Response to Correspondence ALL-2023-01107 “Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy”P.J. de Kam1, S. Zielen2, J.A. Bernstein3, U. Berger4, M. Berger5, M. Cuevas6, D. Cypcar7, A. Fuhr-Horst8, W.A. Greisner9, M. Jandl10, S. Laßmann11, M. Worm12, J. Matz13, E. Sher14, C. Smith15, G.C. Steven16, R. Mösges17,18, M.H. Shamji19,20, L. DuBuske21, F. Borghese1, K. Oluwayi1, T. Zwingers1, M. Seybold1, O. Armfield1, M.D. Heath1, S.J. Hewings1, M.F. Kramer1, M.A. Skinner1Allergy Therapeutics plc, Worthing, United KingdomChildren and Adolescents Dept., Allergology, Pulmonology & Cystic fibrosis, Goethe University, Frankfurt, GermanyBernstein Clinical Research Center, LLC, Cincinnati, OH, United States of AmericaAerobiology and Pollen Research Unit, Dept. Oto-Rhino-Laryngology, Medical University Vienna, Vienna, Austria.Wiener Gesundheitsverbund, Hospital Hietzing, Department of Otorhinolaryngology, Vienna, AustriaClinic and Polyclinic of Otorhinolaryngology, University Clinic Carl Gustav Carus, TU Dresden, GermanyAllergy Partners of Western North Carolina, Asheville, NC, United States of AmericaENT Research- Institut für klinische Studien, Essen, GermanyBluegrass Allergy Research, Lexington, KY, United States of AmericaHamburger Institut für Therapieforschung GmbH, Hamburg, GermanyStudienzentrum Dr. Sabine Laßmann, Saalfeld, GermanyUniversitätsmedizin Berlin, Department of Dermatology and Allergy - Charite Campus Mitte, Berlin, GermanyChesapeake Clinical Research, Inc. White Marsh, MD, United States of AmericaAllergy Partners of New Jersey, Ocean, NJ, United States of AmericaCertified Research Associates, Cortland, NY, United States of AmericaAllergy Asthma & Sinus Center, S.C., Greenfield, WI, United States of AmericaIMSB (Institute of Computational Biology and Medical Statistics), University at Cologne, Cologne, GermanyClinCompetence, Cologne, GermanyImmunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, United KingdomAsthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United KingdomDivision of Allergy and Immunology, Department of Internal Medicine, George Washington University Hospital, Washington, DC, United States of America

Comment on “The risk assessment of uveitis after COVID-19 diagnosis”Patrick Wu,1 Chin-Yuan Yii,2 Su-Boon Yong3,4,5College of Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USADivision of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, TaiwanDepartment of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, TaiwanDepartment of Medicine, College of Medicine, China Medical University, Taichung, TaiwanCenter for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan.Corresponding authors:Chin-Yuan Yii, MDDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, TaiwanAddress: No.77, Guangtai Rd., Pingzhen Dist., Taoyuan City 32449, Taiwan Telephone: +886 3 494 1234Email: yiichinyuan@gmail.com2. Su-Boon Yong, MD PhDDepartment of Medicine, College of Medicine, China Medical University, Taichung, TaiwanAddress: No. 2, Yuh-Der Road, Taichung City 404, TaiwanTelephone: 00886-4-22052121Email: yongsuboon@gmail.comFirst author:Patrick Wu, BSCollege of Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USAAddress: 5000 Lakewood Ranch Blvd, Bradenton, FL 34211, USATelephone: +1(301)3375805Email: PWu36911@med.lecom.eduData availability statement: Not applicable. This letter to the editor does not require data collection.Funding statement: Not applicable. Authorship for letter to the editor did not receive any funding.Conflict of interest disclosure: The authors do not have any conflict of interests to declare.Ethics approval statement: Not applicable.Patient consent statement: Not applicable.Permission to reproduce material from other sources: Not applicable.Clinical trial registration: Not applicable.AbstractSeveral suggestions were made for the study by Hsia et al1 regarding uveitis risk following COVID-19 diagnosis. We recommend the authors align the racial composition of study groups more closely with that of U.S. demographics. In addition, we recommend the study to include possibility of false negatives from PCR testing. Lastly, we suggest the authors to consider cases of self-limiting uveitis and relapses independent of COVID-19.Keywords: uveitis risk, COVID-19, racial composition, PCR testing, self-limiting uveitis, relapsesTo the Editor,We read with great interest the study by Hsia et al1regarding the risk assessment of uveitis after COVID-diagnosis. We appreciate the authors’ attention to detail by eliminating possible confounding variables that may contribute to uveitis development. Furthermore, we were impressed by the robust study design incorporating propensity score matching, long follow-ups, and immense study size of more than 4 million patients using the TriNetX analytics platform.Nevertheless, to enhance this study, we recommend the following considerations.First, this study utilized the US research network, covering about 92 million patients to form a COVID-19 cohort and a non-COVID-19 control group, each with 2 million patients, of which 62.5% and 62.4% were white, respectively. This underrepresents the white population by 13% compared to the 75.5% white representation in the 2022 US census. Future studies should align the racial composition of study groups more closely with national demographics.Second, the authors identified COVID-19 cases based on positive PCR tests or antibody immunoassays. Yet, Binny et al’s study in New Zealand illustrates how PCR test sensitivity fluctuates across the COVID-19 infection timeline, influenced by viral load and patient age.2 The sensitivity of PCR tests peaks at 92.7% between 4 to 5 days post-infection, then drops to 88% from 5 to 14 days, while specificity remains near 100%.2 This indicates a higher likelihood of false negatives and very low false positives in PCR testing. Highlighting this significant limitation in the discussion section would be beneficial.Third, this study excluded those diagnosed with uveitis within 6 months before COVID-19 infection, potentially overlooking undiagnosed, self-limiting cases that may resurface post-infection. 10% of intermediate uveitis cases resolve on their own, and anterior uveitis, while often self-limiting, can cause severe complications.3,4 Moreover, uveitis relapses, as reported in Grunwald et al’s study, could occur independently of COVID-19, leading to misattribution of these cases to COVID-19.5 These aspects represent potential limitations of the study that warrant discussion.In conclusion, the study by Hsia et al1 is a major milestone towards incorporating uveitis assessment among COVID-19 patients in healthcare guidelines. This study has tremendous potential to save numerous patients from glaucoma, cataracts, and permanent vision loss. To improve this study, we recommend authors to adjust study groups so that white patients are adequately represented, discuss the possibility of false negatives from PCR testing, and consider cases of self-limiting uveitis and relapses independent of COVID-19.Acknowledgements: noneReferencesHsia NY, Hsu AY, Wang YH, Li JX, Chen HS, Wei JC, Lin CJ, Tsai YY. The risk assessment of uveitis after COVID-19 diagnosis: A multicenter population-based study. J Med Virol. 2023 Oct;95(10):e29188. doi: 10.1002/jmv.29188. PMID: 37881132.Binny RN, Priest P, French NP, Parry M, Lustig A, Hendy SC, Maclaren OJ, Ridings KM, Steyn N, Vattiato G, Plank MJ. Sensitivity of Reverse Transcription Polymerase Chain Reaction Tests for Severe Acute Respiratory Syndrome Coronavirus 2 Through Time. J Infect Dis. 2022 Dec 28;227(1):9-17. doi: 10.1093/infdis/jiac317. PMID: 35876500; PMCID: PMC9384503.Maggon R. INTERMEDIATE UVEITIS PARS PLANITIS. Med J Armed Forces India. 2001 Jan;57(1):84-5. doi: 10.1016/S0377-1237(01)80106-4. Epub 2011 Jul 21. PMID: 27365593; PMCID: PMC4925061.Islam N, Pavesio C. Uveitis (acute anterior). BMJ Clin Evid. 2010 Apr 8;2010:0705. PMID: 21736765; PMCID: PMC2907596.Grunwald L, Newcomb CW, Daniel E, Kaçmaz RO, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Foster CS, Kempen JH; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Risk of relapse in primary acute anterior uveitis. Ophthalmology. 2011 Oct;118(10):1911-5. doi: 10.1016/j.ophtha.2011.02.044. Epub 2011 Jun 16. PMID: 21680024; PMCID: PMC3179829.

POLE codes for DNA polymerase epsilon (Pol ε) and variants of Pol ε catalytic subunit 1 can be pathogenic. We recently reported a novel POLE gene variant (p.[D1131fs];[T1891del]) which leads to bone marrow failure in two Japanese sisters. Here, we describe the successful course of hematopoietic stem cell transplantation of these two sisters. Both cases were born with congenital anemia and remained transfusion dependent. Their bone marrow showed gradually proceeding trilineage dysplasia. They both underwent HCT from an unrelated bone marrow donor and successfully achieved engraftment. Ten and eight years have passed respectively, and they are doing well without transfusion.

Title: Low attenuation areas in necrotizing soft tissue infectionAuthors: Masanori Kawataki MD1, Yuta Oda MD2

Netherton syndrome (NS) is a rare autosomal recessive genodermatosis (OMIM #256500) characterized by superficial scaling, atopic manifestations, and multisystemic complications. It is caused by loss-of-function mutations in the SPINK5 gene, which encode a key kallikrein protease inhibitor. There are two subtypes of the syndrome that differ in clinical presentation and immune

Successful treatment of refractory prurigo nodularis with abrocitinibFang Sun1, Zhenzhen Wu11 Derpartment of Dermatology, Affiliated AoYang Hospital of Jiangsu University, Zhangjiagang, Jiangsu, ChinaCorresponding author: Zhenzhen Wu, Derpartment of Dermatology, Affiliated AoYang Hospital of Jiangsu University, Zhangjiagang, Jiangsu, ChinaZhangjiagang 222 Gangcheng Road, Jiangsu, China, E-mail: 19951236675 @163.com

Introduction: Scrub typhus is a neglected life threatening acute febrile illness caused by bacteria Orientia tsutsugamushi and it is a vector-borne zoonotic disease. In 2009, scrub typhus outbreak at Gedu has awakened Bhutan on the awareness and testing of the disease.Information and data of the study highlights the need for in depth surveillance, awareness among prescribers and initiate preventive measures in the country. Methods: We used retrospective descriptive study through review of laboratory registers across three health centres in Zhemgang district, south central Bhutan. The laboratories registers have been transcribed into CSV file using Microsoft excel. Variables of interest were collected from the registers and then analysed using open statistical software R, (R Core Team (2020). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.) And use of mStats package, (MyoMinnOo (2020). mStats: Epidemiological DataAnalysis. R package version 3.4.0.) Results: Of the total 922 tests prescribed for suspected scrub typhus in the three health centers in Zhemgang, only 8.2 % (n=76) were tested positive. Of these, Panbang Hospital had highest reported positive for scrub typhus with 56.6 %( n=43) followed by Yebilaptsa Hospital 35.5 %( n=27) and Zhemgang Hospital with 7.9 %( n=6). The female gender is comparably more affected as opposed to male with 57.9% (n=44) of the positive cases being female. The prevalence of scrub typhus seems to be affected by the seasonal variation as the months of Spring, Summer and Autumn together accounts for 98.7%(n=75) of total positive cases. The year 2019 noted significant scrub typhus cases accounting to 89.5 %(n=68) of the total positive cases over the two years. Conclusions:The overall tests tested positive of the scrub typhus infection within two years was 8.2%.

Introduction:A medical condition characterized by the congenital absence of skin, predominantly affecting the lower extremities, blisters on both skin and mucous membranes, and congenital absence and deformities in nails, has been identified within a familial context(1). The inheritance pattern aligns with a fully penetrant, autosomal dominant gene(1).In 1966, Bart introduced Bart syndrome, a condition marked by the simultaneous occurrence of congenital epidermolysis bullosa, localized congenital absence of skin affecting the extremities, and the abnormal shedding or dystrophy of nails(2). This syndrome is fascinating in the medical field due to its more optimistic prognosis when contrasted with other epidermolysis bullosa types(2). This type is known as Aplasia cutis congenital type VI(3).In this study, we have presented a case of a neonate with some disorders that guide us to different diagnoses and syndromes, such as CHIME syndrome and Barth syndrome, that have contributed.

Fluoride (F) has been employed worldwide to control dental caries. More recently, it has been suggested that the consumption of low doses of F in the drinking water may reduce blood glucose levels, introducing a new perspective for the use of F for the management of blood glucose. However, the exact mechanism by which F affects blood glucose levels remains largely unexplored. Given that the small gut plays a pivotal role in glucose homeostasis, the aim of this present study was to investigate the proteomic changes induced by low doses of F in the ileum of female non-obese-diabetic (NOD) mice. Forty-two female NOD mice were divided into two groups based on the F concentration in their for 14 weeks: 0 (control) or 10 mg/L. At the end of the experimental period, the ileum was collected for proteomic and Western Blotting analyses. Proteomic analysis indicated an increase in isoforms of actin, gastrotropin (confirmed by Western Blotting), several H2B histones and enzymes involved in antioxidant processes, as well as a decrease in enzymes essential for energy metabolism. In summary, our data indicates an adaptive response of the organism to preserve protein synthesis in the ileum, despite significant alterations in energy metabolism typically induced by F, therefore highlighting the safety of controlled fluoridation in water supplies.

In this article, we study an unified resilient asymmetric bipartite consensus (URABC) problem for nonlinear multi-agent systems with both cooperative and antagonistic interactions under denial-of-service (DoS) attacks. We first prove that the URABC problem is solved by stabilizing the neighborhood asymmetric bipartite consensus error. Then, we develop a distributed compact form dynamic linearization method to linearize the neighborhood asymmetric bipartite consensus error. By using an attack compensation mechanism to eliminate the adverse effects of DoS attacks and an extended discrete state observer to enhance the robustness against unknown dynamics, we finally propose a distributed resilient model-free adaptive control algorithm to solve the URABC problem. A numerical example validates the proposed results.

TitleSuperfetation and Heterotopic Pregnancy: Case Report of Two Rare Phenomena Coexisting and Implications in the Era of Assisted Reproductive Technologies

Deterioration of lung diffusion capacity during childhood in sickle cell diseaseWord count: 1500To the Editor,The American Society of Hematology guidelines, 2019, recommended obtaining pulmonary function tests (PFTs) in patients with sickle cell disease (SCD) with various respiratory symptoms even if they are at their steady state.1 These guidelines acknowledged that the usefulness of routine PFT is unknown because of the lack of research. However, this society further suggested that if the PFTs are obtained, it should be a comprehensive study including lung volumes and lung-diffusing capacity for carbon monoxyde (DLCO), in addition to spirometry.1 A large study in adult patients (n=310) with SCD showed that pulmonary function is abnormal in 90% of adult patients with Hb-SS.2 Common abnormalities included restrictive physiology and decreased DLCO. In this study, decreased DLCO indicated more severe sickle vasculopathy characterized by impaired hepatic and renal function, and a negative linear correlation existed between DLCO and age, suggesting that in adults with Hb-SS, disruption of alveolar–capillary gas exchange progressively deteriorated with time.2 Two recent cross-sectional studies of children with SCD showed that pulmonary function, including DLCO, worsened with age and showed correlations with biological markers of inflammation (induced sputum IL‐6 levels or blood neutrophilia).3,4Overall, these studies highlight the potential interest of DLCO measurement in SCD. The DLCO is the product of KCO (carbon monoxide coefficient of transfer) and alveolar volume (VA) and these two latter indices need to be interpreted separately since the decrease in DLCO is often mitigated by a preserved KCO or even increased KCO in SCD. It has been demonstrated that when corrected for hemoglobin levels, the children with SCD compared to controls of similar age had elevated KCOcorrected. The determination of alveolar-capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) from the lung diffusing capacity for carbon monoxide (DLCO) or for nitric oxide (DLNO) has been done in SCD since the seventies, demonstrating an increase in Vc in SCD. KCO is mathematically linked to both Dm and Vc (1/KCO = VA/Dm + VA/θVc); thus, the increase in KCO is related to Vc increase, but since DLCO has been shown to worsen with age, the changes of DLCO, VA and KCO over time in children with SCD deserve to be studied.The objectives of our study were to describe the evolution of DLCO and its determinants, KCO and VA, and to further assess the initial risk factors of the decrease in DLCO in children/adolescents with SCD. To this end, we retrospectively recorded the routine follow-up PFTs of children with SCD who were included in a prospective cross-sectional study that included the measurement of both DLCO and DLNO with the calculation of Dm and Vc.5

The conversion of CF3-alkenes to gem-difluoroalkenes using reductive cross-coupling strategy has received much attention in recent years, however, the use of green and readily available reducing salt to mediate these reactions remains to be explored. In this work a concise construction of gem-difluoroalkenes, which requires neither a catalyst nor a metal reducing agent, was established. Rongalite, a safe and inexpensive industrial product, was employed as both a radical initiator and reductant. This procedure was compatible with both linear and cyclic diaryliodonium salts, enabling a wide variety of substrates (>70 examples). The utility of this approach was demonstrated through gram-scale synthesis and efficient late-stage functionalizations of anti-inflammatory drugs.

Having a multitude of choices can be advantageous, yet an abundance of options can be detrimental to the decision-making process. Based on existing research, the present study combined electroencephalogram and self-reported methodologies to investigate the neural mechanisms underlying the phenomenon of choice overload. Behavioral data suggested that an increase in the number of options led to negative evaluations and avoidance of choice tendencies, even in the absence of time pressure. Event-related potential results indicated that the large choice set interfered with the early visual process, as evidenced by the small P1 amplitude, and failed to attract more attentional resources in the early stage, as evidenced by the small amplitude of P2 and N2. However, the LPC amplitude was increased in the late stage, suggesting greater investment of attentional resources and higher emotional arousal. Multivariate pattern analysis revealed that the difference between small and large choice set began at around 120ms and the early and late stages were characterized by opposite activation patterns. This suggested that too many options interfered with early processing and necessitate continued processing at a later stage. In summary, both behavioral and ERP results confirm the choice overload effect, and it was observed that individuals tend to subjectively exaggerate the choice overload effect.

Title: Major aortopulmonary collateral artery aneurysms- a rare cause of airway narrowing

A probabilistic limit equilibrium framework combining empirical load transfer factor and anisotropy of soil cohesion is developed to conduct pile-reinforced slope reliability analysis. The anisotropy of soil cohesion is determined conditioned on that the thrust force direction is parallel to the major principal direction and it is easily combined with load transfer factor, which are related with soil parameters, and pile parameters. The proposed method is illustrated against a homogeneous soil slope. The sensitivity studies of pile parameters on FS (calculated at respective means of soil parameters) and β demonstrated that the anisotropy of soil cohesion tends to pose significant effect on reliability index β than on FS. The effect of anisotropy of soil cohesion on FS is found to be slightly different under different pile locations, whereas its effect on β is observed to be least if piles are drilled at the middle part of slope and more significant effect is observed when piles are drilled at the lower and upper part of slope. The plots from the sensitivity studies provide an alternative tool for pile designs aiming at the target reliability index β. The proposed method contributes to the pile-reinforced slope stability within limit equilibrium framework.

We here present a chatbot assistant infrastructure (https://www.ebi.ac.uk/pride/chatbot/) that simplifies user interactions with the PRIDE database, the most popular proteomics data repository. Our system utilizes two advanced Large Language Models (LLM), llama2-13b and chatglm2-6b, and includes a web service API (Application Programming Interface), web interface, and sophisticated algorithms. We have developed a novel approach to construct vector-based representations for enabling the LLM responses, featuring a curated version and a comprehensive database of relevant links and paragraphs for each generated response. An important part of the framework is a benchmark component based on an Elo-ranking system, providing a scalable method for evaluating not only the performance of llama2-13b and chatglm2-6b but also, of any other available and future open-source LLMs. Throughout the benchmarking process, the PRIDE documentation for external users was refined to enhance the clarity and efficacy in addressing user queries. Importantly, while our infrastructure is exemplified through its application in the PRIDE database context, the modular and adaptable nature of our approach positions it as a valuable tool for improving user experiences across a spectrum of bioinformatics and proteomics tools and resources, among other domains. The integration of advanced LLMs, innovative vector-based construction, the benchmarking framework, and optimized documentation collectively form a robust and transferable chatbot assistant infrastructure.

Purpose: Sickle cell disease (SCD) affects all organ systems and is characterized by numerous acute and chronic complications and comorbidities. Standardized codes are needed for complications/comorbidities used in real-world evidence (RWE) studies that rely on administrative and medical coding. This systematic literature review was conducted to produce a comprehensive list of complications/comorbidities associated with SCD, along with their diagnosis codes used in RWE studies. Methods: A search in MEDLINE and Embase identified studies published from 2016-2023. Studies were included if they were conducted in US SCD populations and reported complications/comorbidities and respective International Classification of Diseases, Clinical Modification (ICD-CM) codes. All identified complications/comorbidities and codes were reviewed by a certified medical coding expert and hematologist. Results: Of 1,851 identified studies, 40 were included. The most reported complications/comorbidities were stroke, acute chest syndrome, pulmonary embolism, venous thromboembolism, vaso-occlusive crisis, and priapism. Most of the studies used ICD-9-CM codes (n=21), while some studies used ICD-10-CM codes (n=3) or both (n=16), depending on the study period. Most codes reported in literature were heterogeneous across complications/comorbidities. The medical coding expert recommended modifications for several conditions. Conclusion: While many studies we identified did not report their codes and were excluded from this review, the studies with codes exhibited diverse coding definitions. By providing a standardized set of diagnosis codes that were reported by studies and reviewed by a coding expert and hematologist, our review can serve as a foundation for accurately identifying complications/comorbidities in future research, and may reduce heterogeneity, enhance transparency, and improve reproducibility.