Final analysis of the phase 3 randomized clinical trial comparing HD201 vs. referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting.

BACKGROUND: The TROIKA trial established that HD201 and trastuzumab were equivalent in terms of primary endpoints (total pathological complete response) following neoadjuvant treatment. The objective of the present analysis was to compare survival outcomes and final safety. METHODS: In the TROIKA trial, patients with ERBB2-positive early breast cancer were randomized and treated with either HD201 or the referent trastuzumab. Eligible patients received 8 cycles of either HD201 or referent trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in combination with 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) in the neoadjuvant setting. The patients then underwent surgery followed by 10 cycles of adjuvant HD201 or referent trastuzumab according to their initial randomization to complete one year of trastuzumab-directed therapy. Event-free and overall survival rates were calculated using Kaplan-Meier analysis. The hazard ratio for event-free survival was estimated by Cox proportional hazards regression. RESULTS: The final analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3-38.1 months). A total of 502 randomized patients received either HD201 or the referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. In this population, the 3-year event-free survival rates were 85.6% (95% CI: 80.28-89.52) and 84.9% (95% CI: 79.54-88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (HR 1.02, 95% CI: 0.63-1.63; p = 0.945). The 3-year overall survival rates were comparable between the HD201 (95.6%; 95% CI: 91.90-97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45-97.90) (log rank p = 0.606). During the posttreatment follow-up period, adverse events were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the reference trastuzumab groups, respectively. Serious adverse events were rare and none of which were related to the study treatment. CONCLUSIONS: This final analysis of the TROIKA trial further confirms the comparable efficacy and safety of HD201 and trastuzumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03013504.

Allergenicity and safety of recombinant human C1 esterase inhibitor in patients with allergy to rabbit or cow's milk.

BACKGROUND: Recombinant human C1 inhibitor (rhC1INH) for on-demand treatment of hereditary angioedema is purified from milk of transgenic rabbits. It contains low amounts (<0.002%) of host-related impurities, which could trigger hypersensitivity reactions in patients with rabbit allergy (RA) and/or cow's milk allergy (CMA). OBJECTIVE: This study is an assessment of allergenicity and safety of rhC1INH in patients with RA and/or CMA. METHODS: Patients with CMA and/or RA underwent skin prick test (SPT), intracutaneous test (ICT), and, when results for both were negative, subcutaneous (SC) challenge with up to 2100U (14 mL) rhC1INH. The negative predictive value of the skin test protocol was calculated, defined as the ratio of patients without systemic symptoms of hypersensitivity following SC challenge, over the number of patients having tested negative for both the SPT and the ICT. Adverse events after exposure to rhC1INH were recorded. RESULTS: Twenty-six patients with RA and/or CMA were enrolled. Twenty-four had negative SPT and ICT results for rhC1INH, whereas 2 had negative SPT result but positive ICT result to rhC1INH (only the highest concentration). Twenty-two patients with negative SPT and ICT results underwent SC challenge. None developed allergic symptoms. Local treatment-emergent adverse events occurred in 7 patients (32%) after SC challenge. In 5 these were considered drug related. All were mild. CONCLUSIONS: None of the patients with negative SPT and ICT results for rhC1INH had allergic symptoms during rhC1INH challenge. The negative predictive value of the combination of SPT and ICT for the outcome of the SC challenge was 100% (95% CI, 84.6%-100%). SC administration of rhC1INH was well tolerated.

The Impact of In-Event Health Services at Europe's Largest Electronic Dance Music Festival on Ems and Ed in the Host Community.

BACKGROUND: Electronic dance music festivals (EDMF) can cause a significant disruption in the standard operational capacity of emergency medical services (EMS) and hospitals. We determined whether or not the presence of in-event health services (IEHS) can reduce the impact of Europe's largest EDMF on the host community EMS and local emergency departments (EDs). METHODS: We conducted a pre-post analysis of the impact of Europe's largest EDMF in July 2019, in Boom, Belgium, on the host community EMS and local EDs. Statistical analysis included descriptive statistics, independent t-tests, and χ2 analysis. RESULTS: Of 400,000 attendees, 12,451 presented to IEHS. Most patients only required in-event first aid, but 120 patients had a potentially life-threatening condition. One hundred fifty-two patients needed to be transported by IEHS to nearby hospitals, resulting in a transport-to-hospital rate of 0.38/1000 attendees. Eighteen patients remained admitted to the hospital for >24 h; one died after arrival in the ED. IEHS limited the overall impact of the MGE on regular EMS and nearby hospitals. No predictive model proved optimal when proposing the optimal number and level of IEHS members. CONCLUSIONS: This study shows that IEHS at this event limited ambulance usage and mitigated the event's impact on regular emergency medical and health services.

Validation of a Belgian Prediction Model for Patient Encounters at Belgium's Largest Public Cultural Mass Gathering.

OBJECTIVE: To compare actual patient presentation rates from Belgium's largest public open-air cultural festival with predictions provided by existing models and the Belgian Plan Risk Manifestations model. METHODS: Retrospectively, actual patient presentation rates gathered from the Ghent Festivities (Belgium) during 2013-2019 were compared to predicted patient presentation rates by the Arbon, Hartman, and PRIMA models. RESULTS: During 7 editions, 8673000 people visited the Ghent Festivities; 9146 sought medical assistance resulting in a mean patient presentation rate (PPR) of 1.05. The PRIMA model overestimated the number of patient encounters for each occasion. The other models had a high rate of underprediction. When comparing deviations in predictions between the PRIMA model to the other models, there is a significant difference in the mean deviation (Arbon: T = 0.000, P < 0.0001, r = -0.8701; Hartman: T = 0.000, P < 0.0001, r = -0.869). CONCLUSION: Despite the differences between the predictions of all 3 models, our results suggest that the PRIMA model is a valid tool to predict patient presentations to IEHS during public cultural MG. However, to substantiate the PRIMA model even further, more research is needed to further validate the model for a broad range of MG.

Risk assessment, consequences, and epidemiology of electric scooter accidents admitted to an emergency department: a prospective observational study.

PURPOSE: This study aimed to describe the demographic and clinical characteristics of individuals involved in electric scooter (E-scooter) accidents and the factors associated with these incidents. METHODS: We conducted a prospective observational study of individuals involved in E-scooter accidents admitted to the emergency department of Saint-Pierre Hospital. The highest abbreviated injury score above or equal to two classified the injury as significant. Injuries during working hours were compared to those during off-working hours. RESULTS: During the study period from June 1, 2019, to June 30, 2020, 170 individuals were admitted to the emergency department following an E-scooter accident. In 73.5% of the accidents, rented E-scooters were involved. Of the patients, 68.2% were male, 6.4% wore helmets, and 30% were under the influence of alcohol. Upper limb and cranial injuries were more frequently severe (abbreviated injury score ≥ 2) than other injuries (p < 0.05). Accidents during off-working hours were significantly related to alcohol consumption (p < 0.001), non-usage of helmets (p < 0.01), head and neck injuries (p < 0.01), and rented E-scooters (p < 0.01). Alcohol consumption was itself associated with the non-usage of helmets (p < 0.05) and major head and neck injuries (p < 0.001). CONCLUSION: Given the increasing popularity of E-scooters as an alternative mode of transportation, our study can inform public policy on patterns of injuries associated with E-scooter utilization for future injury prevention policies. Using helmets, avoiding alcohol consumption, and regulating use at night can improve outcomes in E-scooter accidents. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04778332.

Efficacy of HD201 vs Referent Trastuzumab in Patients With ERBB2-Positive Breast Cancer Treated in the Neoadjuvant Setting: A Multicenter Phase 3 Randomized Clinical Trial.

Importance: The drug HD201 is a biosimilar candidate for breast cancer treatment as the reference trastuzumab. Objective: To compare the efficacy of HD201 with referent trastuzumab. Design, Setting, and Participants: This randomized clinical trial (TROIKA) included 502 women with ERBB2-positive early breast cancer treated with either HD201 or referent trastuzumab. It was conducted across 70 centers in 12 countries, including Western and Eastern Europe and Asian countries. Randomization was stratified by tumor hormone receptor status, clinical stage, and geographic region of recruitment. This analysis was conducted on February 12, 2021, after the completion of the adjuvant phase at a median of 31 months (IQR, 28-33 months) of follow-up. Interventions: Patients with ERBB2-positive early breast cancer were randomly assigned to receive HD201 or referent trastuzumab in the neoadjuvant setting for 8 cycles, concurrently with 4 cycles of docetaxel, which was followed by 4 cycles of epirubicin and cyclophosphamide. Patients then underwent surgery, which was followed by treatment with 10 cycles of adjuvant HD201 or referent trastuzumab. Main Outcome and Measures: The primary end point was the total pathological complete response (tpCR) assessed after neoadjuvant treatment. Equivalence was concluded if the 95% CI of the absolute difference in tpCR between arms in the per-protocol set was within the margin of more or less than 15%. Other objectives included the breast pathological complete response, overall response, event-free and overall survival, safety, pharmacokinetics, and immunogenicity. Results: A total of 502 female patients (mean [range] age, 53 [26-82] years) were randomized to receive either HD201 or referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. The baseline characteristics were well balanced between the 2 arms; 195 tumors (38.8%) were hormone receptor-negative , and 213 patients (42.4%) had clinical stage III disease. The tpCR rates were 45% and 48.7% for HD201 and referent trastuzumab, respectively. The difference between the 2 groups was not significant at -3.8% (95% CI, -12.8% to 5.4%) and fell within the predefined equivalence margins. The ratio of the tpCR rates between the 2 arms was 0.92 (95% CI, 0.76 to 1.12). A total of 433 patients (86.1%) presented with 2232 treatment-emergent adverse events of special interest for trastuzumab during the entire treatment period, with 220 (88.0%) and 213 (84.5%) patients in the HD201 and referent trastuzumab groups, respectively. Conclusions and Relevance: The results of this randomized clinical trial found that HD201 demonstrated equivalence to referent trastuzumab in terms of efficacy for the end point of tpCR, with a similar safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT03013504.

Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) results from a genetic deficiency of C1-inhibitor. Two similar independent, randomized, saline controlled, double-blind studies were conducted to evaluate the efficacy and safety of recombinant human C1-inhibitor (rhC1INH) as a treatment of acute angioedema attacks in patients with HAE. OBJECTIVE: Analysis of pooled study results. METHODS: Patients with an eligible attack were randomized to a single intravenous dose of rhC1INH or saline. Efficacy was assessed by using patient-reported visual analog scale outcomes, and safety was assessed by using adverse events and immunogenicity of rhC1INH. RESULTS: rhC1INH at 100 (n = 29) and 50 (n = 12) U/kg body weight resulted in a significant reduction for both the primary endpoint time to the beginning of relief of symptoms compared with saline (n = 29): median, 66 (95% CI, 61-122) minutes, 122 (72-136) minutes, and 495 (245-520) minutes, P < .001 and P = .013, respectively; and for the secondary endpoint time to minimal symptoms, median, 266 (242-490) minutes, 247 (243-484) minutes, and 1210 (970-1500) minutes, P < .001 and P = .001, respectively. Therapeutic failure occurred in 59% (17/29) of the saline group compared with 0% (0/12) of the 50 U/kg group and 10% (3/29) of the 100 U/kg group. Treatment-emergent adverse events were unremarkable and tended to be reported more frequently in the saline group. No postexposure antibody responses against rhC1INH or host-related impurities were observed. CONCLUSION: Administration of rhC1INH at 100 or 50 U/kg was highly effective as a treatment of acute attacks in patients with HAE and appeared to be safe and well tolerated.

Validation of a Belgian Prediction Model for Patient Encounters at Football Mass Gatherings.

BACKGROUND: To validate the Belgian Plan Risk Manifestations (PRIMA) model, actual patient presentation rates (PPRs) from Belgium's largest football stadium were compared with predictions provided by existing models and the Belgian PRIMA model. METHODS: Actual patient presentations gathered from 41 football games (2010-2019) played at the King Baudouin Stadium (Brussels, Belgium) were compared with predictions by existing models and the PRIMA model. All attendees who sought medical help from in-event health services (IEHS) in the stadium or called 1-1-2 within the closed perimeter around the stadium were included. Data were analyzed by ANOVA, Pearson correlation tests, and Wilcoxon singed-rank test. RESULTS: A total of 1,630,549 people attended the matches, with 626 people needing first aid. Both the PRIMA and the Hartman model over-estimated the number of patient encounters for each occasion. The Arbon model under-estimated patient encounters for 9.75% (95% CI, 0.49-19.01) of the events. When comparing deviations in predictions between the PRIMA model to the other models, there was a significant difference in the mean deviation (Arbon: Z = -5.566, P <.001, r = -.61; Hartman: Z = -4.245, P <.001, r = .47). CONCLUSION: When comparing the predicted patient encounters, only the Arbon model under-predicted patient presentations, but the Hartman and the PRIMA models consistently over-predicted. Because of continuous over-prediction, the PRIMA model showed significant differences in mean deviation of predicted PPR. The results of this study suggest that the PRIMA model can be used during planning for domestic and international football matches played at the King Baudouin Stadium, but more data and further research are needed.

Validation of a Belgian Prediction Model for Patient Encounters at Music Mass Gatherings.

INTRODUCTION: A Belgian predictive medical resource tool, Plan Risk Manifestations (PRIMA), for the prediction of the number of patient encounters at mass gatherings (MGs) has recently been developed, in addition to the existing models of Arbon and Hartman. This study presents the results of the validation process for the PRIMA model for music MGs. METHODS: A retrospective study was conducted using data gathered from music MGs in the province of Antwerp (Belgium) during the period of 2012-2016. Data from 87 music MGs were used for the study. The forecast of medical resources for these events was determined by entering the characteristics of individual events into the Arbon, Hartman, and PRIMA models. In order to determine if the PRIMA model is under- or over-predictive, the data gathered were retrospectively compared to the predicted number of resources needed using the aforementioned models. Statistical analysis included means, medians, and interquartile ranges (IQRs). Nonparametric related samples test (Wilcoxon Samples Signed Rank Test) for comparison of the median in deviations in predictions of patient presentation rates (PPRs) was performed using SPSS version 23 (IBM Corp.; Armonk, New York USA). Confidence interval levels were set at 95% and results were deemed statistically significant at P <.05. This triple comparison was used to determine the overall performance of all three models. RESULTS: All three models had an acceptable rate of over-prediction of number of patient encounters ([Arbon 25.29%; 95% CI, 30.91-43.74]; [Hartman 29.89%; 95% CI, 57.10-68.90]; and [PRIMA 19.54%; 95% CI, 57.80-76.20]). But all models also had a high rate of under-prediction of number of patient encounters ([Arbon 74.71%; 95% CI, 453.31-752.52]; [Hartman 70.11%; 95% CI, 546.90-873.77]; and [PRIMA 78.16%; 95% CI, 288.91-464.89]). Only the PRIMA model succeeded in the correct prediction of the number of patient encounters on two occasions (2.3%). CONCLUSION: Results of this study are in-line with existing literature. When comparing the predicted patient encounters, all three models had high rates of under-prediction and moderate rates of over-prediction. When comparing mean deviations, the PRIMA model had the lowest mean deviation of all predicted PPRs. Belgian events of the types included in the presented data may use the PRIMA model with confidence to predict PPRs and estimate the in-event health services (IEHS) requirements.

Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes.

BACKGROUND: Type 1 diabetes mellitus is a T-cell-mediated autoimmune disease that leads to a major loss of insulin-secreting beta cells. The further decline of beta-cell function after clinical onset might be prevented by treatment with CD3 monoclonal antibodies, as suggested by the results of a phase 1 study. To provide proof of this therapeutic principle at the metabolic level, we initiated a phase 2 placebo-controlled trial with a humanized antibody, an aglycosylated human IgG1 antibody directed against CD3 (ChAglyCD3). METHODS: In a multicenter study, 80 patients with new-onset type 1 diabetes were randomly assigned to receive placebo or ChAglyCD3 for six consecutive days. Patients were followed for 18 months, during which their daily insulin needs and residual beta-cell function were assessed according to glucose-clamp-induced C-peptide release before and after the administration of glucagon. RESULTS: At 6, 12, and 18 months, residual beta-cell function was better maintained with ChAglyCD3 than with placebo. The insulin dose increased in the placebo group but not in the ChAglyCD3 group. This effect of ChAglyCD3 was most pronounced among patients with initial residual beta-cell function at or above the 50th percentile of the 80 patients. In this subgroup, the mean insulin dose at 18 months was 0.22 IU per kilogram of body weight per day with ChAglyCD3, as compared with 0.61 IU per kilogram with placebo (P<0.001). In this subgroup, 12 of 16 patients who received ChAglyCD3 (75 percent) received minimal doses of insulin (< or =0.25 IU per kilogram per day) as compared with none of the 21 patients who received placebo. Administration of ChAglyCD3 was associated with a moderate "flu-like" syndrome and transient symptoms of Epstein-Barr viral mononucleosis. CONCLUSIONS: Short-term treatment with CD3 antibody preserves residual beta-cell function for at least 18 months in patients with recent-onset type 1 diabetes.

A novel pacing manoeuvre to diagnose atrial tachycardia.

AIMS: Currently used diagnostic manoeuvres at the electrophysiology study do not always allow for consistent identification of atrial tachycardia (AT), either because of inapplicability of the technique or because of low predictive value and specificity. The aim of this study was to determine whether overdrive atrial pacing during paroxysmal supraventricular tachycardia (SVT) with the same cycle length from both the high right atrium and the coronary sinus can accurately identify or exclude AT by examining the difference between the V-A intervals of the first returning beat of tachycardia between the two pacing sites. METHODS AND RESULTS: Fifty-two patients were included; 24 patients with atrioventricular nodal re-entry tachycardia (AVNRT), 13 patients with atrioventricular re-entry tachycardia (AVRT), and 15 patients with AT. Comparing the 37 non-AT patients with the 15 AT patients, there was a highly significant difference between the mean V-A interval difference, (delta V-A) 2.1 +/- 1.8 ms (range 0-9 ms) vs. 79.1 +/- 42 (range 22-267 ms) (P < 0.001), respectively. None of the patients in the non-AT group had a delta V-A > 10 ms. In contrast, all 15 patients with AT had a delta V-A interval >10 ms. Thus, the diagnostic accuracy of the delta V-A interval cut-off of >10 ms was 100%, with a 95% confidence interval of 93.1-100% for AT. In 11 (73%) of the 15 AT patients, the standard ventricular overdrive pacing manoeuvre was not possible. In 14 of the 15 patients (93%) in the AT group, standard atrial overdrive pacing showed variable V-A intervals, correctly diagnosing AT. In all 52 patients, this measurement was repeated during pacing from the other location. In five patients from the AT group, the result of the second attempt was different from the result of the first attempt. CONCLUSION: We found that atrial differential pacing during paroxysmal SVT without termination of tachycardia and the finding of variable returning V-A interval was highly sensitive and specific for the diagnosis of AT. The manoeuvre can be easily performed in all patients with SVT and is highly reproducible. It is a useful adjunct to the currently available ventricular and atrial pacing manoeuvres.

Analysis of resolution criteria in patients with schizophrenia treated with olanzapine for an acute psychotic episode.

Resolution was defined as achieving the severity component of the remission criteria (simultaneous ratings of mild or less on 8 of the PANSS items evaluating the core symptoms of schizophrenia). Analysis of a 6-week open label study with olanzapine 5-20 mg in 306 patients with acute exacerbation, shows resolution to be a clinically meaningful measure and an achievable outcome for treatment of acute psychosis.

Heterogeneity in distribution of amyloid-positive islets in type-2 diabetic patients.

Amyloid-containing (A+) islets are characteristic for type-2 diabetes (T2D), but their abundance seems variable among patients. It is unclear whether the distribution of A+ islets follows a certain pattern or occurs randomly throughout the pancreatic organ. We investigated the topography of A+ islets in eight pancreata of T2D patients and eight sex- and age-matched non-diabetic subjects. Transversal sections of head, body and tail segments were stained with synaptophysin combined with Congo red to map/quantify islet tissue and amyloid. In the eight T2D pancreata, the overall percentage of A+ islets varied from 4% to 85%. Further analysis in body and tail indicated that peripheral regions exhibited higher percentages of A+ islets than central regions (averages of, respectively, 30% and 17%, P<0.05). Non-diabetic control pancreata also exhibited A+ islets, albeit at a 25-fold lower frequency; a tendency towards higher percentage of A+ islets in peripheral versus central regions was also observed. The higher percentage A+ islets in peripheral regions was associated with a higher density and relative islet over exocrine surface area. These observations on heterogeneity in abundance and distribution of A+ islets need consideration when sampling tissue for studies on human islet amyloidosis. The present methodology allows us to further investigate the susceptibility to amyloidosis of islets in peripheral regions of the pancreas.

Preexisting insulin autoantibodies predict efficacy of otelixizumab in preserving residual ß-cell function in recent-onset type 1 diabetes.

OBJECTIVE: Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose. RESEARCH DESIGN AND METHODS: In the included patients (n = 40 otelixizumab, n = 40 placebo), ß-cell function was assessed as area under the curve (AUC) C-peptide release during a hyperglycemic glucose clamp at baseline (median duration of insulin treatment: 6 days) and every 6 months until 18 months after randomization. (Auto)antibodies against insulin (I[A]A), GAD (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A) were determined on stored sera by liquid-phase radiobinding assay. RESULTS: At baseline, only better preserved AUC C-peptide release and higher levels of IAA were associated with better preservation of ß-cell function and lower insulin needs under anti-CD3 treatment. In multivariate analysis, IAA (P = 0.022) or the interaction of IAA and C-peptide (P = 0.013) independently predicted outcome together with treatment. During follow-up, good responders to anti-CD3 treatment (i.e., IAA(+) participants with relatively preserved ß-cell function [≥ 25% of healthy control subjects]) experienced a less pronounced insulin-induced rise in I(A)A and lower insulin needs. GADA, IA-2A, and ZnT8A levels were not influenced by anti-CD3 treatment, and their changes showed no relation to functional outcome. CONCLUSIONS: There is important specificity of IAA among other diabetes autoantibodies to predict good therapeutic response of recent-onset type 1 diabetic patients to anti-CD3 treatment. If confirmed, future immune intervention trials in type 1 diabetes should consider both relatively preserved functional ß-cell mass and presence of IAA as inclusion criteria.

Assisted reproduction and thyroid autoimmunity: an unfortunate combination?

The association between positive thyroid antibodies and an increased miscarriage rate in pregnancies after assisted reproduction technology (ART) remains controversial. We wanted to clarify this issue by performing a prospective cohort study in 234 women by systematically screening for thyroid peroxidase antibodies (TPO-Ab), serum TSH, and free T(4)(FT(4)) before the first ART cycle. Women with overt thyroid dysfunction were excluded. Fourteen percent of the cohort had positive TPO-Ab. Baseline characteristics [age, 33 +/- 5 yr; TSH, 1.6 (0.02-4.1) mU/liter; and FT(4), 12.2 (9.1-18) ng/liter] were comparable to those of the 86% of women without antibodies [age, 32 +/- 5 yr; TSH, 1.3 (0.05-3.6) mU/liter; and FT(4), 11.7 (9.5-16.5) ng/liter]. In the antibody-positive group, the pregnancy rate was 53% vs. 43% in the antibody-negative group, with an odds ratio of 0.67 [95% confidence interval (CI) (0.32-1.41); P = not significant]; however within the group that was pregnant, the miscarriage rate was 53% and 23%, respectively, with an odds ratio of 3.77 [95% CI (1.29-11.05); P = 0.016]. The age of the women was an independent risk factor for miscarriage, odds ratio 1.08 [95% CI (1.03-1.15); P = 0.005]. We conclude that women with positive TPO-Ab before the first ART cycle have a significantly increased risk for miscarriage.

Relation between disease phenotype and HLA-DQ genotype in diabetic patients diagnosed in early adulthood.

We investigated inaugural disease phenotype in relation to the presence or absence of diabetes-associated autoantibodies and human leukocyte antigen (HLA) DQ risk genotypes in adult-onset diabetic patients. Blood samples and questionnaires were obtained from 1584 recent-onset Belgian Caucasian patients (age 15-39 yr at diagnosis of primary diabetes) who were recruited by the Belgian Diabetes Registry over an 11-yr period. At clinical diagnosis, antibody-positive patients (n = 1198) were on average younger and had more symptoms, a more acute disease onset, lower body mass index, and random C-peptide levels, but higher insulin needs, glycemia, and prevalence of ketonuria, HLA-DQ, and 5' insulin gene susceptibility genotypes (P < 0.001 vs. antibody-negative patients; n = 386). In antibody-positive patients, these characteristics did not differ according to HLA-DQ genotype. However, in antibody-negative subjects, we found that patients were younger (P = 0.001); had a lower body mass index (P < 0.001), higher insulin needs (P = 0.014), and amylasemia (P = 0.001); and tended to have a higher glycemia and lower C-peptide in the presence of susceptible HLA-DQ genotypes. Differences according to HLA-DQ genotype subsisted after careful age-matching. In conclusion, we found no relation between initial disease phenotype and HLA-DQ genotype in antibody-positive diabetic young adults. In contrast, antibody-negative patients displayed more type 1-like features when carrying susceptible HLA-DQ genotypes known to promote the development of antibody-positive diabetes. The overrepresentation of these susceptibility genotypes in antibody-negative patients suggests the existence of an immune-mediated disease process with as yet unidentified immune markers in a subgroup of seronegative patients.

Glass and antimony electrodes for oesophageal pH monitoring in distressed infants: how different are they?

OBJECTIVE: Although antimony electrodes are by far the most popular for performing oesophageal pH monitoring, there are few data comparing the accuracy of glass and antimony electrodes. Therefore, we tested the accuracy of both electrodes in the prediction of oesophagitis. METHOD: pH monitoring using a glass electrode and an antimony electrode was performed in 60 distressed infants, aged between 1 and 6 months. An upper endoscopy with oesophageal biopsies was also performed in all infants. RESULTS: A reflux index (percentage of the total time with pH < 4.0) greater than 5% was considered to be abnormal and was found in 40/60 patients. Histological oesophagitis was present in 26/60 infants. The reflux index was > 5% with the glass electrode in 18/26 children with histological oesophagitis and with the antimony electrode in 10/26 children with histological oesophagitis. Histology of the oesophagus was normal in 22/40 children with abnormal pH monitoring. With the glass electrode, the mean reflux index in the group with oesophagitis was significantly higher than in the group with normal histology, although there was an important overlap. With the antimony electrode, the mean reflux indices in the groups with and without oesophagitis were not different. Regarding normal/abnormal, there was discordance in 35% of the pH studies. No reflux index could be related to a clinically useful sensitivity and specificity to predict oesophagitis. CONCLUSION: The reflux index does not accurately predict oesophagitis. Oesophageal pH monitoring and endoscopy provide complementary information.

The effect of two moisturisers on skin barrier damage in allergic contact dermatitis.

Nickel (Ni)-induced allergic contact dermatitis (ACD) was performed in human volunteers to study the role of moisturisers in preventing ACD-related skin barrier damage. 15 Ni-sensitive females (mean age: 29.5 years; range: 23-38) were included. On days 1, 21, 24 and 26, TEWL, stratum corneum (SC)-capacitance and clinical score were evaluated on four test sites on the right and left forearms. Both a highly and a poorly hydrating moisturising formulation were applied on two sites from days 1 to 21, after which Ni-ACD was induced on the 2 pre-treated sites and one non-treated area. On day 24, TEWL values were significantly increased on the site pre-treated with poorly hydrating product compared to the rich formulation pre-treated site. SC-hydration was significantly improved on the latter site on days 21, 23 and 26. Long-term use of inadequate moisturiser increases skin barrier damage due to Ni-ACD.

Minimal functional ß-cell mass in intraportal implants that reduces glycemic variability in type 1 diabetic recipients.

OBJECTIVE: Previous work has shown a correlation between ß-cell number in cultured islet cell grafts and their ability to induce C-peptide secretion after intraportal implantation in C-peptide-negative type1 diabetic patients. In this cross-sectional study, we examined the minimal functional ß-cell mass (FBM) in the implant that induces metabolic improvement. RESEARCH DESIGN AND METHODS: Glucose clamps assessed FBM in 42 recipients with established implants. C-peptide release during each phase was expressed as percentage of healthy control values. Its relative magnitude during a second hyperglycemic phase was most discriminative and therefore selected as a parameter to be correlated with metabolic effects. RESULTS: Recipients with functioning ß-cell implants exhibited average FBM corresponding to 18% of that in normal control subjects (interquartile range 10-33%). Its relative magnitude negatively correlated with HbA1c levels (r = -0.47), daily insulin dose (r = -0.75), and coefficient of variation of fasting glycemia (CVfg) (r = -0.78, retained in multivariate analysis). A correlation between FBM and CVfg <25% appeared from the receiver operating characteristic curve (0.97 [95% CI 0.93-1.00]). All patients with FBM >37% exhibited CVfg <25% and a >50% reduction of their pretransplant CVfg; this occurred in none with FBM <5%. Implants with FBM >18% reduced CVfg from a median pretransplant value of 46 to <25%. CONCLUSIONS: Glucose clamping assesses the degree of restoration in FBM achieved by islet cell implants. Values >37% of normal control subjects appear needed to reduce glycemic variability in type 1 diabetic recipients. Further studies should examine whether the test can help guide decisions on additional islet cell transplants and on adjusting or stopping immunotherapy.

Inferior and lateral electrocardiographic repolarization abnormalities in Brugada syndrome.

BACKGROUND: Repolarization abnormalities in the inferior-lateral leads in Brugada syndrome (BS) have not been systematically investigated. METHODS AND RESULTS: 280 patients (age, 41+/-18 years; 168 males) with BS were screened for inferior-lateral repolarization abnormalities. The repolarization abnormalities were classified either as early repolarization pattern or coved > or = 2-mm Brugada pattern and as spontaneous or class I antiarrhythmic drug (AAD) induced. Thirty-two patients (11%) had inferior-lateral spontaneous early repolarization pattern. These patients were less likely to be asymptomatic at first presentation (13 of 32 versus 156 of 248 patients, P=0.02), and spontaneous type I ECG was more frequent among them (38% versus 21%, P=0.05). The spontaneous early repolarization pattern occurred more frequently among patients with BS than in 283 family members not having BS (11% versus 6%, P=0.03). Class I AAD administration provoked inferior-lateral coved Brugada pattern in 13 patients with BS. These patients had longer baseline PR intervals (206+/-48 versus 172+/-31 ms, P<0.001) and class I AAD-induced QRS interval prolongation (108 to 178 versus 102 ms to 131 ms, P<0.001). In 3 patients, the class I AAD-provoked coved Brugada pattern was only present in the inferior leads. CONCLUSIONS: Inferior-lateral early repolarization pattern occurs spontaneously relatively frequently in BS. These patients have a more severe phenotype. Class I AAD administration provokes inferior-lateral coved Brugada pattern in 4.6% of patients. We report for the first time 3 patients in whom the class I AAD-provoked coved Brugada pattern was only observed in the inferior leads.