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Evey Howley,1 E Graham Davies,1 Alexandra Y Kreins1,2 1Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 2Infection, Immunity and Inflammation Research & Teaching Department, University College London, London, UKCorrespondence: Alexandra Y Kreins, Email a.kreins@ucl.ac.ukAbstract: Inborn errors of thymic stromal cell development and function which are associated with congenital athymia result in life-threatening immunodeficiency with susceptibility to infections and autoimmunity. Athymic patients can be treated by thymus transplantation using cultured donor thymus tissue. Outcomes in patients treated at Duke University Medical Center and Great Ormond Street Hospital (GOSH) over the past three decades have shown that sufficient T-cell immunity can be recovered to clear and prevent infections, but post-treatment autoimmune manifestations are relatively common. Whilst thymus transplantation offers the chance of long-term survival, significant challenges remain to optimise the outcomes for the patients. In this review, we will discuss unmet needs and offer practical guidance based on the experience of the European Thymus Transplantation programme at GOSH. Newborn screening (NBS) for severe combined immunodeficiency (SCID) and routine use of next-generation sequencing (NGS) platforms have improved early recognition of congenital athymia and increasing numbers of patients are being referred for thymus transplantation. Nevertheless, there remain delays in diagnosis, in particular when the cause is genetically undefined, and treatment accessibility needs to be improved. The majority of athymic patients have syndromic features with acute and chronic complex health issues, requiring life-long multidisciplinary and multicentre collaboration to optimise their medical and social care. Comprehensive follow up after thymus transplantation including monitoring of immunological results, management of co-morbidities and patient and family quality-of-life experience, is vital to understanding long-term outcomes for this rare cohort of patients. Alongside translational research into improving strategies for thymus replacement therapy, patient-focused clinical research will facilitate the design of strategies to improve the overall care for athymic patients.Keywords: athymia, thymus transplantation, immunodeficiency, DiGeorge syndrome, SCID, rare diseases, quality of life

Summary: One of the major challenges facing cloud computing is to accurately predict future resource usage to provision data centers for future demands. Cloud resources are constantly in a state of flux, making it difficult for forecasting algorithms to produce accurate predictions for short times scales (ie, 5 minutes to 1 hour). This motivates the research presented in this paper, which compares nonlinear and linear forecasting methods with a sequence prediction algorithm known as a recurrent neural network to predict CPU utilization and network bandwidth usage for live migration. Experimental results demonstrate that a multitime‐ahead prediction algorithm reduces bandwidth consumption during critical times and improves overall efficiency of a data center. [ABSTRACT FROM AUTHOR]

Twelve males (six moderate drinkers and six abstainers) were studied for the influence of varying dosages of alcohol on cardiorespiratory function and work performance. The subjects underwent three separate maximal exercise tests which consisted of progressive workloads on the bicycle ergometer. Prior to each work bout the subject consumed either a placebo (0.0 ml.kg-1), small (0.44 ml.kg-1), or a moderate (0.88 ml.kg-1) dose of a 95 per cent ethanol solution. Analysis of the results indicated that the ingestion of a small or moderate amount of alcohol had no significant effect on heart rate, blood pressure, ventilation, oxygen uptake or work performance. [ABSTRACT FROM PUBLISHER]

The application of automated blood pressure measurement during exercise has been limited by inaccuracies introduced by the effects of accompanying motion and noise. We evaluated a newly developed automated blood pressure monitor for measuring exercise blood pressure (Colin STBP-680; Colin, San Antonio, Texas, USA). The STBP-680 uses acoustic transduction with the assistance of the electrocardiogram R-wave to trigger the sampling period for blood pressure measurement. The automated monitor readings were compared with simultaneous technician mercury sphygmomanometric readings in the same arm. Blood pressure was measured in 18 men at rest and during exercise at 40% VO2 peak, (low intensity), 70% VO2 peak (moderate intensity) and VO2 peak (high intensity) on the cycle ergometer. Mean(s.d.) systolic blood pressure difference between the automated monitor and mercury manometer readings at rest and during exercise at low, moderate and high work intensities were 3(0) mmHg, 3(2) mmHg, 1(1) mmHg, and 0(11) mmHg respectively (analysis of variance; P > 0.05). Resting diastolic blood pressure obtained with the STBP-680 was similar to the mercury manometer readings (78(10) versus 81(7) mmHg (P > 0.05). Exercise diastolic pressure at the low level of work intensity was almost identical between the automated monitor and mercury manometer readings (64(8) versus 65(10) mmHg (not significant)). Diastolic blood pressure readings between the STBP-680 and mercury manometer showed a greater difference at the moderate and high workloads (11 mmHg and 9 mmHg, respectively), but this difference was not significant (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM PUBLISHER]

Congenital athymia is a life-limiting disorder due to rare inborn errors of immunity causing impaired thymus organogenesis or abnormal thymic stromal cell development and function. Athymic infants have a T-lymphocyte-negative, B-lymphocyte-positive, natural killer cell-positive immunophenotype with profound T-lymphocyte deficiency and are susceptible to severe infections and autoimmunity. Patients variably display syndromic features. Expanding access to newborn screening for severe combined immunodeficiency and T lymphocytopenia and broad genetic testing, including next-generation sequencing technologies, increasingly facilitate their timely identification. The recommended first-line treatment is allogeneic thymus transplantation, which is a specialized procedure available in Europe and the United States. Outcomes for athymic patients are best with early diagnosis and thymus transplantation before the development of infectious and inflammatory complications. These guidelines on behalf of the European Society for Immunodeficiencies provide a comprehensive review for clinicians who manage patients with inborn thymic stromal cell defects; they offer clinical practice recommendations focused on the diagnosis, investigation, risk stratification, and management of congenital athymia with the aim of improving patient outcomes., Competing Interests: Disclosure statement A.Y.K. is supported by the Wellcome Trust (222096/Z/20/Z). F.D. is supported by an NIHR Academic Clinical Lectureship and an Academy for Medical Sciences Starter Grant. E.H. and E.G.D. are supported by a grant from the Great Ormond Street Hospital Children’s Charity. O.E.’s laboratory is supported by grants from the Swedish Research Council (2018-02752 and 2022-00781) and the Swedish state under an ALF agreement between the Swedish government and the county councils (ALFGBG-965795). A.V. is supported by a core grant from the Telethon Foundation. F.J.T.’s laboratory is supported in part by EU H2020 grant RECOMB (755170–(b)) and has received funding from the European UnionHorizon 2020 research and innovation program as well as from reNEW, the Novo Nordisk Foundation for Stem Cell Research (NNF21CC0073729). G.A. is supported by an MRC Programme Grant to GA (MR/T029765/a). and G.H. is supported by the Wellcome Trust (211944/Z/18/Z). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Congenital athymia is a rare T-lymphocytopaenic condition, which requires early corrective treatment with thymus transplantation (TT). Athymic patients are increasingly identified through newborn screening (NBS) for severe combined immunodeficiency (SCID). Lack of relatable information resources contributes to challenging patient and family journeys during the diagnostic period following abnormal NBS results. Patient and Public Involvement and Engagement (PPIE) activities, including parental involvement in paediatrics, are valuable initiatives to improve clinical communication and parental information strategies. Parents of infants with suspected athymia were therefore invited to discuss the information they received during the diagnostic period following NBS with the aim to identify parental information needs and targeted strategies to address these adequately. Parents reported that athymia was not considered with them as a possible differential diagnosis until weeks after initial NBS results. Whilst appropriate clinical information about athymia and TT was available upon referral to specialist immunology services, improved access to easy-to-understand information from reliable sources, including from clinical nurse specialists and peer support systems, remained desirable. A roadmap concept, with written or digital information, addressing parental needs in real time during a potentially complex diagnostic journey, was proposed and is transferrable to other inborn errors of immunity (IEI) and rare diseases. This PPIE activity provides insight into the information needs of parents of infants with suspected athymia who are identified through SCID NBS, and highlights the role for PPIE in promoting patient- and family-centred strategies to improve IEI care., (© 2024. The Author(s).)

Chronic human norovirus (HuNoV) infections in immunocompromised patients result in severe disease, yet approved antivirals are lacking. RNA-dependent RNA polymerase (RdRp) inhibitors inducing viral mutagenesis display broad-spectrum in vitro antiviral activity, but clinical efficacy in HuNoV infections is anecdotal and the potential emergence of drug-resistant variants is concerning. Upon favipiravir (and nitazoxanide) treatment of four immunocompromised patients with life-threatening HuNoV infections, viral whole-genome sequencing showed accumulation of favipiravir-induced mutations which coincided with clinical improvement although treatment failed to clear HuNoV. Infection of zebrafish larvae demonstrated drug-associated loss of viral infectivity and favipiravir treatment showed efficacy despite occurrence of RdRp variants potentially causing favipiravir resistance. This indicates that within-host resistance evolution did not reverse loss of viral fitness caused by genome-wide accumulation of sequence changes. This off-label approach supports the use of mutagenic antivirals for treating prolonged RNA viral infections and further informs the debate surrounding their impact on virus evolution., Competing Interests: Declaration of competing interest Authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom)., Objective: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH., Methods: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation., Results: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation., Conclusion: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)