clipping isn’t required and discontinuity and callus within the lateral cortex of the ribs is easy to identify (Figure 2) but should not be confused with the costochondral junction (figures 3 and 4). The costochondral junction is identified by the presence of hypoechoic cartilage and it should be noted that the margins of adjacent ribs are normally irregular at this site. In contrast, a rib fracture does not contain hypoechoic cartilage, though the rib margins are likely to be irregular and commonly periosteal new bone may be seen.In this case of hindlimb lameness due to fracture of the 18th rib , the horse took 12 months to recover and resume ridden exercise with conservative therapy. Ultrasonographic examination can monitor fracture healing and is useful in identifying non-healing fractures which may represent surgical candidates. Hall and colleagues (2022) reported six horses which underwent surgery due to failed initial conservative management which resulted in continued fracture instability, callus at the fracture site or fracture displacement causing impingement on adjacent ribs. One horse which underwent wedge ostectomy and internal fixation with a locking compression plate returned to its previous level of exercise. All other surgically managed cases (5/73) underwent partial rib resection. Most horses in this study were managed conservatively (67/73). Given the very small number of surgically managed cases it is not possible to determine if fracture healing or outcome would have been improved if surgical intervention had been performed in more cases.Peri-regional analgesia of a rib fracture is commonly used in human medicine as a therapeutic aid and is easy to perform in the horse. In this instance the ipsilateral hindlimb lameness was partially alleviated by this technique in the acute stage of lameness and completely abolished in the chronic stage of lameness. Perineural analgesia can result in increased radiopharmaceutical uptake within the soft tissues on bone phase scintigraphy, up to 7 days post blocking , with 50% of horses having uptake at the site of a tibial perineural injection one day post injection, 25% of horses at the block site 3 days post injection and 1 horse with increased radiopharmaceutical uptake 7 days post injection. An appropriate washout period is recommended prior to scintigraphy if perineural analgesia has been performed to prevent false positive results.Although rib fractures are largely under reported in adult horses this case report and recent retrospective studies confirm they should be considered a differential diagnosis for cases of poor performance and both fore and hind limb lameness. Diagnostic analgesia could be used to determine significance of the rib fracture in cases of hind limb lameness.
The asymmetric hydrogenation of N-heteroarenes provides an efficient method for the synthesis of optically active cyclic secondary amines. In this paper, we described an asymmetric hydrogenation of phenanthridines using a chiral mono-alkene-derived borane. A variety of dihydrophenanthridines were furnished in high yields with up to 93% ee. The current catalytic system was very sensitive for the steric hindrance of phenanthridines. Bulky substituents at one phenyl group of phenanthridines were required to obtain the high enantioselectivity. But large substituents adjacent to the C=N bonds would diminish the reactivity sharply.
Correspondence to “Association between Chronic Rhinosinusitis and New Onset Asthma Implications for Prevention”To the Editor,We have attentively reviewed the article by Schwartz et al. titled ’Sinus inflammation and chronic rhinosinusitis are associated with a diagnosis of new onset asthma in the following year’1. This study significantly advances our understanding of the relationship between chronic rhinosinusitis (CRS) and the onset of new asthma diagnoses. However, we would like to offer some suggestions.First and foremost, it is important to consider potential confounders that might influence the observed association between CRS and the development of asthma. Factors such as environmental exposures or socio-economic status could potentially impact this relationship.2,3Secondly, this study focuses on the CRS-asthma association but doesn’t probe how CRS treatments affect asthma outcomes. Phillips et al4showed timely CRS treatments, such as functional endoscopic sinus surgery (FESS) might lower asthma risks. Addressing eosinophilic inflammation and related conditions, e.g. depression, could also influence asthma results5,6. Understanding CRS treatment impacts on asthma is crucial for patient care, necessitating more research to inform clinical guidance.Furthermore, it’s important to consider that this study might have overestimated the connection between chronic rhinosinusitis (CRS) and asthma due to certain methodological limitations. The study did not take into account the 12-week duration requirement for CRS, potentially leading to an overrepresentation of cases and an overestimation of the associations . Additionally, the reliance on electronic health records (EHR) for identifying disease outcomes introduces the possibility of measurement errors or biases, which could further contribute to the overestimation of the observed associations . Therefore, it is crucial for future research endeavors to refine their methods and address these limitations in order to obtain a more accurate understanding of the strength of the CRS-asthma association.In conclusion, this study by Schwartz et al.’s research highlights a link between CRS and new asthma cases, but further exploration is needed on potential confounders, the effect of CRS treatments, and potential overestimations.1. Schwartz BS, Pollak JS, Bandeen-Roche K, et al. Sinus inflammation and chronic rhinosinusitis are associated with a diagnosis of new onset asthma in the following year. Allergy . Oct 2023;78(10):2659-2668. doi:10.1111/all.157712. Celebi Sozener Z, Cevhertas L, Nadeau K, Akdis M, Akdis CA. Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol . Jun 2020;145(6):1517-1528. doi:10.1016/j.jaci.2020.04.0243. Velasquez N, Gardiner L, Cheng TZ, et al. Relationship between socioeconomic status, exposure to airborne pollutants, and chronic rhinosinusitis disease severity. Int Forum Allergy Rhinol . Feb 2022;12(2):172-180. doi:10.1002/alr.228844. Phillips KM, Bergmark RW, Hoehle LP, Caradonna DS, Gray ST, Sedaghat AR. Chronic rhinosinusitis exacerbations are differentially associated with lost productivity based on asthma status. Rhinology . Dec 1 2018;56(4):323-329. doi:10.4193/Rhin18.0335. Shah SA, Kobayashi M. Pathogenesis of chronic rhinosinusitis with nasal polyp and a prominent T2 endotype. Heliyon . Sep 2023;9(9):e19249. doi:10.1016/j.heliyon.2023.e192496. Brunner WM, Schreiner PJ, Sood A, Jacobs DR, Jr. Depression and risk of incident asthma in adults. The CARDIA study. Am J Respir Crit Care Med . May 1 2014;189(9):1044-51. doi:10.1164/rccm.201307-1349OCAuthorIressa Cheng 1, Chin-Yuan Yii MD2,3. Su-Boon Yong4,5,Liang-Chun Shih MD, PhD 4,61 School of Medicine, Chung Shan Medical University, Taichung, Taiwan.2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, Taiwan;3 Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan.4 Department of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.5 Department of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, Taiwan.6 Department of Otorhinolaryngology-Head and Neck SurgeryAuthor Contributions:Iressa Cheng: Conceptualization, Writing - Original Draft PreparationChin-Yuan Yii: Conceptualization, Writing - Review & EditingLiang-Chun Shih: Writing - Review & EditingJiu Yao Wang: Conceptualization, Writing - Review & Editing, SupervisionSu-Boon Yong: Conceptualization, Writing - Review & Editing, Supervision, Project Administrationconflict of interests :The authors declare no conflict of interest.Corresponding author:1.Su-Boon Yong MD, PhD.Department of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.Department of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, Taiwan.email@example.com. Jiu Yao Wang MD, PhDCenter for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan, China.Department of Allergy, Immunology, and Rheumatology (AIR), China Medical University Children’s Hospital, Taichung, Taiwan, China.firstname.lastname@example.org
The [2.2]paracyclophane-derived oxazole-pyrimidine ligands with planar chirality (PYMCOX) were designed, synthesized and successfully applied in nickel-catalyzed asymmetric 1,2-reduction of α,β-unsaturated ketones, affording the chiral allylic alcohols with up to 99% yield and 99% ee. Meanwhile, this reduction reaction could be conducted on gram-scale without loss of activity and enantioselectivity, and the chiral ligand could be conveniently recovered with high yield.
Indole-based atropisomers are a very important class of axially chiral compounds. However, the atroposelective synthesis of axially chiral 2-arylindole remains largely unexplored. In this study, we report the successful synthesis of atropisomeric 2-arylindoles using direct amination of indoles with p-quinonediimines in the presence of chiral phosphoric acid as a catalyst. Quinonediimine acts as an aminating reagent through formal polarity inversion of imine. The malonate group on the 2-aryl of 2-indoles was found to be essential for high enantioselectivity of the products. This could be due to the additional interaction between the ester group and the catalyst, as well as the intramolecular hydrogen bonding. Our findings provide a new strategy for the asymmetric construction of 2-arylindole atropisomers.
A metal-free, green, and sustainable functionalization of unactivated alkyl sp3 C–H bonds is reported using iodine (III) as a feasible dehydrogenation agent under visible light or KBr, and alkyl chlorides, bromides, alcohols, and ketones could be constructed by addi-tion of different coupling reagents. Cheap and safe iodobenzene diacetate was used to form a strong radical to activate the alkyl sp3 C–H bond in a highly efficient manner, which can construct different alkylation products by adding corresponding coupling reagents.
This pilot experiment examines if a loss in muscle proteostasis occurs in people with obesity and whether endurance exercise positively influences either the abundance profile or turnover rate of proteins in this population. Men with (n = 3) or without (n = 4) obesity were recruited and underwent a 14-d measurement protocol of daily deuterium oxide (D2O) consumption and serial biopsies of vastus lateralis muscle. Men with obesity then completed 10-weeks of high-intensity interval training (HIIT), encompassing 3 sessions per week of cycle ergometer exercise with 1 min intervals at 100 % maximum aerobic power interspersed by 1 min recovery periods. The number of intervals per session progressed from 4 to 8, and during weeks 8-10 the 14-d measurement protocol was repeated. Proteomic analysis detected 352 differences (p < 0.05, false discovery rate < 5%) in protein abundance and 19 (p < 0.05) differences in protein turnover, including components of the ubiquitin-proteasome system. HIIT altered the abundance of 53 proteins and increased the turnover rate of 22 proteins (p < 0.05) and tended to benefit proteostasis by increasing muscle protein turnover rates. Obesity and insulin resistance are associated with compromised muscle proteostasis, which may be partially restored by endurance exercise.
Editorial. Platelet purinergic receptors and non-thrombotic diseases.Simon C. Pitchford1* and Dingxin Pan.11Pulmonary Pharmacology Unit, Institute of Pharmaceutical Science, King’s College London, London, UK.*Author for correspondence and reprint requests:Dr Simon PitchfordPulmonary Pharmacology UnitInstitute of Pharmaceutical Science5.43 Franklin Wilkins Building150 Stamford StreetWaterloo CampusKing’s College LondonLondon UKSE1 9NHPhone: +44 2078484266Fax: +44 207 8484788Simon.email@example.com
Abstract :Background: A noval radiologic sign in patients with renal failure and UE with metabolic acidosis has recently been identified as the lentiform fork sign. On magnetic resonance imaging (MRI), the ”lentiform fork sign” has been described as bilateral symmetrical hyperintensities in the basal ganglia encircled by a hyperintese rim delineating the lentiform nucleus. Changes in uremic solute retention, aberrant blood-brain barrier transport, disorderd vascular reactivity, altered electrolyte and acid-base balance, and altered hormone metabolism are the most likely causes of the condition.Case presentation : 56-year-old man with end-stage renal disease was brought to the emergency room for a progressive change in mental status and involuntary arm movements over the previous five days, which were also accompanied by mild dyspnea.A brain MRI was performed, and it revealed hyperintensity on T2/FLAIR in the white matter surrounding the basal ganglia. The haloperidol was stopped, and there more dialysis sessions were carried out.Conclusion : intensified hemodialysis and glycemic control are the cornerstones of treating DUS with likely reversible clinical symptoms and remission of imaging abnormalities.
Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dyspeptic diseases. In addition to their well-known risk profile, PPI consumption is related to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around 1-3%, due to the extraordinarily high rate of prescription and consumption of PPIs are related to a substantial risk. In this Position Paper, we provide clinicians with practical evidence-based recommendations for the diagnosis and management of HSRs to PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more in-depth investigations in the topic.
Editorial Comment on “Atopic outcomes at 2 years in the CORAL cohort, born in COVID-19 lockdown”Sandoval-Ruballos, Mónica1, Carmen Riggioni2,3, Jon Genuneit41 Pediatric Allergy and Immunology Clinic, Guatemala, Guatemala.2Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.3Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore.4 Pediatric Epidemiology, Department of Pediatrics, Medical Faculty, Leipzig University, Leipzig, GermanyAtopic conditions have been on the rise globally, particularly in industrialized nations.(1) This phenomenon has spurred interest in the potential connection between the surge in allergic disorders and modern lifestyles characterized by reduced microbial exposure and increased hygiene practices. While the hygiene theory proposes that the early childhood microbial environment plays a pivotal role in shaping immune system development, reducing the risk of atopic conditions, more recent findings have emphasized the role of a defective epithelial barrier. This recent perspective suggests that the upsurge in agents damaging the epithelial barrier, associated with industrialization and modern living, is at the core of the escalation of allergic, autoimmune, and other chronic conditions. Notably, these effects may have intensified during the pandemic. (2) (3)The SARS-CoV-2 pandemic in early 2020 prompted various lockdowns and stringent hygiene measures, offering an intriguing opportunity to investigate the impact of these altered environmental factors on the prevalence of atopic conditions. The CORAL study is a longitudinal observational project, following 365 infants born in Ireland, during the initial pandemic period (March-May 2020) from enrollment to 24 months of age. (4) The authors compared the occurrence of allergic diseases with a pre-pandemic Irish cohort (BASELINE study 2008-2011). (5) This investigation aims to shed light on the pandemic’s potential impact on infant allergic disease development.At first glance, the CORAL cohort exhibited higher rates of atopic dermatitis (AD) at both 12 and 24 months compared to BASELINE. However, this finding may reflect a gradual increase in AD incidence within their population, given that the BASELINE cohort was born about one decade earlier. Alternatively, the early-life environment during the lockdowns may have played a role. In addition, the authors delineated three patterns of AD. A more severe AD phenotype was noted among infants with persistent AD diagnosis at 24 months, and AD-persistent infants were more likely to be sensitized. This observation aligns with prior studies, highlighting the significance of severity, and atopic sensitization as relevant determinants of AD prognosis.(6)While AD rates were higher in the CORAL cohort, they exhibited lower rates of food sensitization and allergy compared to BASELINE, particularly significant in peanut sensitization and egg allergy, with a non-significant trend towards lower peanut allergy. Importantly, parents received complementary feeding advice at 6 months, emphasizing early peanut introduction. Therefore, these outcomes may be attributed to recommended early allergen introduction, along with other factors like increased breastfeeding, fewer infections during the first 12 months (7), lower antibiotic exposure, and sustained dietary allergen exposure during lockdown. The relevance of early allergen introduction, especially for peanut and egg, has gained prominence in international guidelines more recently, owing to accumulating evidence underscoring its role in directly reducing the development of food allergy (8).At 24 months, antibiotic usage and childcare outside home increased AD likelihood potentially linked to decreased infection rates and antibiotic use in children not attending daycare, preserving microbiota integrity. Intriguingly, despite more AD cases in children attending daycare, they exhibited lower allergic sensitization rates. Aeroallergen sensitization at 24 months was more pronounced among children cared for solely at home, thus reflecting environmental influence. From a theoretical perspective, it is plausible that the lockdown measures, which led to a substantial increase in indoor confinement, may have resulted in heightened exposure to indoor allergens,(9) consequently leading to higher sensitization rates. Furthermore, allergic sensitization at 12 and 24 months was associated with AD at both time points and with asthma diagnosis at 24 months.Despite its valuable insights, the CORAL study has limitations, including a small cohort size and potential selection bias, as it represented only 12% of eligible children. Here, high breastfeeding rates and low parental smoking rates may limit generalizability. Additionally, the small sample size might hinder the identification of associations that might be evident in larger cohorts.Other studies conducted during the pandemic have primarily focused on assessing the impact on allergic conditions during lockdowns. They have often reported positive effects of interventions such as hygiene, mask usage, and social distancing in reducing air pollution and lowering infection rates, potentially resulting in a reduced impact on allergic conditions (10). The CORAL study stands out among these studies due to its specific objective of evaluating the effect of lockdowns on the incidence of allergic diseases. Finally, it provides valuable insights into how the pandemic have influenced the health of infants born during this period. While the increased incidence of AD initially raises concerns, the lower rates of food sensitization and allergies suggest the positive effects of evolving allergy practices, particularly early allergen introduction. Furthermore, the beneficial impacts of lockdown, such as increased breastfeeding and reduced antibiotic use, may outweigh the anticipated risks associated with reduced early-life microbial exposures.This study enhances our understanding of the real-world impact of early-life environments on allergic disease risk. Continuous monitoring of the CORAL cohort into later childhood will reveal the lasting consequences of being born during the pandemic. These findings underscore the intricate interplay between environmental factors, infant health, and the development of allergies in a rapidly evolving landscape of healthcare practices.
1. Using the Farapulse pulse configuration and ablation procedure results in a significant esophageal temperature increase that is underestimated using the Circa probe and it is likely significantly higher temperature can be recorded at close proximity to the ablation electrodes. 2. A near-field tissue ablation is a mix of irreversible electroporation and thermal injury. 3. The bipolar energy delivery using the Farawave-catheter limits the field and thermal ablation to close proximity to the bipolar ablation electrodes limiting the impact on extracardiac tissues. 4. In the two published papers accompanying this editorial, the Farapulse PFA technology is shown to have no short or long-term adverse effect on the esophagus. However, reported phrenic nerve conduction stunning may occur (7,8). It is also noted that while Meininghaus et al. reported significant esophageal acute injuries using RF and Cryo no long-term data is provided that these findings resulted in long-term disabilities. 5. PFA is hampered by the inability to adequately assess irreversible lesion formation in real-time. 6. The advantage provided by using PFA ablation technology is added safety and faster procedure time. These conclusions need further affirmation when the technology is widely used.
Late Development of Pneumatoceles in Necrotizing PneumoniaSila Y. Kocer 1, Nathan C. Hull MD2, D. Dean Potter, Jr. MD 3, Theresa Madigan MD 4, Jennifer M. Boland MD5 and Nadir Demirel MD 61Ondokuz Mayis University School of Medicine, Samsun, Turkey2Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA. Email address: firstname.lastname@example.orgDivision of Pediatric Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA. Email address: email@example.comDivision of Pediatric Infectious Diseases, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA. Email address: firstname.lastname@example.orgDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. Email address: email@example.comDivision of Pediatric Pulmonology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA. Email address: firstname.lastname@example.orgCorrespondence : Sila Y. Kocer, Ondokuz Mayis University School of Medicine, Körfez, 55270 Samsun, Turkey. Email address: email@example.com. Tel.: +905514571963Conflict of interest: The authors declare no conflict of interest.Author contributions : Sila Y. Kocer: Writing – original draft. Nathan C. Hull: Writing – review and editing.D. Dean Potter Jr.: Writing – review and editing.Theresa Madigan: Writing – review and editing.Jennifer M. Boland: Writing – review and editing.Nadir Demirel: Writing – review and editing.Keywords : Lung cysts; complicated pneumonia; lobectomy; imaging; childrenTo the editor,Community-acquired pneumonia (CAP) is one of the most common serious infections in children, although it usually has a good prognosis1. Necrotizing pneumonia (NP), a rare but severe complication of CAP, consists of the destruction of the consolidated lung parenchyma, potentially leading to the formation of thin-walled cavities known as pneumatoceles 2. While they often resolve spontaneously without sequalae, progressively enlarging pneumatoceles have been reported 5. We report a pediatric case with an unusual course of pneumatocele development.A 3-year-old female with history of congenital hypothyroidism and mild asthma presented to her primary care physician for evaluation of intermittent fever for the past 6 days, with a maximum temperature of 38.8°C. She had a worsening wet cough and complained of chest pain while coughing. Lung examination was normal except for mild tachypnea. Based on the patient’s presentation, empiric oral amoxicillin 90 mg/kg/day was started for possible CAP. The patient presented to the clinic on day 6 of her antibiotic treatment with persistent low-grade fever and ongoing cough. She had normal vital signs, and there were no signs of respiratory distress. The lung examination revealed crackles at right lung fields. A chest X-ray (CXR) showed a large consolidation and an airspace with an air-fluid level in the right upper lobe (RUL) (Figure 1A). There was no pleural effusion. The patient was diagnosed with complicated pneumonia and was referred to our hospital.A chest computed tomography (CT) without intravenous (IV) contrast showed a large consolidation in the RUL with scattered internal cystic areas containing air-fluid levels (Figure 1B, C). These findings raised concern for NP, abscess, or congenital pulmonary airway malformation with superimposed pneumonia. Laboratory test results showed mild anemia (hemoglobin concentration of 10 g/dl), leukocytosis (white blood cell count of 14.1 x 109/L), thrombocytosis (platelet count of 752 x 109/L), and high C-reactive protein (CRP) (80 mg/L, normal: <5 mg/L). She was admitted and started on IV ceftriaxone and IV vancomycin. She remained afebrile during admission and was clinically well appearing. A nasal swab culture for Methicillin-resistant Staphylococcus aureus was negative, therefore, on day 2 of admission, IV vancomycin was discontinued. AStreptococcus pneumoniae urine antigen test was positive. Serologic testing for endemic fungi was negative. A QuantiFERON-TB Gold was indeterminate due to inadequate mitogen response. On day 3 of admission, in preparation for discharge, IV ceftriaxone was switched to oral cefdinir 14 mg/kg/day to complete a 4-week course. She remained afebrile and well after an additional 24-hour period of observation and was subsequently discharged.Towards the conclusion of her antibiotic course, a follow-up CXR showed near resolution of the RUL consolidative opacity with a few small residual lucencies in the RUL, presumed to be residual pneumatoceles (Figure 1D). She was asymptomatic without a cough, and her lung examination was normal. Inflammatory markers, including CRP and sedimentation rate, as well as white blood cell count and platelet count, were in the normal range. One month later, while the patient remained asymptomatic, a follow-up CXR revealed an enlarged pneumatocele (Figure 2A, B). A chest CT with IV contrast demonstrated a 7.2 x 5.3 x 7.6 cm air-filled cavity in the RUL (Figure 2C, D). No definite connection to the adjacent airways was seen on the chest CT. The patient then underwent a thoracoscopic right upper lobectomy. The procedure was challenging due to adhesions and bleeding (Figure 2E). The pathology examination of the resected lung tissue showed a simple fibrous-walled cyst devoid of epithelial lining, consistent with pneumatocele (Figure 2F). Gram stain, fungal smear, bacterial culture and fungal culture of the explanted lung tissue were negative. The patient made a full recovery, both radiologically and clinically.Patients with NP usually present with symptoms of CAP, unresponsiveness to initial outpatient treatment, such as high fever, cough, tachypnea, and general unwell appearance 1. The initial treatment of NP consists of IV antibiotics covering the most common etiologic agents of NP, which are known to be S. pneumoniae , Group AStreptococci and S. aureus . The optimal duration of antimicrobial therapy is not clearly defined; however, usually prolonged with a median duration of 4 weeks reported in the literature2, which aligns with guideline suggestions for therapy of empyema and parapneumonic effusion 3. Improvement in clinical and laboratory parameters usually allows for IV to oral antibiotic transition, which was accomplished relatively early for our patient, due to her less severe initial presentation and rapid clinical improvement. Pneumatoceles, air-filled cysts that can arise as a complication of NP, typically regress over weeks to months when NP is treated, but might require segmental or lobar resection if they become tense (exceeding more than 50% of the involved lobe), infected, or rupture 1. In our patient, many of the small pneumatoceles decreased in size after antibiotic treatment, with subsequent delayed and marked enlargement of one of them. A report on giant lung cysts emerging after NP suggested that, when patients remain clinically stable, treatment of pneumatoceles should be conservative with antibiotics alone regardless of the size of the cysts, as interventional procedures carry a risk of complications such as bronchopleural fistula 4. However, a study that proposed a treatment algorithm for pneumatoceles, recommended surgical resection for those that remained unresolved despite a conservative approach and gradually grew in size and wall thickness5. Our patient had no symptoms related to the pneumatocele. Nevertheless, it can be challenging to anticipate the progression of pneumatoceles, as they can enlarge enough to compromise respiration. The unusual expansion within a span of 1 month in our case, led to the decision of surgical resection.To summarize, we present a 3-year-old otherwise healthy girl with NP. After 4 weeks of antibiotic therapy, the right lung consolidations resolved and pneumatoceles decreased in size. However, one month later, while she remained clinically asymptomatic, a follow-up CXR revealed the progressive enlargement of a pneumatocele which eventually required surgical resection. Based on this experience, we suggest a close radiological follow-up of patients with post-infectious pneumatoceles, regardless of symptoms, until complete radiologic resolution is demonstrated.References1. de Benedictis FM, Kerem E, Chang AB, Colin AA, Zar HJ, Bush A. Complicated pneumonia in children. Lancet. 2020;396(10253):786–798. doi:https://doi.org/10.1016/s0140-6736(20)31550-62. Masters IB, Isles AF, Grimwood K. Necrotizing pneumonia: an emerging problem in children? Pneumonia (Nathan). 2017;9(1). doi:https://doi.org/10.1186/s41479-017-0035-03. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, Kaplan SL, Mace SE, McCracken GH, Moore MR, et al. The Management of Community-Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25–e76. doi:https://doi.org/10.1093/cid/cir5314. Gross I, Gordon O, Cohen‐Cymberknoh M, Reiter J, Tsabari R, Gileles‐Hillel A, Erlichman I, Hevroni A, Shoseyov D, Kerem E. Giant lung cysts following necrotizing pneumonia: Resolution with conservative treatment. Pediatr Pulmonol. 2019;54(6):901–906. doi:https://doi.org/10.1002/ppul.243215. Imamoğlu M, Cay A, Koşucu P, Ozdemir O, Cobanoğlu U, Orhan F, Akyol A, Sarihan H. Pneumatoceles in postpneumonic empyema: an algorithmic approach. J Pediatr Surg. 2005;40(7):1111–1117. doi:https://doi.org/10.1016/j.jpedsurg.2005.03.048Authors and affiliations : Sila Y. Kocer 1, Nathan C. Hull MD 2, D. Dean Potter, Jr. MD3, Theresa Madigan MD 4, Jennifer M. Boland MD 5 and Nadir Demirel MD 61Ondokuz Mayis University School of Medicine, Samsun, Turkey2Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA. Email address: firstname.lastname@example.orgDivision of Pediatric Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA. Email address: email@example.comDivision of Pediatric Infectious Diseases, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA. Email address: firstname.lastname@example.orgDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. Email address: email@example.comDivision of Pediatric Pulmonology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA. Email address: firstname.lastname@example.orgConflict of interest: The authors declare no conflict of interest.
Aim: The pharmacokinetics of doravirine have been studied in clinical trials, but not in real-world settings. Our study aims to characterize and identify factors influencing doravirine pharmacokinetics (a CYP3A4 substrate) in real-world people with HIV (PWH). Methods: A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. Results: A one-compartment model with first-order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 reduced CL by 50%, and a 30% decrease in CL was observed in an 80-year-old compared to a 55-year-old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between-subject variability in CL. Model-based simulations predicted 2.8-fold and 1.6-fold increases in median steady-state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co-administered. Conclusion: Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected non-adherence or pregnancy.