OBJECTIVE: The purpose of this study was to develop a questionnaire to examine the future acceptance of Automatic insulin delivery systems (AIDs), their perceived usefulness, ease of use, and trust in the device in subjects with type 1 diabetes (T1D).
METHODS: A questionnaire in Italian, based on the Technology Acceptance Model, was developed to examine intention to use AIDs, considered as a measure of future acceptance, and its determinants to use the system. A total of 43 questions for children and 46 for parents were included, and a 5-point Likert scale was used.
RESULTS: 239 subjects with T1D using multiple daily injections (MDI) or sensor-augmented pump (SAP) and their parents completed the questionnaire. The completion rate was excellent, with almost 100% of items answered. The overall Cronbach\'s coefficient for children and adolescents was 0.92 and 0.93 for parents, indicating excellent internal consistency in both groups. Parent-youth agreement was 0.699 (95% confidence interval: 0.689-0.709), indicating a good agreement between the two evaluations. Factor analysis identified measurement factors for the \"artificial pancreas (AP)-acceptance labeled benefits and hassles of AIDs, and the internal consistency of the total scale was alpha = 0.94 for subjects with T1D and 0.95 for parents. The level of AP acceptance was more than neutral: 3.91 ± 0.47 and 3.99 ± 0.43 (p = 0.07) for youths and parents, respectively (possible score range 1 to 5, neutral score is 3.0). Parents reported higher scores in the benefit items than children-adolescents (p = 0.04).
CONCLUSIONS: We developed a new questionnaire based on the items available in the literature, and we demonstrated that the \"AP-acceptance\" reveals a meaningful factor structure, good internal reliability, and agreement between parent-young people evaluations. This measure could be a valuable resource for clinicians and researchers to assess AP acceptance in pediatric patients with T1D and their parents. This patient profiling approach could help to enroll candidates for AIDs with proper expectations and who most likely will benefit from the system.

Antibody diversification is essential for an effective immune response, with somatic hypermutation (SHM) serving as a key molecular process in this adaptation. Activation-induced cytidine deaminase (AID) initiates SHM by inducing DNA lesions, which are ultimately resolved into point mutations, as well as small insertions and deletions (indels). These mutational outcomes contribute to antibody affinity maturation. The mechanisms responsible for generating point mutations and indels involve the base excision repair (BER) and mismatch repair (MMR) pathways, which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur. In this regard, translesion synthesis (TLS) polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions. This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM. Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies (bnAbs) and autoantibodies, and has implications for vaccine design and therapeutics.

Personalized cancer therapeutics bring directed treatment options to patients based on their tumor\'s genetic signature. Unfortunately, tumor genomes are remarkably adaptable, and acquired resistance through gene mutation frequently occurs. Identifying mutations that promote resistance within drug-treated patient populations can be cost, resource, and time intensive. Accordingly, base editing, enabled by Cas9-deaminase domain fusions, has emerged as a promising approach for rapid, large-scale gene variant screening in situ. Here, we adapt and optimize a conditional activation-induced cytidine deaminase (AID)-dead Cas9 (dCas9) system, which demonstrates greater heterogeneity of edits with an expanded footprint compared to the most commonly utilized cytosine base editor, BE4. In combination with a custom single guide RNA (sgRNA) library, we identify individual and compound variants in epidermal growth factor receptor (EGFR) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) that confer resistance to established EGFR inhibitors. This system and analytical pipeline provide a simple, highly scalable platform for cis or trans drug-modifying variant discovery and for uncovering valuable insights into protein structure-function relationships.

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) by introducing base substitutions into antibody genes, a process enabling antibody affinity maturation in immune response. How a mutator is tamed to precisely and safely generate programmed DNA lesions in a physiological process remains unsettled, as its dysregulation drives lymphomagenesis. Recent research has revealed several hidden features of AID-initiated mutagenesis: preferential activity on flexible DNA substrates, restrained activity within chromatin loop domains, unique DNA repair factors to differentially decode AID-caused lesions, and diverse consequences of aberrant deamination. Here, we depict the multifaceted regulation of AID activity with a focus on emerging concepts/factors and discuss their implications for the design of base editors (BEs) that install somatic mutations to correct deleterious genomic variants.

OBJECTIVE: To investigate whether the positive effects on glycaemic outcomes of 3-month automated insulin delivery (AID) achieved in 2- to 6-year-old children endure over an extended duration and how AID treatment affects time in tight range (TITR), defined as 3.9-7.8 mmol/L.
METHODS: We analysed 18 months of follow-up data from a non-randomized, prospective, single-arm clinical trial (n = 35) conducted between 2021 and 2023. The main outcome measures were changes in time in range (TIR), glycated haemoglobin (HbA1c), time above range (TAR), TITR, and mean sensor glucose (SG) value during follow-up visits (at 0, 6, 12 and 18 months). The MiniMed 780G AID system in SmartGuard Mode was used for 18 months. Parental diabetes distress was evaluated at 3 and 18 months with the validated Problem Areas in Diabetes-Parent, revised (PAID-PR) survey.
RESULTS: Between 0 and 6 months, TIR and TITR increased, and HbA1c, mean SG value and TAR decreased significantly (p < 0.001); the favourable effect persisted through 18 months of follow-up. Between 3 and 18 months, PAID-PR score declined significantly (0 months: mean score 37.5; 3 months: mean score 28.6 [p = 0.06]; 18 months: mean score 24.6 [p < 0.001]).
CONCLUSIONS: Treatment with AID significantly increased TITR and TIR in young children. The positive effect of AID on glycaemic control observed after 6 months persisted throughout the 18 months of follow-up. Similarly, parental diabetes distress remained reduced during 18 months follow-up. These findings are reassuring and suggest that AID treatment improves glycaemic control and reduces parental diabetes distress in young children over an extended 18-month follow-up.

Aid relations in protracted displacement comprise a diversity of actors with different influence and involvement over time. Building on the case of Sri Lanka\'s northern Muslim\'s expulsion from the north of the country in 1990, this paper investigates the dynamic space of aid relations in their drawn-out internal displacement. The study draws on 38 key informant interviews and 10 focus-group discussions, conducted in Sri Lanka (Jaffna, Mannar, Puttalam, and Colombo) in 2022. The paper contributes new knowledge of the local dynamics of assistance in protracted displacement, by analysing the roles of a wide set of actors within this dynamic space of aid relations over time. The analysis incorporates angles and voices often overlooked in mainstream humanitarian studies, including internally displaced persons, hosts, and Middle Eastern aid funders. The study argues that a long-term perspective and a variety of voices provide foundations for more productive engagement with localisation in humanitarian action in protracted displacement crises.
تتشكل علاقات تقديم المعونة في حالات النزوح الممتد بمجموعة متنوعة من الجهات الفاعلة التي يختلف تأثيرها ومشاركتها بمرور الوقت، واستنادًا إلى حالة طرد مسلمي شمال سري لانكا من شمال البلاد في عام 1990، نبحث في الحيز الديناميكي لعلاقات تقديم المعونة في نزوحهم الداخلي الممتد، ونعتمد في ذلك على 38 مقابلة مع المخبرين الرئيسيين وعشر مناقشات جماعية مركزة أُجريت في سري لانكا (جافنا، ومانار، وبوتالام، وكولومبو) عام 2022، وتساهم المقالة بمعرفة جديدة حول الديناميكيات المحلية لتقديم المعونة في حالات النزوح الممتد من خلال تحليل أدوار مجموعة واسعة من الجهات الفاعلة في هذا الحيز الديناميكي لعلاقات تقديم المعونة على مر الوقت، ويتضمن التحليل زوايا وأصوات غالبًا ما يتم تجاهلها في الدراسات الإنسانية السائدة، بما في ذلك النازحين الداخلين، والمضيفين، وممولي المعونة من الشرق الأوسط، ونحن نحتج بأن المنظور طويل الأمد وتنوع الأصوات يوفران أسسًا لمشاركة أكثر إنتاجية في التوطين في العمل الإنساني في أزمات النزوح الممتدة.
长期流离失所的援助关系是由长期具有不同影响和参与的多种行为者构成的。在1990年斯里兰卡北部穆斯林被从北部驱逐的案例的基础上，我们研究援助关系在旷日持久的境内流离失所中的动态空间。我们借鉴了2022年在斯里兰卡（贾夫纳、马纳尔、普塔勒姆和科伦坡）进行的38次关键知情者访谈和10次焦点小组讨论。本文通过分析长期援助关系的这个动态空间中广泛的一组行为者的作用，为长期流离失所的当地援助动态提供了新的认知。该分析包括主流人道主义学中经常被忽视的角度和声音，包括IDP(国内流离失所者)、东道国和中东援助资助者。我们认为，长期的视角和声音的多样性为在旷日持久的流离失所危机中更富有成效地参与人道行动的本地化奠定了基础。.

Healthcare cost-effectiveness analysis is increasingly used to inform priority-setting in low- and middle-income countries and by global health donors. As part of such analyses, cost-effectiveness thresholds are commonly used to determine what is, or is not, cost-effective. Recent years have seen a shift in best practice from a rule-of-thumb 1x or 3x per capita GDP threshold towards using thresholds that, in theory, reflect the opportunity cost of new investments within a given country. In this paper, we observe that international donors face both different resource constraints and opportunity costs compared to national decision-makers. Hence, their perspective on cost-effectiveness thresholds must be different. We discuss the potential implications of distinguishing between national and donor thresholds and outline broad options for how to approach setting a donor-perspective threshold. Further work is needed to clarify healthcare cost-effectiveness threshold theory in the context of international aid and to develop practical policy frameworks for implementation.

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In response to antigens, B cells undergo affinity maturation and class switching mediated by activation-induced cytidine deaminase (AID) in germinal centers (GCs) of secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of GC antibody diversification is of fundamental importance but not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in GC B cells in a CD40-dependent manner, interacts with AID and negatively regulates antibody affinity maturation and class switching by inhibiting AID function. AIRE deficiency in B cells caused altered antibody repertoire, increased somatic hypermutations, elevated autoantibodies to T helper 17 effector cytokines and defective control of skin Candida albicans. These results define a GC B cell checkpoint of humoral immunity and illuminate new approaches of generating high-affinity neutralizing antibodies for immunotherapy.

UNASSIGNED: The blockade of interleukine-1 (anakinra and canakinumab) is a well-known highly effective tool for monogenic autoinflammatory diseases (AIDs), such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinaemia D syndrome, and cryopyrin-associated periodic syndrome, but this treatment has not been assessed for patients with undifferentiated AIDs (uAIDs). Our study aimed to assess the safety and efficacy of canakinumab for patients with uAIDs.
UNASSIGNED: Information on 32 patients with uAIDs was retrospectively collected and analyzed. Next-generation sequencing and Federici criteria were used for the exclusion of the known monogenic AID.
UNASSIGNED: The median age of the first episode was 2.5 years (IQR: 1.3; 5.5), that of the disease diagnosis was 5.7 years (IQR: 2.5;12.7), and that of diagnostic delay was 1.1 years (IQR: 0.4; 6.1). Patients had variations in the following genes: IL10, NLRP12, STAT2, C8B, LPIN2, NLRC4, PSMB8, PRF1, CARD14, IFIH1, LYST, NFAT5, PLCG2, COPA, IL23R, STXBP2, IL36RN, JAK1, DDX58, LACC1, LRBA, TNFRSF11A, PTHR1, STAT4, TNFRSF1B, TNFAIP3, TREX1, and SLC7A7. The main clinical features were fever (100%), rash (91%; maculopapular predominantly), joint involvement (72%), splenomegaly (66%), hepatomegaly (59%), lymphadenopathy (50%), myalgia (28%), heart involvement (31%), intestinal involvement (19%); eye involvement (9%), pleuritis (16%), ascites (6%), deafness, hydrocephalia (3%), and failure to thrive (25%). Initial treatment before canakinumab consisted of non-biologic therapies: non-steroidal anti-inflammatory drugs (NSAID) (91%), corticosteroids (88%), methotrexate (38%), intravenous immunoglobulin (IVIG) (34%), cyclosporine A (25%), colchicine (6%) cyclophosphamide (6%), sulfasalazine (3%), mycophenolate mofetil (3%), hydroxychloroquine (3%), and biologic drugs: tocilizumab (62%), sarilumab, etanercept, adalimumab, rituximab, and infliximab (all 3%). Canakinumab induced complete remission in 27 patients (84%) and partial remission in one patient (3%). Two patients (6%) were primary non-responders, and two patients (6%) further developed secondary inefficacy. All patients with partial efficacy or inefficacy were switched to tocilizumab (n = 4) and sarilumab (n = 1). The total duration of canakinumab treatment was 3.6 (0.1; 8.7) years. During the study, there were no reported Serious Adverse Events (SAEs). The patients experienced non-frequent mild respiratory infections at a rate that is similar as before canakinumab is administered. Additionally, one patient developed leucopenia, but it was not necessary to stop canakinumab for this patient.
UNASSIGNED: The treatment of patients with uAIDs using canakinumab was safe and effective. Further randomized clinical trials are required to confirm the efficacy and safety.