Association Between Leg Muscle Thickness and Walking Test with the Haemophilia-Specific Functional Parameters.

OBJECTIVE: To evaluate the muscle thickness and walking test in people with haemophilia A (PWH) and their correlation to joint health and functional impairments. DESIGN: Cross-sectional study. RESULTS: 29 severe/moderate PWH were enrolled. Muscle thickness of quadriceps and medial gastrocnemius were measured using ultrasound. Joint health and functional capacity were assessed using Haemophilia Joint Health Score (HJHS), Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US), 6-Minute Walking test (6MWT), Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), and Haemophilia Activities List (HAL). Quadriceps muscle thickness significantly correlated with HJHS knee, HEAD-US knee, and HAL. Calf muscle thickness significantly correlated with the HJHS ankle. After adjusted age and BMI, calf muscle thickness was inversely associated with the HJHS ankle. 6MWT was found to significantly correlate with HJHS total, HEAD-US total, Haem-A-QoL, and HAL. CONCLUSION: Muscle thickness and the distance of 6MWT were linked to assessment of joint health, quality of life and activity participation in PWH. Ultrasound measurement of muscle thickness and walking test appear to be useful tools for the assessment of joint health and functional status in PWH.

Intramural Hematoma of Gastrointestinal Tract in People with Hemophilia A and B.

People with hemophilia (PWH), especially severe hemophilia, often experience bleeding episodes, which occur mostly at major joints. Intramural hematoma of the gastrointestinal (GI) tract is a rare, potentially life-threatening clinical bleeding manifestation in PWH. Prompt identification and timely administration of clotting factor concentrates are of utmost importance for effective management and optimal patient outcomes. In this report, we present the case of a 48-year-old male with severe hemophilia A. The patient developed a spontaneous intramural hematoma of the jejunum, leading to signs of acute abdomen, bloody stool, and paralytic ileus. Conservative management with factor VIII (FVIII) infusion was successfully administered. However, within a span of three months, the patient suffered from a recurrent episode of intramural hematoma, which was again effectively treated with conservative therapy. Subsequently, prophylactic FVIII therapy was administered to the patient, resulting in the absence of recurrence for over three years. Inspired by this case, we conducted a comprehensive review of the relevant literature and gathered data from 79 reported cases of intramural hematoma that were documented between the years 1956 and 2022. We classified these cases based on the site affected within the gastrointestinal (GI) tract (spread across five different locations) and proceeded to conduct a simple pooling analysis on the data collected, which subsequently revealed that the overall mortality rate of intramural hematoma in people with hemophilia (PWH) was found to be 12.2%, while children have a higher mortality rate (23.3%) than adults (4.9%). We hope this case report and literature review increase awareness of this rare bleeding manifestation in PWH, the effectiveness of conservative treatment, and the possibility of prophylaxis against recurrence.

Feasibility and Toxicity of Interval-Compressed Chemotherapy in Asian Children and Young Adults with Sarcoma.

Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200-2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5-10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15-24 days. Median nadirs (IQR) were neutrophil count, 134 (30-396) × 106/L at day 11 (10-12), recovery by day 15 (14-17) and platelet count, 35 (23-83) × 109/L at day 11 (10-13), recovery by day 17 (14-21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas.

Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors. METHODS: This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete. FINDINGS: Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported. INTERPRETATION: In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia. FUNDING: Sanofi.

Clinical Predictors and Prediction Models for rFVIII-Fc Half Life in Real-World People with Severe Hemophilia A.

The half life of recombinant factor VIII-Fc (rFVIII-Fc) for people with hemophilia A (PwHA) varies greatly. Understanding the factors influencing the variation and assessment of rFVIII-Fc half life is important for personalized treatment. Eighty-five severe-type PwHA with rFVIII-Fc treatment receiving an evaluation of half life by the Web-Accessible Population Pharmacokinetic (PK) Service-Hemophilia during 2019-2021 were retrospectively enrolled. The 50-patient PK profiles before 2021 were used for analysis and developing prediction models of half life, and the 35-patient PK profiles in 2021 were used for external validation. The patients in the development cohort were aged 8-64, with a median rFVIII-Fc half life of 20.75 h (range, 8.25-41.5 h). By multivariate linear regression analysis, we found two, four, and five predictors of rFVIII-Fc half life for the blood groups non-O, O patients, and overall patients, respectively, including baseline VWF:Ag, BMI, VWF:activity/VWF:Ag ratio, body weight, O blood group, inhibitor history, HCV infection, and hematocrit. The three prediction equations of rFVIII-Fc half life (T) were respectively developed as T for non-O group patients = -0.81 + 0.63 × (BMI, kg/m2) + 6.07 × (baseline VWF:Ag, IU/mL), T for O group patients = -0.68 + 13.30 × (baseline VWF:Ag, IU/mL) + 0.27 × (BW, kg) - 1.17 × (BMI, kg/m2) + 16.02 × (VWF:activity/VWF:Ag ratio), and T for overall patients = -1.76 + 7.24 × (baseline VWF:Ag, IU/mL) - 3.84 × (Inhibitor history) + 2.99 × (HCV infection) - 2.83 × (O blood group) + 0.30 × (Hct, %), which explained 51.97%, 75.17%, and 66.38% of the half life variability, respectively. For external validation, there was a significant correlation between the predicted and observed half lives in the validation cohort. The median half life deviation was +1.53 h, +1.28 h, and +1.79 h for the equations of non-O group, O group, and overall group patients, respectively. In total, eight predictors influencing rFVIII-Fc half life were identified. Prediction equations of rFVIII-Fc half life were developed for the non-O and O blood groups and overall PwHA with a good degree of external validation. The equations could be applied to patients aged 8-64 without the need for PK blood sampling and clinically valuable for personalized therapy.

Real-world bleeding outcomes and product utilization in people with severe-type hemophilia A before and after switching to extended half-life rFVIIIFc prophylaxis therapy.

BACKGROUND: Recombinant factor VIII-Fc (rFVIIIFc) became available in Taiwan in 2018. Before this date, no people with hemophilia A (PwHA) were enrolled in a clinical trial of rFVIIIFc. We investigated changes in bleeding outcomes and product utilization in PwHA switching from rFVIII to rFVIIIFc. METHODS: Data were collected for Taiwanese PwHA (severe-type) who switched from rFVIII to rFVIIIFc, including annualized bleeding rate (ABR) and weekly dose consumption 12 months pre-switch and > 6 months post-switch. RESULTS: The 51 patients were divided into 3 groups according to their pre-switch treatment: on-demand treatment, intermittent periodic prophylaxis, and regular prophylaxis. In every group, the post-switch median ABR was significantly reduced, with no significant differences between groups. Meanwhile, the post-switch median weekly dose of each group was significantly increased. In 32 patients on pre-switch prophylaxis, switching brought a further reduction in median ABR, associated with a significant increase in median weekly dose. No adverse effects or novel inhibitor development were seen. CONCLUSION: This is the first report from Asia on real-world experience of rFVIIIFc, showing that switching to rFVIIIFc prophylaxis led to further reduction in ABR and increase in weekly dose for all patient groups, even those on pre-switch rFVIII prophylaxis.

Adrenal Crisis Mimicking COVID-19 Encephalopathy in a Teenager with Craniopharyngioma.

There is an increasing number of reported cases with neurological manifestations of COVID-19 in children. Symptoms include headache, general malaise, ageusia, seizure and alterations in consciousness. The differential diagnosis includes several potentially lethal conditions including encephalopathy, encephalitis, intracranial hemorrhage, thrombosis and adrenal crisis. We report the case of a 17-year-old boy with a positive antigen test of COVID-19 who presented with fever for one day, altered mental status and seizure, subsequently diagnosed with adrenal insufficiency. He had a history of panhypopituitarism secondary to a suprasellar craniopharyngioma treated with surgical resection; he was treated with regular hormone replacement therapy. After prompt administration of intravenous hydrocortisone, his mental status returned to normal within four hours. He recovered without neurologic complications. Adrenal insufficiency can present with neurological manifestations mimicking COVID-19 encephalopathy. Prompt recognition and treatment of adrenal insufficiency, especially in patients with brain tumors, Addison's disease or those recently treated with corticosteroids, can rapidly improve the clinical condition and prevent long-term consequences.

Atypical Teratoid/Rhabdoid Tumor in Taiwan: A Nationwide, Population-Based Study.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly aggressive embryonal brain tumor most commonly presenting in young children. METHODS: We performed a nationwide, population-based study of AT/RT (ICD-O-3 code: 9508/3) in Taiwan using the Taiwan Cancer Registry Database and the National Death Certificate Database. RESULTS: A total of 47 cases (male/female = 29:18; median age at diagnosis, 23.3 months (IQR: 12.5-87.9)) were diagnosed with AT/RT between 1999 and 2014. AT/RT had higher prevalence in males (61.70%), in children < 36 months (55.32%), and at infratentorial or spinal locations (46.81%). Survival analyses demonstrated that patients ≥ 3 years of age (n = 21 (45%)) had a 5y-OS of 41% (p < 0.0001), treatment with radiotherapy only (n = 5 (11%)) led to a 5y-OS of 60%, treatment with chemotherapy with or without radiotherapy (n = 27 (62%)) was associated with a 5y-OS of 45% (p < 0.0001), and patients with a supratentorial tumor (n = 11 (23%)) had a 5y-OS of 51.95%. Predictors of better survival on univariate Cox proportional hazard modeling and confirmed with multivariate analysis included older age (≥1 year), supratentorial sites, and the administration of radiotherapy, chemotherapy, or both. Gender had no effect on survival. CONCLUSION: Older age, supratentorial site, and treatment with radiotherapy, chemotherapy, or both significantly improves the survival of patients with AT/RT.

Evolution of congenital haemophilia care in Taiwan.

Haemophilia care in Taiwan has come a long way over the past 35 years, from the absence of specialised haemophilia treatment centres before 1984 to the establishment of treatment centers in the majority of medical centers, the listing of haemophilia as a catastrophic illness with full treatment reimbursement by the Taiwan National Health Insurance (NHI), and the implementation of full NHI coverage for prophylaxis therapy. This has led to outcome improvements such as reduced bleed-related morbidity and mortality, fewer viral infections, and enhanced overall multi-modality care. Most people with haemophilia (PWH) are now able to live normal, active lives. Early diagnosis has improved through increased awareness, physician education, and prenatal diagnosis; while comprehensive care, including state of the art rehabilitation and orthopaedic management for haemophilic arthropathy, eradication therapy for chronic hepatitis C, and better treatments for human immunodeficiency virus, allows PWH to enjoy a better quality of life and improved survival. Efforts are now being made to raise prophylaxis rates through full NHI reimbursement and the use of extended half-life recombinant factor products. Overall, Taiwan has made great strides in haemophilia care and we would like to share these experiences for the benefit of all healthcare providers involved in haemophilia care.

A Comparative Evaluation of an Automated Functional Assay for Von Willebrand Factor Activity in Type 1 Von Willebrand Disease.

BACKGROUND: von Willebrand factor ristocetin cofactor activity (VWF:RCo) is the standard functional assay used for von Willebrand disease (VWD) diagnosis. However, it has some drawbacks including being time consuming and labor intensive and having high inter-laboratory variability. The HemosIL VWF activity assay has the advantages of both high speed and automation. The purpose of this study was to prospectively compare these two functional assays for type 1 VWD detection. METHODS: Plasma samples from 108 subjects were assessed in this study. HemosIL VWF activity was measured with the HemosIL latex immunoturbidimetric commercial kits by the ACL TOP coagulation analyzer. VWF:RCo was measured by platelet aggregation method. Pearson correlation analyses were performed to estimate the correlation of HemosIL VWF activity with VWF:RCo. Receiver-operator characteristic (ROC) curve analysis was used to evaluate the performance of the two diagnostic tests. RESULTS: The correlation coefficient between VWF:RCo and HemosIL VWF activity was 0.874 overall and was 0.761 and 0.811 in the cohorts of type 1 VWD and non-VWD, respectively. The sensitivity and specificity of HemosIL VWF activity assay for type 1 VWD identification were 94.7% and 80.0%, respectively, and the ROC curve of HemosIL VWF activity was larger than that of VWF:RCo (0.928 vs 0.863, p=0.0138). Finally, the positive and negative predictive values of the HemosIL VWF activity assay for type 1 VWD detection were 72.0% and 96.6%, respectively. CONCLUSION: Our results demonstrate that the HemosIL VWF activity assay was an effective method for type 1 VWD screening and diagnosis. It carried good sensitivity and specificity and had a higher ROC curve than VWF:RCo besides showing good correlation with VWF:RCo. With its advantages of greater speed and automated performance, these results suggest that the HemosIL VWF activity assay was reliable and precise in the clinical setting.

Deep intronic variant c.5999-277G>A of F8 gene may be a hot spot mutation for mild hemophilia A patients without mutation in exonic DNA.

BACKGROUND: In 10%-18% of mild-type hemophilia A (HA) patients, mutations cannot be found by routine DNA analysis. OBJECTIVE: We aimed to identify the genetic defects by mRNA analysis of F8 gene in mild HA patients without mutation in exonic DNA. PATIENTS AND METHODS: From 2006 to 2016, we identified F8 exon mutations in 39 of 49 mild HA patients using routine genetic testing. We then evaluated the 10 remaining patients from six unrelated families without exonic DNA mutation by performing cDNA sequence analysis. RESULTS: Nine of the 10 (90%) patients were confirmed to have F8 gene mutation. Eight patients from four unrelated families were notably found to have presence of an aberrant 675-bp fragment. Sequencing of this fragment showed that there were two separate new alternative splicing exons of 35 bp and 55 bp within intron 18, which formed a 90-bp insertion between exon 18 and exon 19 (E18ins90bpE19) in the mRNA. Based on direct sequencing, this alternative splicing transcript appears to have resulted from deep intronic variant c.5999-277G>A of intron 18. CONCLUSIONS: Our study suggests that deep intronic variant of c.5999-277G>A may be a hot spot mutation for mild hemophilia patients without mutation in exonic DNA.

Obesity and overweight in patients with hemophilia: Prevalence by age, clinical correlates, and impact on joint bleeding.

BACKGROUND: The prevalence of obesity in patients with hemophilia (PWH) varies among different ethnicities, and its influence on joint bleeding and hemophilic arthropathy has not been studied in Taiwan population. We explored the prevalence and clinical correlates of obesity and the impact of body mass index (BMI) on annual joint bleeding rate (AJBR) and hemophilic arthropathy in PWH in Taiwan. METHODS: We retrospectively collected clinical information on 140 severe/40 moderate PWH from 2006 to 2014. The patients' median age was 31.5 years, ranged from 6 to 73 years. Their BMI, 6 index joints score by Pettersson scoring, AJBR, and other clinical data were analyzed. RESULTS: The prevalence of overweight and obesity by age group was 7.1% in PWH aged ≤10 years, and rapidly increased to 34.5% in PWH aged 11 to 18 years, 46.7% in PWH aged 18 to 29 years, 61.8% in PWH aged 30 to 39 years, 60.6% in PWH aged 40 to 49 years, and 48% in PWH aged ≥50 years, respectively. Two peak rates were 72.7% in PWH aged 35 to 44 years and 66.7% in PWH aged >65 years. Age, HCV infection, knee score, elbow score, and total 6 index joints scores were found to correlate positively with BMI. However, subtype and severity of hemophilia, ankle scores, HBV and HIV infection did not correlate with BMI. Finally, BMI was found to correlate positively with AJBR in both adult and pediatric PWH. CONCLUSION: The prevalence of overweight and obesity in adolescent and adult PWH was higher than those in the general male population in Taiwan, which rapidly increased with age to peak in PWH aged 35 to 44 years and >65 years. High index joint score, with the exception of ankle scores, positively correlated with high BMI. Further, BMI and obesity also had positive correlation with AJBR in PWH. To our knowledge, this is the first study examining these associations in PWH in Taiwan.

Pediatric acute lymphoblastic leukemia with t(1;19)/TCF3-PBX1 in Taiwan.

BACKGROUND: In childhood acute lymphoblastic leukemia (ALL), t(1;19)(q23;p13.3) with TCF3-PBX1 fusion is one of the most frequent translocations. Historically, it has been associated with poor prognosis. Intensive treatment, however, has improved its outcome. We determined the outcome of children with this genotype treated with contemporary intensive chemotherapy in Taiwan. PROCEDURE: In Taiwan Pediatric Oncology Group 2002 ALL studies, genotypes were determined by cytogenetic analysis and/or reverse transcriptase polymerase chain reaction assay. Based on presenting features, immunophenotype and genotype, patients were assigned to one of the three risk groups: standard risk (SR), high risk (HR), or very high risk (VHR). The patients with t(1;19)/TCF3-PBX1 were treated in the HR arm receiving more intensive chemotherapy. The outcomes of patients with t(1;19)/TCF3-PBX1 were compared to that of patients with other subtypes of B-precursor ALL (B-ALL). RESULTS: Of the 1,129 patients with B-ALL, 64 (5.7%) had t(1;19)/TCF3-PBX1; 51 of whom were treated in the HR arm, but 11 were treated in the VHR and 2 in the SR arm because of physician's preference. As a group, 64 patients with t(1;19)/TCF3-PBX1 had similar 5-year event-free survival (83.3 ± 4.8%) as those with TEL-AML1 (85.2 ± 3.4%, P = 0.984) or those with hyperdiploidy >50 (84.0 ± 3.1%, P = 0.748). The cumulative risk of any (isolated plus combined) central nervous system relapse among patients with t(1;19)/TCF3-PBX1 (8.7 ± 3.8%) tended to be higher than that of patients with TEL-AML1 (5.8 ± 2.3%, P = 0.749) or those with hyperdiploidy (4.1 ± 1.8%, P = 0.135), albeit the differences did not reach statistical significance. CONCLUSIONS: With contemporary intensive chemotherapy, children with t(1;19)/TCF3-PBX1 fared as well as those with favorable genotypes (TEL-AML1 or hyperdiploidy).

Novel synthetic benzimidazole-derived oligosaccharide, M3BIM, prevents ex vivo platelet aggregation and in vivo thromboembolism.

BACKGROUND: Thrombus formation, a phenomenon primarily related to increased platelet activation, plays a key role in cardiovascular and cerebrovascular diseases. Although the established antiplatelet agents, such as aspirin and clopidogrel, have been shown to be beneficial in treating thromboembolic diseases, they have considerable limitations. Hence, the development of more effective and safe antithrombotic agents is necessary to satisfy a substantial unmet clinical need. In recent years, the favorable properties of imidazole-related drugs have prompted medicinal chemists to synthesize numerous novel therapeutic agents. The chemical structure of the benzimidazole backbone has proven antiplatelet properties. Moreover, synthetic oligosaccharides have exhibited antiplatelet properties. Therefore, we developed a new aldo-benzimidazole-derived oligosaccharide compound, M3BIM, for achieving a stronger antiplatelet effect than the drugs which are being used in clinical aspects. We investigated the effects of M3BIM on platelet activation ex vivo and its antithrombotic activity in vivo. RESULTS: M3BIM (10-50 µM) exhibited a more potent activity in inhibiting platelet aggregation stimulated by collagen than it did in inhibiting that stimulated by thrombin in washed human platelets. The M3BIM treatment revealed no cytotoxicity in zebrafish embryos, even at the highest concentration of 100 µM. In addition, M3BIM inhibited the phosphorylation of phospholipase Cγ2, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase 2 and c-Jun N-terminal kinase 1), and markedly reduced the ATP-release reaction and intracellular calcium mobilization in collagen-activated platelets. By contrast, M3BIM showed no effects on either collagen-induced p38 MAPK and Akt phosphorylation or phorbol 12, 13-dibutyrate-induced PKC activation and platelet aggregation. Moreover, the M3BIM treatment substantially prolonged the closure time in human whole blood, and increased the occlusion time in mesenteric microvessels and attenuated cerebral infarction in mice. For the study of anticoagulant activities, M3BIM showed no significant effects in the prolongation of activated partial thromboplastin time and prothrombin time in mice. CONCLUSION: The findings of our study suggest that M3BIM is a potential therapeutic agent for preventing or treating thromboembolic disorders.

Risk and mortality of gastrointestinal hemorrhage in patients with thrombocytopenia: Two nationwide retrospective cohort studies.

INTRODUCTION: The association between thrombocytopenia (TP) and gastrointestinal hemorrhage was not completely understood. The purpose of this study is to evaluate the risk of gastrointestinal hemorrhage and post-hemorrhage mortality in patients with TP. METHODS: Using the Taiwan National Health Insurance Research Database, we identified 1033 adults aged ≥18 years diagnosed with TP in 2000-2003. Non-TP cohort consisted of 10,330 adults randomly selected and matched by age and sex from the same dataset. Incident events of gastrointestinal hemorrhage occurring after TP from January 1, 2000, through December 31, 2008, were ascertained from medical claims. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of gastrointestinal hemorrhage associated with TP were calculated. Another nested cohort study consisted of 27,369 patients with hospitalization due to gastrointestinal hemorrhage between January 1, 2004, and December 31, 2010. We calculated the adjusted odds ratios (ORs) and 95% CIs of 30-day mortality after gastrointestinal hemorrhage in patients with and without TP during admission. RESULTS: The incidences of gastrointestinal hemorrhage for people with and without TP were 14.5 and 5.07 per 1000 person-years, respectively (P<0.0001). Compared to people without TP, patients with TP had increased risk of gastrointestinal hemorrhage (HR, 2.61; 95% CI, 2.05-3.32). In the nested cohort study, TP was associated with post-hemorrhage mortality (OR, 1.98; 95% CI, 1.09-3.59). CONCLUSION: Patients with TP showed higher risks of gastrointestinal hemorrhage and post-hemorrhage mortality. Our findings suggest the urgency of preventing and managing gastrointestinal hemorrhage by a multidisciplinary medical team for this specific population.

Development of serum IgA and IgM levels in breast-fed and formula-fed infants during the first week of life.

BACKGROUND: IgA and IgM antibodies play important roles to protect infants in early life AIM: To study the effects of breast milk feeding versus formula feeding in early infancy on the development of serum IgA and IgM. METHODS: A group of 220 healthy infants born after uncomplicated pregnancies and deliveries were enrolled. The infants were divided into three groups according to feeding type: breast-fed (BF), formula-fed (FF), and mixed-fed (MF). Capillary blood was collected for serum IgA and IgM detection at the first week of life. RESULTS: The average concentrations of serum IgA and IgM in all infants were 1.171±1.079 and 256.2±165.8 µg/ml, respectively. There were significantly higher concentrations of serum IgA in the FF group than MF group at 3, 4 and 6 days of age and BF group at 5 and 6 days old. Paired serum IgA concentrations revealed that IgA significantly decreased in the BF group, but not in the FF and MF groups. Meanwhile, paired serum IgM concentrations revealed that IgM increased significantly during early infancy in all groups. However, the IgM levels had no difference among the 3 groups within 7 days of age. CONCLUSIONS: Our study demonstrated the development of serum IgA and IgM in early life. Formula feeding induced higher serum IgA concentrations than breast-feeding within 7 days of age. However, serum IgM concentration was significantly increased in early life in all groups but had no differences between the different feeding types. Breast-feeding may protect antigen loading in early life.