Autoantigen Exposure in Murine Fetuses Elicited Nonpathogenic Autoimmunity.

BACKGROUND AND AIM: Autoimmunity refers to the presence of autoantibodies and autoreactive lymphocytes against the structural molecules of an individual's cells or tissues, known as self-antigens or autoantigens. It might exist in the absence of autoimmune disease. However, how autoimmunity develops remains a mystery, despite the discovery of autoantibodies in human cord blood. METHODS: Murine fetuses on day 14 of gestation were subjected to intraperitoneal injection of murine thyroid peroxidase (TPO) peptides or collagen type II (CII) at graded doses via transuterine approach. Postnatally, the recipients were examined for autoantibodies by ELISA and autoreactive lymphocytes by in vitro incorporation of tritium and for the development of autoimmune thyroiditis or arthritis. RESULTS: At one month of age, the recipients did not secrete significant levels of anti-TPO or CII IgG2a in sera until a dose of 0.5 µg TPO or 5.0 µg CII was injected in utero. Serum anti-TPO or CII IgG2a persisted for at least two to four months postnatally. In recipients with elevated autoantibodies, their lymphocytes also showed proliferative responses specifically to TPO or CII. However, the development of autoantibodies and autoreactive lymphocytes was not associated with inflammatory cell infiltration of thyroid glands or paw joints even though anti-TPO or CII IgG2a was enhanced by postnatal TPO or CII challenge. CONCLUSION: Fetal exposure to free autoantigens could be immunogenic, shedding new light on the in utero origin of autoantibodies and autoreactive lymphocytes. The development of autoimmunity requires a threshold intensity of autoantigen exposure in the fetus.

Clinical features and lymphocyte immunophenotyping analysis in primary immunodeficiency patients with non-transplant lymphoproliferative disorders.

Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the "Disease of immune dysregulation" category. Of 96 Taiwanese patients during 2003-2022, 31 (median 66, range 0.03-675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.

Taiwan ocular inflammation society consensus recommendations for the management of juvenile idiopathic arthritis-associated uveitis.

We presented the development of a consensus guideline for managing juvenile idiopathic arthritis-associated uveitis (JIAU) in Taiwan, considering regional differences in manifestation and epidemiology. The Taiwan Ocular Inflammation Society (TOIS) committee formulated this guideline using a modified Delphi approach with two panel meetings. Recommendations were based on a comprehensive evidence-based literature review and expert clinical experiences, and were graded according to the Oxford Centre for Evidence-Based Medicine's "Levels of Evidence" guideline (March 2009). The TOIS consensus guideline consists of 10 recommendations in four categories: screening and diagnosis, treatment, complications, and monitoring, covering a total of 27 items. These recommendations received over 75% agreement from the panelists. Early diagnosis and a coordinated referral system between ophthalmologists and pediatric rheumatologists are crucial to prevent irreversible visual impairment in children with JIAU. However, achieving a balance between disease activity and medication use remains a key challenge in JIAU management, necessitating further clinical studies.

An Exploration of Pediatricians' Professional Identities: A Q-Methodology Study.

Professional identities may influence a wide range of attitudes, ethical standards, professional commitments and patient safety. This study aimed to explore the important elements that comprise pediatricians' professional identities. A Q-methodology was used to identify the similarities and differences in professional identity. Forty pediatricians were recruited from two tertiary referral hospitals in Taiwan. A list of statements was developed by five attending physicians and three residents. R software was used to analyze the Q-sorts to load the viewpoints and formulate the viewpoint arrays. Additional qualitative data-one-to-one personal interviews-were analyzed. Twenty-eight of forty pediatricians, 11 males and 17 females, with an average age of 39.9 (27-62) years, were associated with four viewpoints. We labeled the four viewpoints identified for professional identity as (1) professional recognition, (2) patient communication, (3) empathy and (4) insight. The professional recognition viewpoint comprised of youngest participants-28-36 years-with the majority as residents (77.8%), while the empathy viewpoint comprised the oldest participants-38-62 years-with all as attending physicians. All participants in the empathy and insight viewpoints were married. This study found professional identity to be a multifaceted concept for pediatricians, especially in the areas of professional recognition, patient communication, empathy and insight into patient care.

C1-C2 subluxation in enthesitis-related arthritis: two case reports and literature review of ten cases.

BACKGROUND: C1-C2 subluxation is a rare complication of enthesitis-related arthritis (ERA). If left untreated, it may lead to functional impairment or cervical spinal cord compression. This study aims to highlight key points regarding the management of C1-C2 subluxation in ERA. CASE PRESENTATION: We present two cases of C1-C2 subluxation: an 8-year-old boy with ERA and 16-year-old boy with ERA with bilateral sacroiliitis. Ten cases of ERA in the literature were reviewed. The diagnosis of C1-C2 subluxation is mostly based on radiographs and cervical spine computed tomography. All patients were treated with non-steroidal anti-inflammatory drugs. Six ERA patients were treated surgically for cervical fusion. Most ERA patients with sacroiliitis had cervical collar protection. Neurologic abnormalities after treatment were not reported. Despite the use of cervical collar, cervical fusion and persisting ankylosis were found in two ERA patients with sacroiliitis without surgical treatment. CONCLUSIONS: Cervical spine protection and ruling out spinal cord compression should be prioritized, in addition to controlling the underlying inflammation in ERA. Cervical halter traction may be applied after severe cervical inflammation is excluded. To reduce the risk of complications, early recognition and appropriate treatments of C1-C2 subluxation in ERA are essential.

Prevalence, associated factors, and impact of adolescent asthma in Taiwan: Global Asthma Network phase I survey.

Background: The prevalence of asthma in Taiwan was increasing in the past 30 years, causing a great impact on adolescent health. This study aimed to investigate the current prevalence, impact, and associated factors of asthma in Taiwanese adolescents. Material and methods: Parents or guardians provided passive consent at home prior to the survey. Adolescents aged 13-14 years completed a questionnaire survey in 2017 in Taipei, Taiwan. The prevalence, impact, and associated factors of asthma were analyzed. We also compared the asthma prevalence with the prevalence in 1995 and 2001. Results: We analyzed 3474 validated questionnaires. The prevalence of physician-diagnosed asthma was 12.4%. The prevalence of current wheezing was 9.2% in 2017, which was 5.2% in 1995 and 7.0% in 2001. 3.3% of 13-14-year-old adolescents had severe asthma symptoms. Asthma significantly impacted the lives of adolescents. Of the students with asthma, 10.9% had school absenteeism, 16.5% urgently needed to see a doctor, 9.5% went to the emergency department, and 3.5% were admitted to hospitals within the preceding 12 months. The associated factors for physician-diagnosed asthma in Taiwanese adolescents were male (prevalence ratio [PR], 1.38; 95% confidence interval [CI], 1.05-1.83; p = 0.02), maternal history of asthma (PR, 2.61; 95% CI, 1.69-4.02; p < 0.01), and recent paracetamol use at least once per month (PR, 2.60; 95% CI, 1.24-5.42; p = 0.01). The associated factors for school absenteeism were nocturnal cough (PR, 1.99; 95% CI, 1.16-3.41; p = 0.01), current wheezing (PR, 7.52; 95% CI, 4.39-12.9; p < 0.01), and recent paracetamol use (at least once per month, PR, 3.16; 95% CI, 1.10-9.06; p = 0.03; at least once per year, PR, 2.19; 95% CI, 1.25-3.83; p < 0.01). Conclusions: The prevalence of physician-diagnosed asthma was 12.4%. Asthma substantially impacted the lives of adolescents. Reducing nocturnal cough, wheezing frequency, and paracetamol usage might help decrease school absenteeism.

Clinical Features and Genetic Analysis of Taiwanese Primary Immunodeficiency Patients with Prolonged Diarrhea and Monogenetic Inflammatory Bowel Disease.

PURPOSE: Diarrhea lasting longer than 14 days which fails to respond to conventional management is defined as severe and protracted diarrhea and might overlap with inflammatory bowel disease (IBD). METHODS: The prevalence, associated pathogens, and prognosis of severe and protracted diarrhea without IBD (SD) and with monogenetic IBD (mono-IBD) in primary immunodeficiency patients (PID) were investigated in Taiwan. RESULTS: A total of 301 patients were enrolled between 2003 and 2022, with predominantly pediatric-onset PID. Of these, 24 PID patients developed the SD phenotype before prophylactic treatment, including Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG1 (one each), CVID (two), and SCID (one) without identified mutations. The most detectable pathogens were pseudomonas and salmonella (six each), and all patients improved after approximately 2 weeks of antibiotic and/or IVIG treatments. Six (25.0%) mortalities without HSCT implementation were due to respiratory failure from interstitial pneumonia (3 SCID and 1 CGD), intracranial hemorrhage (WAS), and lymphoma (HIGM). In the mono-IBD group, seventeen patients with mutant TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), LRBA (1), TTC37 (3), IL10RA (1), STAT1 (1), ZAP70 (1), PIK3CD (1), and PIK3R1 (1) genes failed to respond to aggressive treatments. Nine mono-IBD patients with TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), and LRBA (1) mutations were fatal in the absence of HSCT. The mono-IBD group had a significantly earlier age of diarrhea onset (1.7 vs 33.3 months, p = 0.0056), a longer TPN duration (34.2 vs 7.0 months, p < 0.0001), a shorter follow-up period (41.6 vs 132.6 months, p = 0.007), and a higher mortality rate (58.9 vs 25.0%, p = 0.012) compared with the SD group. CONCLUSION: When compared to those with the SD phenotype, the mono-IBD patients had significant early-onset and poor responses to empiric antibiotics, IVIG, and steroids. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.

Rising prevalence of food allergies in Taiwan: An epidemiological study.

BACKGROUND: Food allergies are becoming more prevalent globally. The purpose of this study was to investigate the epidemiology of food allergies in Taiwan. METHODS: In 2017, a food allergy questionnaire was administered to 6-7-year-old children, 13-14-year-old adolescents, and their parents in Taipei. The results were compared to those from a previous survey conducted in 2004. RESULTS: A total of 16,200 questionnaires were completed, revealing a rise in the prevalence of food allergies from 7.7% to 10.4% in the pediatric group and from 6.4% to 12.5% in the adult group. Peanut allergies also increased to 1.1%. Shrimp and crabs were the most common allergens, with urticaria being the most common symptom. Shortness of breath or wheezing occurred in 10% of individuals, while 2.1% experienced syncope or shock, and 0.1% were admitted to an intensive care unit. Personal history of allergic rhinitis and atopic dermatitis, as well as family histories of food allergies, were risk factors for food allergy in 6-7-year-old children. In the 13-14-year-old group, personal history of asthma, allergic rhinitis, or atopic dermatitis, recent use of acetaminophen, and living with dogs were risk factors. Females, personal histories of asthma, allergic rhinitis, atopic dermatitis, and moist and damp at home were risk factors in adults. Breastfeeding was a protective factor in 6-7-year-old children. CONCLUSION: The increasing prevalence of food allergies, including peanut allergies, in Taiwan warrants attention from physicians to provide appropriate care and education to patients with food allergies. The protective effect of breastfeeding against food allergies shall be emphasized.

Contribution of genetic variants associated with primary immunodeficiencies to childhood-onset systemic lupus erythematous.

BACKGROUND: A dysregulated immune response is a hallmark of autoimmune disorders. Evidence suggests that systemic autoimmune diseases and primary immunodeficiency disorders (PIDs) may be similar diseases with different clinical phenotypes. OBJECTIVE: This study aimed to investigate the burden of PID-associated genetic variants in patients with childhood-onset systemic lupus erythematosus (cSLE). METHODS: We enrolled 118 cSLE patients regularly followed at Chang Gung Memorial Hospital. Targeted next-generation sequencing identified PID genetic variants in patients versus 1475 unrelated healthy individuals, which were further filtered by allelic frequency and various functional scores. Customized immune assays tested the functions of the identified variants. RESULTS: On filtration, 36 patients (30.5%) harbored rare variants in PID-associated genes predicted to be damaging. One homozygous TREX1 (c.294dupA) mutation and 4 heterozygous variants with possible dominant PID traits, including BCL11B (c.G1040T), NFKB1 (c.T695G), and NFKB2 (c.G1210A, c.G1651A), were discovered. With recessive traits, variants were found across all PID types; one fifth involved phagocyte number or function defects. Predicted pathogenic PID variants were more predominant in those with a family history of lupus, regardless of infection susceptibility. Moreover, mutation loads were greater among cSLE patients than controls despite sex or age at disease onset. While greater mutation loads were observed among cSLE patients with peripubertal disease onset, no significant differences in sex or phenotype were noted among cSLE patients. CONCLUSION: cSLE is mostly not monogenic. Gene-specific analysis and mutation load investigations suggested that rare and predicted damaging variants in PID-related genes can potentially contribute to cSLE susceptibility.

Effect of national curriculum reform on medical students' preparedness for practice: a prospective cohort study from undergraduate to postgraduate periods.

BACKGROUND: In recent years, a national curriculum reform was implemented in undergraduate medical education in Taiwan to reduce clinical rotation training from 3 years to 2 years. The last generation of the old curriculum and the first generation of the new curriculum both graduated in 2019. This study aimed to compare the learning outcomes of the medical students in these two curriculum groups in terms of preparedness for practice during the transition from undergraduate to postgraduate study. METHODS: This was a 3-year prospective, longitudinal, comparative cohort study between 2017 and 2020. Medical students from both the 7-year and 6-year curriculum groups received biannual questionnaire surveys starting 18 months before graduation and running until 11 months after graduation. The measurement tools were the Preparedness for Hospital Practice Questionnaire (PHPQ) and Copenhagen Burnout Inventory (CBI). Personal demographic information was also collected. Linear mixed models were used to determine the effect of curriculum change on learners' preparedness and burnout levels. RESULTS: A total of 130 medical students from the two cohorts provided 563 measurements during the study period. Compared to their counterparts following the old curriculum, the participants following the new curriculum showed a lower level of preparedness when first entering clinical rotation (p = 0.027) and just after graduating (p = 0.049), especially in the domains of clinical confidence (p = 0.021) and patient management p = 0.015). The multivariate linear mixed model revealed gradual increases in preparedness and burnout in serial measurements in both curriculum groups. Students following the new curriculum, which involved a shortened clinical rotation, showed a slightly lower overall preparedness (p = 0.035) and the same level of burnout (p = 0.692) after adjustment. The factor of year of change did not show a significant effect on either preparedness (p = 0.258) or burnout (p = 0.457). CONCLUSION: Shortened clinical rotation training for medical undergraduates is associated with a decrease in preparedness for practice during the transition from undergraduate to postgraduate study. Clinical confidence and patient management are the main domains affected.

Evaluating Clinical Educators' Competence in an East Asian Context: Who Values What?

Background: How to evaluate clinical educators is an important question in faculty development. The issue of who are best placed to evaluate their performance is also critical. However, the whos and the hows of clinical educator evaluation may differ culturally. This study aims to understand what comprises suitable evaluation criteria, alongside who is best placed to undertake the evaluation of clinical educators in medicine within an East Asian culture: specifically Taiwan. Methods: An 84-item web-based questionnaire was created based on a literature review and medical educational experts' opinions focusing on potential raters (i.e., who) and domains (i.e., what) for evaluating clinical educators. Using purposive sampling, we sent 500 questionnaires to clinical educators, residents, Post-Graduate Year Trainees (PGYs), Year-4~6/Year-7 medical students (M4~6/M7) and nurses. Results: We received 258 respondents with 52% response rate. All groups, except nurses, chose "teaching ability" as the most important domain. This contrasts with research from Western contexts that highlights role modeling, leadership and enthusiasm. The clinical educators and nurses have the same choices of the top five items in the "personal qualities" domain, but different choices in "assessment ability" and "curriculum planning" domains. The best fit rater groups for evaluating clinical educators were educators themselves and PGYs. Conclusions: There may well be specific suitable domains and populations for evaluating clinical educators' competence in East Asian culture contexts. Further research in these contexts is required to examine the reach of these findings.

Taiwan guidelines for the diagnosis and management of pediatric atopic dermatitis: Consensus statement of the Taiwan Academy of Pediatric Allergy, Asthma and Immunology.

Atopic dermatitis (also known as atopic eczema) is a chronic relapsing inflammatory skin disease commonly seen in children, with increasing prevalence over the past few decades in many countries including Taiwan. The management of pediatric atopic dermatitis can be challenging, particularly as treatment options are expanding with the emergence of novel systemic and topical anti-inflammatory medications in recent years. The Taiwan Academy of Pediatric Allergy, Asthma and Immunology (TAPAAI) has developed the Taiwan guidelines for the diagnosis and management of pediatric atopic dermatitis, which provides a concise overview of its epidemiology, clinical characteristics and diagnosis, mechanisms, treatments, and education. The contents of this guideline integrate the principles of recent national and international guidelines for the diagnosis and management of atopic dermatitis, latest research findings, and expert opinions of experienced pediatric allergy specialists in Taiwan. For practical purposes, this guideline presents simplified and easy-to-use diagnostic criteria and severity grading for pediatric atopic dermatitis. A stepwise treatment algorithm is also proposed to expedite rational, cost-effective, and evidence-based management strategy. This guideline, developed based on current best evidence and real-world experience of pediatric allergy experts in Taiwan, is intended to facilitate practical, up-to-date management of pediatric atopic dermatitis among physicians.

Developing a competency-based framework for resident-as-teacher.

BACKGROUND/PURPOSE: Residents play an important role as teachers of junior colleagues and medical students. Clinical teaching also helps residents in clinical learning. However, the skills required for residents to be competent teachers are rarely described systemically. Beyond the widely adopted six core competencies for postgraduate training by the Accreditation Council for Graduate Medical Education (ACGME), the teaching competencies should be further developed, and the milestones should be clearly defined to serve as better references for resident training programs. METHODS: Twenty members, including five experts from major teaching hospitals across Taiwan and 15 from a public medical center, were invited to a workgroup to collaboratively develop a competency-based framework. The development process was similar to that suggested by the ACGME. The teaching competencies framework were drafted by an experienced physician educator. The draft was sent to each group member, and feedback was collected. Two workgroup meetings were held for consensus formation. The contents of the teaching competencies of residents were confirmed after two rounds of revision. The outline of the framework was also reported at an international meeting in September 2019. RESULTS: Two core competencies, instruction and assessment, with three sub-competencies and 37 milestones, were adopted in the final edition of resident-as-teacher competencies. The sub-competencies were "dissemination of knowledge" and "teaching of procedural skills" for instruction, and "direct observation and feedback" for assessment. CONCLUSION: A competency-based framework for resident-as-teacher was developed. The framework can be applied in combination with other existing competencies for holistic postgraduate training programs.

Clinical Features of Female Taiwanese Carriers with X-linked Chronic Granulomatous Disease from 2004 to 2019.

PURPOSE: Female carriers with X-linked chronic granulomatous disease (XL-CGD) who have < 10% reactive oxygen species (ROS) production due to profound X-chromosome inactivation (XCI or lyonization) are more susceptible to infections. We assessed ROS production in Taiwanese female carriers with XL-CGD to investigate whether the level of ROS correlated to their clinical features of infection, autoimmunity, and autoinflammation. METHODS: Clinical course, ROS production, flavocytochrome b558 (Cyto b558) expression, and genetic analysis in carriers were investigated after identifying their index cases between 2004 and 2019. RESULTS: A total of 19 mothers (median 27 years; range 25-60 years) and three of four girls (range 4-6 years) relative to 22 male index XL-CGD cases from 19 unrelated families were enrolled. Approximately half (8/19, 42%) of the mothers had novel one-allele mutations. Twenty-two of the 23 females were carriers. One carrier with de novo [Arg290X]CYBB who suffered from refractory salmonella sepsis and chorioretinitis as an XL-CGD phenotype had extreme XCI, absent Cyto b558 expression, and only 8% ROS production. The remaining carriers had bimodal patterns of Cyto b558 expressions (median 40.2%, 26.8-52.4%) and ROS production (38.3%, range 28.2-54.2%) sufficient to prevent significant infections, although neck lymphadenitis recurred in one mother and sister who had ROS expressions of 28.2% and 38.0%, respectively. However, none of the carriers had manifestations of autoimmunity or autoinflammation (e.g., photosensitivity, aphthous stomatitis, or joint disorders), of which each was seen in approximately one-third of XL-CGD carriers from the Western world. CONCLUSION: One carrier had undetectable Cyto b558 expression and an extremely low ROS production, and consequently presented with an XL-CGD phenotype. One mother and her daughter experienced recurrent neck lymphadenitis despite having sufficient ROS production. Significant autoimmunity/autoinflammation did not develop in any of the carriers. Studies with a longer follow-up period are needed to validate our findings.

Age, gender, height and weight in relation to joint cartilage thickness among school-aged children from ultrasonographic measurement.

BACKGROUND: Among school-age children, the decrease of cartilage thickness (Cth) with increasing age is well known. However, the influence of body mass index (BMI), height or weight on Cth has not been revealed. Here in, we aim to establish an age- and gender-specific Cth standard reference among Asians and investigate the possible prestige of BMI, height and weight. METHODS: A cross-sectional study was performed in healthy Asian children. Bilateral knees, ankles, wrists, second metacarpophalangeals (MCPs) and proximal interphalangeals (PIPs) were measured using ultrasound. The children's height, weight and BMI were also recorded for later adjustment. RESULTS: A total of 200 school age Asian children (including 86 girls and 114 boys, aged between 5 to 13 years-old) were investigated. Cth differences were observed in the knees, ankles, wrists, MCPs and PIPs between sexes (p < 0.05), with girls having thinner cartilage thickness. While Cth decreases with increasing age (p < 0.0001, 0.039, 0.001, 0.023, 0.091 in girls' knees, ankles, wrists, MCPs and PIPs and p = 0.002, 0.001, < 0.0001, 0.001, 0.045 in boys', respectively). Our data showed that weight, height and BMI are not the main factors contributing to Cth. A formula to calculate gender-specific cartilage thickness for Asian school age children is suggested. There was no difference in Cth after adjusting for height or weight between Asian or Caucasian group. CONCLUSIONS: A formula to calculate gender-specific cartilage thickness for Asian school age children is suggested. Height, weight and BMI were not the major contributor for Cth among school age children.

Fetal Macrophages Exposed to Salmonella Antigens Elicit Protective Immunity Against Overwhelming Salmonella Challenge in A Murine Model.

Despite the evidence for fetal immunization following maternal infection, it remained a mystery how the fetal immune system was primed by vertically-transmitted pathogens or microbial antigens, especially before its full maturation. We previously demonstrated the capacity of fetal macrophages for endocytosing oncoprotein and allergens to bridge towards adaptive immunity in postnatal life. To investigate the immunological consequences of fetal contact with microbial antigens and the role of fetal macrophages in the defense against infection before T-cell development, we exposed gestational day 14 murine fetuses and their macrophages to flagellin and heat-killed Salmonella Typhimurium. Recipients with in utero exposure to Salmonella antigens or adoptive transfer of microbial antigen-loaded fetal macrophages were examined for immune responses to Salmonella antigens and resistance to virulent Salmonella challenge. Fetal exposure to microbial antigens or adoptive transfer of microbial antigen-loaded fetal macrophages could confer antigen-specific adaptive immunity. However, protective immunity against lethal Salmonella challenge was only granted to those receiving heat-killed Salmonella antigens, presenting as heightened recall responses of serum anti-lipopolysaccharide immunoglobulins and interferon-gamma. In immunized recipients surviving Salmonella challenge, their serum transfer to succeeding recipients provided immediate protection from lethal Salmonella challenge in preference to lymphocyte transfer, indicating a more active role of humoral immunity in the prevention of Salmonella invasiveness. Our study sheds insight on the role of fetal macrophages in immunogenicity to transplacental pathogens regardless of fetal lymphocyte maturity, paving the way for fetal macrophage therapies to enhance vaccine responsiveness or increase resistance to pathogenic microorganisms in perinatal life.

Active learning of medical students in Taiwan: a realist evaluation.

BACKGROUND: Active learning is defined as any instructional method that engages students in the learning process. Cultural differences in learning patterns can play an important role in engagement with active learning. We aimed to examine process models of active learning to understand what works, for whom and why. METHODS: Forty-eight sixth- and seventh-year medical students with experience of active learning methods were purposively selected to participate in ten group interviews. Interactions around active learning were analysed using a realist evaluation framework to unpack the 'context-mechanism-outcome' (CMO) configurations. RESULTS: Three core CMO configurations, including cultural, training and individual domains, were identified. In the cultural context of a strong hierarchical culture, the mechanisms of fear prompted students to be silent (outcome) and dare not give their opinions. In the training context of teacher-student familiarity alongside teachers' guidance, the mechanisms of learning motivation, self-regulation and enthusiasm were triggered, prompting positive learning outcomes and competencies (outcome). In the individual context of learning how to learn actively at an early stage within the medical learning environment, the mechanisms of internalisation, professional identity and stress resulted in recognising active learning and advanced preparation (outcomes). CONCLUSIONS: We identified three CMO configurations of Taiwanese medical students' active learning. The connections among hierarchical culture, fear, teachers' guidance, motivation, the medical environment and professional identity have been shown to affect the complex interactions of learning outcomes. Fear derived from a hierarchical culture is a concern as it is a significant and specific contextual factor, often sparking fear with negative outcomes.

Distinct Clinical Features and Novel Mutations in Taiwanese Patients With X-Linked Agammaglobulinemia.

Background: X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase (BTK) gene and is the most common genetic mutation in patients with congenital agammaglobulinemia. The aim of this study was to analyze the clinical features, genetic defects, and/or BTK expression in patients suspected of having XLA who were referred from the Taiwan Foundation of Rare Disorders (TFRD). Methods: Patients with recurrent bacterial infections in the first 2 years of life, serum IgG/A/M below 2 standard deviations of the normal range, and ≦2% CD19+B cells were enrolled during the period of 2004-2019. The frequency of infections, pathogens, B-lymphocyte subsets, and family pedigree were recorded. Peripheral blood samples were sent to our institute for BTK expression and genetic analysis. Results: Nineteen (from 16 families) out of 29 patients had BTK mutations, including 7 missense mutations, 7 splicing mutations, 1 nonsense mutation, 2 huge deletions, and 2 nucleotide deletions. Six novel mutations were detected: c.504G>T [p.K168N], c.895-2A>G [p.Del K290 fs 23*], c.910T>G [p.F304V], c.1132T>C [p.T334H], c.1562A>T [p.D521V], and c.1957delG [Del p.D653 fs plus 45 a.a.]. All patients with BTK mutations had obviously decreased BTK expressions. Pseudomonas sepsis developed in 14 patients and led to both Shanghai fever and recurrent hemophagocytic lymphohistiocytosis (HLH). Recurrent sinopulmonary infections and bronchiectasis occurred in 11 patients. One patient died of pseudomonas sepsis and another died of hepatocellular carcinoma before receiving optimal treatment. Two patients with contiguous gene deletion syndrome (CGS) encompassing the TIMM8A/DDP1 gene presented with early-onset progressive post-lingual sensorineural Deafness, gradual Dystonia, and Optic Neuronopathy syndrome (DDON) or Mohr-Tranebjaerg syndrome (MTS). Conclusion: Pseudomonas sepsis was more common (74%) than recurrent sinopulmonary infections in Taiwanese XLA patients, and related to Shanghai fever and recurrent HLH, both of which were prevented by regular immunoglobulin infusions. Approximately 10% of patients belonged to CGS involving the TIMM8A/DDP1 gene and presented with the DDON/MTS phenotype in need of aggressive psychomotor therapy.

Lower T Regulatory and Th17 Cell Populations Predicted by RT-PCR-Amplified FOXP3 and RORγt Genes Are Not Rare in Patients With Primary Immunodeficiency Diseases.

Deficiencies in T regulatory (Treg) and Th17 cells attenuate peripheral tolerance and the IL-17 family of cytokines, contributing to autoimmune disorders and opportunistic (fungal) infections, respectively. Because of limited blood samples from patients with primary immunodeficiency diseases (PIDs), a positive correlation/linear relationship between Treg and Th17 cells and their respective expressions of transcription factors forkhead box P3 (FOXP3) and retinoic acid-related orphan receptor γ (RORγt) by real-time PCR (RT-PCR) amplification, was used to predict the percentages of Treg and Th17 cells in peripheral blood. Compared to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, the percentages of Treg and Th17 cells were calculated as the linear relationship to the 2-ΔCT value (cycle threshold). Among 91 PIDs patients, 68 and 78 had predicted Treg and Th17 percentages below 5% of the normal ranges (0.859 and 0.734%, respectively), which expanded different categories beyond obvious T cell deficiency. Notably, FOXP3 was undetectable in one patient (CVID), RORγt was undetectable in six patients (one CVID, one CID, two neutropenia, one WAS, and one CMC), and both were undetectable in four patients (two SCID, one STAT1, and one periodic fever). In contrast, two patients with auto-IFNγ antibodies had increased susceptibility to intracellular mycobacterial infections, interrupted Th1 development and subsequent elevation in the Th17 cells. Both predicted Treg and Th17 percentages in the PIDs patients were more independent of age (months) than in the controls. The predicted Th17/Treg ratio in the PIDs patients, overall, was lower than that in the healthy controls (0.79 ± 0.075 vs. 1.16 ± 0.208; p = 0.038). In conclusion, lower predicted Treg and Th17 cell populations calculated by RT-PCR-amplified FOXP3 and RORγt in PIDs patients at diagnosis can explain the higher potential phenotypes of autoimmune disorders and opportunistic infections, although effective interventions in the early stage might have prevented such phenotypic development and caused a statistical bias in the comparisons.

Fetal exposure to oncoantigen elicited antigen-specific adaptive immunity against tumorigenesis.

BACKGROUND: Envisioned as a similar process to tumorigenesis in terms of biological behaviors and molecular basis, embryogenesis necessitates an immune surveillance system to eliminate erratically transformed cells. Our previous study demonstrated that fetal macrophage-like phagocytes triggered Th2-skewed immunity following endocytosing prenatally administered ovalbumin to facilitate postnatal allergic airway responses, highlighting the critical role fetal phagocytes played in dealing with antigens present in developing fetuses and shaping subsequent immune responses. It prompted us to examine whether fetuses could mount Th1 tumoricidal immunity against tumorigenesis following in utero exposure to tumor antigens. METHODS: Gestational day 14 murine fetuses underwent in utero injection of Th1-promoting human papilloma virus (HPV) E7 peptides. Postnatally, recipients were examined for immunological consequences and the resistance to TC-1 tumorigenesis. RESULTS: Fetal exposure to HPV E7 did not cause tolerance but rather immunization in the recipients, characterized by proinflammatory Th1 polarization of their lymphocytes. Fetal macrophage-like phagocytes were responsible for taking up HPV E7 and triggering HPV E7-specific T-cell cytotoxicity and humoral immunity that rendered recipients resistant to TC-1 tumorigenesis in postnatal life. Adoptive transfer of HPV E7-loaded fetal phagocytes also elicited Th1 immunity with rapid expansion of HPV E7-specific cytotoxic CD8+ T-cell clones in response to TC-1 cell challenge so as to protect the recipients from TC-1 tumorigenesis, but failed to completely eliminate pre-existing TC-1 cells despite perceptible attenuation of local TC-1 tumor growth. CONCLUSIONS: Our study revealed that Th2-biasing fetus was not immune-privileged to foreign peptides, but competent to mount Th1 cytotoxic immunity and generate immunoglobulins against tumorigenesis following in utero exposure to Th1-promoting oncoantigen. It shed light on the role of fetal macrophage-like phagocytes in bridging toward tumor antigen-specific cellular and humoral immunity potentially as an immune surveillance system to eliminate transformed cells that might be egressing during embryogenesis and leftover until postnatal life.