Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients with EBV+ disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.
background children's interstitial lung diseases (chilD) cover many rare entities, frequently not diagnosed or studied in detail. there is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register. Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chilD cases. Methods a web-based chilD management platform with a registry and biobank was successfully designed and implemented. results Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chilD. in 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, london 12%, Hannover 31%, ankara 1% and Paris 5%). in 13%, the diagnosis reached by the referring team was not confirmed by peer review. among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%). the ability of nine expert clinicians to subcategorise the final diagnosis into the chilD-eU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation. Conclusions We have shown that chilD-eU has generated a platform to help the clinical assessment of chilD. Trial registration number results, nct02852928.
A prospective study was performed to better define the role of computers in teaching radiology to medical students. Two hundred twentyfive 3rd-year students were randomly assigned to one of four groups and exposed to 10 radiology cases as well as to a voluntary weekly radiology lecture. Group A used computer-based cases with interactive elements; group B used computer-based cases without interactive elements; group C used paper-based cases with interactive elements; and group D was not exposed to the cases and served as a control group. On a multiple-choice question test, groups A, B, and C showed significant improvement (ϩ11.2%, ϩ15.1%, and ϩ13.0%, respectively), whereas group D did not (ϩ0.6%). On an image interpretation test, group A showed the most improvement (ϩ15.7% [P Ͻ .001]), followed by group B (ϩ15.1% [P Ͻ .01]) and group C (ϩ10.2% [P Ͻ .05]); group D showed no significant improvement (ϩ8.5%). No significant differences in the learning outcome were found between the two interactive groups (computer based and paper based). Computerbased teaching with case studies (with or without interactivity) improves students' problem-solving ability in radiology.
RATIONALE: Persistent tachypnea of infancy (PTI) is a specific clinical entity of undefined etiology comprising the two diseases neuroendocrine cell hyperplasia of infancy (NEHI) and pulmonary interstitial glycogenosis. The outcome of typical NEHI is favorable. The outcome may be different for patients without a typical NEHI presentation, and thus a lung biopsy to differentiate the diseases is indicated. OBJECTIVES: To determine whether infants with the characteristic clinical presentation and computed tomographic (CT) imaging of NEHI (referred to as "usual PTI") have long-term outcome and biopsy findings similar to those of infants with an aberrant presentation and/or with additional localized minor CT findings (referred to as "aberrant PTI"). METHODS: In a retrospective cohort study, 89 infants with PTI were diagnosed on the basis of clinical symptoms and, if available, CT scans and lung biopsies. Long-term outcome in childhood was measured on the basis of current status. MEASUREMENTS AND MAIN RESULTS: Infants with usual PTI had the same respiratory and overall outcomes during follow-up of up to 12 years (mean, 3.8 yr) as infants who had some additional localized minor findings (aberrant PTI) visualized on CT images. Both usual and aberrant PTI had a relatively favorable prognosis, with 50% of the subjects fully recovered by age 2.6 years. None of the infants died during the study period. This was independent of the presence or absence of histological examination. CONCLUSIONS: PTI can be diagnosed on the basis of typical history taking, clinical findings, and a high-quality CT scan. Further diagnostic measures, including lung biopsies, may be limited to rare, complicated cases, reducing the need for an invasive and potentially harmful procedure. AbstractRationale: Persistent tachypnea of infancy (PTI) is a specific clinical entity of undefined etiology comprising the two diseases neuroendocrine cell hyperplasia of infancy (NEHI) and pulmonary interstitial glycogenosis. The outcome of typical NEHI is favorable. The outcome may be different for patients without a typical NEHI presentation, and thus a lung biopsy to differentiate the diseases is indicated.
Sorafenib in combination with PLADO may be a promising approach in pediatric HCC; HFSR was the most important toxicity. Data based on prospective studies are needed to evaluate pharmacokinetics, resectability rates, and survival in pediatric HCC treated with sorafenib.
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