Relationship between the type of hormone replacement therapy and incidence of breast cancer in Korea.

OBJECTIVE: This study aimed to investigate the relationship between hormone replacement therapy (HRT) types and breast cancer (BC) incidence in postmenopausal women in Korea. METHODS: The nested case-control study used data from the National Health Insurance Service database. Among the women aged ≥50 years who menopaused between 2004 and 2007, BC incidence up to 2017 was analyzed in 36,446 women using or having used HRT for >1 year and in 36,446 women who did not use any HRT for more than 1 year. HRT types and duration were classified into three categories. RESULTS: BC risk (BCR) decreased with tibolone use for all ages. With HRT initiation in women aged ≥50 years, BCR was lower with tibolone and estrogen-progestogen therapy. HRT for <3 years showed lower BCR with tibolone, while higher BCR was observed with estrogen-only therapy. BCR was lower in women of all ages on HRT for >5 years than in the control group. CONCLUSIONS: For women in their 50s, tibolone use lowers BCR; for all ages, the use of any HRT for >5 years showed lower BCR in Korea. These divergent results from western countries could be associated with the specific characteristics of BC in Korea.

Endoscopically assisted malarplasty: L-rotation technique.

INTRODUCTION: Endoscopically assisted malarplasty with a greenstick fracture is a method for preserving the body eminence and improving arch protrusion. However, this technique is inadequate when malar body reduction is required. To compensate for these limitations, we developed a new surgical technique using the endoscope to reduce body protrusion. MATERIAL AND METHODS: We enrolled 261 patients who visited our clinic for zygoma reduction from January 2017 to December 2018. Their mean age was 31 (range 17-63) years. After a scalp incision, an incomplete osteotomy was created from the most prominent portion of the zygoma body to the zygomaticomaxillary suture line. A complete osteotomy was performed on the arch. These osteotomies resulted in an L-shaped zygoma segment after tapping the bone with a mallet. RESULTS: Of the 261 patients who underwent our L-rotation technique, 242 also received a corticotomy. Of those patients, 15 underwent a different degree of zygoma reduction on both sides. A floating zygomatic segment occurred in four cases, although no further surgery was required. One patient's zygomatic segment dropped on one side, requiring rigid fixation through the intraoral approach. Most patients were satisfied and there were no specific complications. CONCLUSIONS: Endoscopically assisted malarplasty using an L-rotation technique enables the protrusion of both the arch and body to be reduced. The zygoma reduction can be modified based on the location of the incomplete osteotomoy line and the number of corticotomies required.

Seldinger vs modified Seldinger techniques for ultrasound-guided central venous catheterisation in neonates: a randomised controlled trial.

BACKGROUND: Central venous catheterisation in neonates is difficult. The purpose of this study was to compare the Seldinger and modified Seldinger techniques for ultrasound-guided internal jugular vein catheterisation in neonates. METHODS: In this randomised, controlled trial, 120 neonates (≤1 month old) requiring central venous catheterisation under general anaesthesia were allocated into either the Seldinger (n=60) or the modified Seldinger (n=60) group. The primary outcome was the incidence of successful catheterisation on the first attempt. We also assessed the incidences of successful puncture on the first attempt, successful guide wire insertion on the first attempt, and successful final catheterisation. RESULTS: The primary outcome, the incidence of successful catheterisation on the first attempt was higher in the modified Seldinger group than in the Seldinger group (83% vs 65%; relative risk=1.282; 95% confidence interval, 1.032-1.594; P=0.025). The incidence of successful guide wire insertion on the first attempt was also higher in the modified Seldinger group (95% vs 75%; relative risk=1.267; 95% confidence interval, 1.082-1.482; P=0.003). Other incidences did not differ significantly between the groups. CONCLUSIONS: For ultrasound-guided internal jugular vein catheterisation in neonates, the modified Seldinger technique showed superiority over the Seldinger technique in terms of successful catheterisation and guide wire insertion on the first attempt. CLINICAL TRIAL REGISTRATION: NCT02688595.

Flexion decreases the ventilation quality of the Ambu® AuraGain™ laryngeal mask in paralysed children: A prospective randomised crossover study.

BACKGROUND: The influence of different head and neck positions on ventilation with the Ambu® AuraGain™ remains unevaluated in children. This study assessed the influence of different head and neck positions on ventilation with the AuraGain™ in paediatric patients. METHODS: In this prospective, randomised crossover study, children ≤7 years of age who were scheduled for elective surgery under general anaesthesia were enrolled. An AuraGain™ was placed in all patients; mechanical ventilation was performed using a volume-controlled mode with a tidal volume of 10 mL/kg. Respiratory rate was adjusted to maintain a ET CO2 of 35-40 mm Hg. The oropharyngeal leak pressure, expiratory tidal volume, peak inspiratory pressure, ventilation score and fibreoptic bronchoscopic view score were assessed for the neutral head and neck position, and then for the flexed, extended and rotated head and neck positions in a random order. RESULTS: Compared with the neutral position, the oropharyngeal leak pressure increased in the flexed position (P < .001), and decreased in the extended (P = .014) and rotated position (P = .002). The expiratory tidal volume and ventilation score were significantly reduced during flexion (all P < .005), and were comparable among the neutral, extended and rotated positions. The fibreoptic score improved in the extended and rotated position (all P < .001). Only the flexion ventilation score was lower compared with the neutral position (P = .014). CONCLUSIONS: Clinically, the flexed head and neck positions negatively affected ventilation due to obstruction of the airway. Ventilation with AuraGain™ can be effectively performed with the head and neck in the neutral, extended and rotated position in paediatric patients.

Whole-Tumor Histogram and Texture Analyses of DTI for Evaluation of IDH1-Mutation and 1p/19q-Codeletion Status in World Health Organization Grade II Gliomas.

BACKGROUND AND PURPOSE: Prediction of the isocitrate dehydrogenase 1 (IDH1)-mutation and 1p/19q-codeletion status of World Health Organization grade ll gliomas preoperatively may assist in predicting prognosis and planning treatment strategies. Our aim was to characterize the histogram and texture analyses of apparent diffusion coefficient and fractional anisotropy maps to determine IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. MATERIALS AND METHODS: Ninety-three patients with World Health Organization grade II gliomas with known IDH1-mutation and 1p/19q-codeletion status (18 IDH1 wild-type, 45 IDH1 mutant and no 1p/19q codeletion, 30 IDH1-mutant and 1p/19q codeleted tumors) underwent DTI. ROIs were drawn on every section of the T2-weighted images and transferred to the ADC and the fractional anisotropy maps to derive volume-based data of the entire tumor. Histogram and texture analyses were correlated with the IDH1-mutation and 1p/19q-codeletion status. The predictive powers of imaging features for IDH1 wild-type tumors and 1p/19q-codeletion status in IDH1-mutant subgroups were evaluated using the least absolute shrinkage and selection operator. RESULTS: Various histogram and texture parameters differed significantly according to IDH1-mutation and 1p/19q-codeletion status. The skewness and energy of ADC, 10th and 25th percentiles, and correlation of fractional anisotropy were independent predictors of an IDH1 wild-type in the least absolute shrinkage and selection operator. The area under the receiver operating curve for the prediction model was 0.853. The skewness and cluster shade of ADC, energy, and correlation of fractional anisotropy were independent predictors of a 1p/19q codeletion in IDH1-mutant tumors in the least absolute shrinkage and selection operator. The area under the receiver operating curve was 0.807. CONCLUSIONS: Whole-tumor histogram and texture features of the ADC and fractional anisotropy maps are useful for predicting the IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas.

The effect of 6% hydroxyethyl starch (130/0.4) on acute kidney injury in paediatric cardiac surgery: a prospective, randomised trial.

We have evaluated the effect of a colloid solution on acute kidney injury in paediatric cardiac surgery. A total of 195 patients were ramdomly divided into an hydroxyethyl starch group and a control group. In the starch group, 6% hydroxyethyl starch 130/0.4 (Volulyte® ) was used as the primary fluid for volume resuscitation but was limited to 30 ml.kg-1 . In the control group, only crystalloid fluid was used during the peri-operative period. The incidence of acute kidney injury, peri-operative transfusion, clinical outcomes and laboratory data were compared. The incidence of acute kidney injury determined by Paediatric Risk, Injury, Failure, Loss, End-stage renal disease (pRIFLE) and Acute Kidney Injury Network (AKIN) criteria were no different between the two groups (starch group 40.8% vs. control group 30.0%; p = 0.150 using pRIFLE; 19.6% vs. 21.1% respectively, p = 0.602 using AKIN). There were no differences in clinical outcomes such as mortality, major adverse events, intensive care unit stay or duration of mechanical ventilation. Clotting time as measured using rotational thromboelastometry (ROTEM) was prolonged, and clot firmness after 10 min and maximal clot firmness were shorter in the starch group compared with the control group after sternal closure. There was no difference in transfusion between the two groups. Patients with acute kidney injury had worse clinical courses than those without acute kidney injury. We conclude that intra-operative use of 6% hydroxyethyl starch 130/0.4 up to 30 ml.kg-1 was not associated with postoperative acute kidney injury in paediatric cardiac patients.

Real-time ultrasound-guided axillary vein cannulation in children: a randomised controlled trial.

The axillary vein is a good site for ultrasound-guided central venous cannulation in terms of infection rate, patient comfort and its anatomical relationship with the clavicle and lungs. We compared real-time ultrasound-guided axillary vein cannulation with conventional infraclavicular landmark-guided subclavian vein cannulation in children. A total of 132 paediatric patients were randomly allocated to either ultrasound-guided axillary vein (axillary group) or landmark-guided subclavian vein (landmark group). The outcomes measured were success rate after two attempts, first-attempt success rate, time to cannulation and complication rate. The success rate after two attempts was 83% in the axillary group compared with 63% in the landmark group (odds ratio 2.85, 95%CI 1.25-6.48, p = 0.010). The first-attempt success rate was 46% for the axillary group and 40% for the landmark group (p = 0.274) and median time to cannulation was 156 s for the axillary group and 180 s for the landmark group (p = 0.286). There were no differences in complication rates between the two groups, although three episodes of subclavian artery puncture occurred in the landmark group (p = 0.08). We conclude that axillary vein cannulation using a real-time ultrasound-guided in-plane technique is useful and effective in paediatric patients.

Assessment of dynamic variables of fluid responsiveness to predict desufflation-induced hypotension during paediatric laparoscopic surgery.

BACKGROUND: During laparoscopic surgery in paediatric patients, sudden hypotension may occur following peritoneal desufflation due to hypovolaemia or an acute increase in gastrointestinal venous capacitance by the release of intra-abdominal pressure. This study examined whether dynamic variables of fluid responsiveness during pneumoperitoneum can predict the occurrence of hypotension following desufflation. METHODS: A total of 120 paediatric subjects were prospectively enrolled. A predictor was derived from the initial 83 subjects and validated thereafter in 37 high-risk subjects. The pleth variability index, respiratory variation in the pulse oximetry plethysmographic waveform (ΔPOP), systolic pressure variation and pulse pressure variation during pneumoperitoneum were obtained 1 min before desufflation. Predictors of desufflation-induced hypotension were investigated using the multivariable logistic regression analysis. Predictability was assessed using the area under the receiver-operating characteristic curve (AUC). RESULTS: In the derivation cohort, 27% (n=23) of subjects developed hypotension. Only ΔPOP was found to be a predictor, and showed high predictability of desufflation-induced hypotension [AUC 0.87, P<0.0001, 95% confidence interval (CI): 0.78-0.93]. A ΔPOP cut-off point of 38% predicted hypotension with a sensitivity of 83% and a specificity of 90%. In the validation cohort, 43% (n=16) of subjects developed hypotension, and ΔPOP was verified to be highly predictive of the occurrence of hypotension (AUC 0.90, P<0.0001, 95% CI: 0.76-0.98). The sensitivity and specificity of a ΔPOP cut-off point of 38% to predict hypotension was 88% and 90%, respectively. CONCLUSIONS: The ΔPOP during pneumoperitoneum is useful in predicting desufflation-induced hypotension during paediatric laparoscopic surgery. CLINICAL TRIAL REGISTRATION: NCT02536521.

The Initial Area Under the Curve Derived from Dynamic Contrast-Enhanced MRI Improves Prognosis Prediction in Glioblastoma with Unmethylated MGMT Promoter.

BACKGROUND AND PURPOSE: Although perfusion and permeability MR parameters have known to have prognostic value, they have reproducibility issues. Our aim was to evaluate whether the initial area under the time-to-signal intensity curve (IAUC) derived from dynamic contrast-enhanced MR imaging can improve prognosis prediction in patients with glioblastoma with known MGMT status. MATERIALS AND METHODS: We retrospectively examined 88 patients with glioblastoma who underwent preoperative dynamic contrast-enhanced MR imaging. The means of IAUC values at 30 and 60 seconds (IAUC30mean and IAUC60mean) were extracted from enhancing tumors. The prognostic values of IAUC parameters for overall survival and progression-free survival were assessed with log-rank tests, according to the MGMT status. Multivariate overall survival and progression-free survival models before and after adding the IAUC parameters as covariates were explored by net reclassification improvement after receiver operating characteristic analysis for 1.5-year overall survival and 1-year progression-free survival and by random survival forest. RESULTS: High IAUC parameters were associated with worse overall survival and progression-free survival in the unmethylated MGMT group, but not in the methylated group. In the unmethylated MGMT group, 1.5-year overall survival and 1-year progression-free survival prediction improved significantly after adding IAUC parameters (overall survival area under the receiver operating characteristic curve, 0.86; progression-free survival area under the receiver operating characteristic curve, 0.74-0.76) to the model with other prognostic factors (overall survival area under the receiver operating characteristic curve, 0.81; progression-free survival area under the receiver operating characteristic curve, 0.69; P < .05 for all) except in the case of IAUC60mean for 1-year progression-free survival prediction (P = .059). Random survival forest models indicated that the IAUC parameters were the second or most important predictors in the unmethylated MGMT group, except in the case of the IAUC60mean for progression-free survival. CONCLUSIONS: IAUC can be a useful prognostic imaging biomarker in patients with glioblastoma with known MGMT status, improving prediction of glioblastoma prognosis with the unmethylated MGMT promoter status.

Systematic review with meta-analysis: the efficacy of vonoprazan-based triple therapy on Helicobacter pylori eradication.

BACKGROUND: In order to increase eradication rates, vonoprazan, a novel potassium-competitive acid blocker, has been used in Helicobacter pylori eradication therapy. AIM: To summarise the results of the efficacy of vonoprazan-based triple therapy, helping clinicians to better understand the benefit of vonoprazan in the treatment of H. pylori infection. METHODS: We conducted a systematic literature search on MEDLINE, EMBASE, and the Cochrane Library using the primary keywords "vonoprazan," "takecab", "TAK-438," "potassium," "competitive," "potassium-competitive," "Helicobacter," and "pylori." Studies were included if they evaluated the eradication rate between the vonoprazan-based and proton pump inhibitor (PPI)-based triple therapies. RESULTS: Ten studies and 10 644 patients were evaluated. The crude H. pylori eradication rate determined by intention-to-treat analysis was 87.9% and 72.8% in the vonoprazan-based triple therapy and PPI-based triple therapy respectively. The eradication rate of the vonoprazan-based triple therapy was superior to that of the PPI-based triple therapy (pooled risk ratio [RR] [95% confidence interval (CI)]=1.19 [1.15-1.24]) In addition, there was no significant difference in dropout rate due to adverse event between the regimens (pooled RR of the vonoprazan-based triple therapy [95% CI]=0.69 [0.23-2.03]). The incidence of any adverse events also did not differ between the regimens (pooled RR [95% CI]=1.02 [0.78-1.34]). CONCLUSIONS: The vonoprazan-based triple therapy showed superior efficacy in terms of H. pylori eradication as compared to the PPI-based triple therapy. In addition, the vonoprazan-based triple therapy showed comparable tolerability and incidence of adverse events.

Hypoxia Inducible Factor 1: A Urinary Biomarker of Kidney Disease.

Identifying noninvasive biomarkers of kidney disease is valuable for diagnostic and therapeutic purposes. Hypoxia inducible factor 1 (HIF-1) expression is known to be elevated in the kidneys in several renal disease pathologies. We hypothesized that the urinary HIF-1a mRNA level may be a suitable biomarker for expression of this protein in chronic kidney disease (CKD). We compared HIF-1a mRNA levels from urine pellets of CKD and healthy subjects. To ensure that urinary HIF-1a mRNA is of kidney origin, we examined colocalization of HIF-1a mRNA with two kidney specific markers in urine cells. We found that HIF-1a mRNA is readily quantifiable in urine pellets and its expression was significantly higher in CKD patients compared with healthy adults. We also showed that the urinary HIF-1a mRNA comes primarily from cells of renal origin. Our data suggest that urinary HIF-1a mRNA is a potential biomarker in CKD and can be noninvasively assessed in patients.

Effects of an alveolar recruitment manoeuvre guided by lung ultrasound on anaesthesia-induced atelectasis in infants: a randomised, controlled trial.

Atelectasis occurs in the majority of children undergoing general anaesthesia. Lung ultrasound has shown reliable sensitivity and specificity for diagnosing anaesthesia-induced atelectasis. We assessed the effects of a recruitment manoeuvre on atelectasis using lung ultrasound in infants undergoing general anaesthesia. Forty infants, randomly allocated to either a recruitment manoeuvre group or a control group, received volume-controlled ventilation with 5 cmH2 O positive end-expiratory pressure. Lung ultrasound examination was performed twice in each patient, the first a minute after starting mechanical ventilation of the lungs and the second at the end of surgery. Patients in the recruitment manoeuvre group received ultrasound-guided recruitment manoeuvres after each lung ultrasound examination. The incidence of significant anaesthesia-induced atelectasis at the second lung ultrasound examination was less in the recruitment manoeuvre group compared with the control group (25% vs. 80%; p = 0.001; odds ratio (OR) 0.083; 95% confidence interval (CI): 0.019-0.370). The median (IQR [range]) lung ultrasound scores for consolidation and B-lines on the second examination were lower in the recruitment manoeuvre group compared with the control group; 6.0 (3.0-9.3 [0.0-14.0]) vs. 13.5 (11.0-16.5 [8.0-23.0]); p < 0.001 and 6.5 (3.0-12.0 [0.0-28.0]) vs. 15.0 (10.8-20.5 [7.0-28.0]); p < 0.001, respectively. The lung ultrasound scores for consolidation on the first and second examinations showed a negative correlation with age (r = -0.340, p = 0.008; r = -0.380, p = 0.003). We conclude that ultrasound-guided recruitment manoeuvres with positive end-expiratory pressure proved useful in reducing the incidence of anaesthesia-induced atelectasis in infants, although 5 cmH2 O positive end-expiratory pressure alone was not sufficient to eliminate it. In addition, the younger the patient, the more susceptible they were to atelectasis.

Development of a nomogram for predicting the probability of postoperative delirium in patients undergoing free flap reconstruction for head and neck cancer.

PURPOSE: To develop nomogram for prediction of postoperative delirium (POD) in patients undergoing ablative and reconstruction surgery for head and neck cancer. METHODS: Total 341 patients were retrospectively analyzed, and clinical variables in preoperative, intraoperative and postoperative periods were compared between delirium group (n = 89) and non-delirium group (n = 252). Multivariate logistic regression, receiver operating characteristics curve, and area under the curve (AUC) were used to generate and test a nomogram, which performance was evaluated by 10-fold cross validation (CV) procedure. RESULTS: In univariate and multivariate analysis, age, history of psychiatric disorder, marital status, preoperative numeric rating scale for pain, ASA classification, and ICU stay period were identified as significant risk factors. Using these factors, nomogram for predicting the POD was developed and it showed sensitivity of 61.8%, specificity of 75.4%, PPV of 47.0%, and NPV of 84.8% (Youden's index of 0.372). In 10-fold cross validation set, corresponding values were 44.9%, 84.1%, 50.0% and 81.2% (Youden's index of 0.337). AUC was comparable between two sets (0.7407 and 0.6898). CONCLUSIONS: Proposed nomogram showed fair discriminative power for POD risk in head and neck cancer patients undergoing major surgery.

Effect of early vs. late tracheostomy on clinical outcomes in critically ill pediatric patients.

BACKGROUND: Few studies investigated the optimal timing for tracheostomy and its influence on the clinical outcomes in critically ill pediatric patients. This study evaluated the differences in clinical outcomes between early and late tracheostomy in pediatric intensive care unit (ICU) patients. METHODS: We assessed 111 pediatric patients. Patients who underwent a tracheostomy within 14 days of mechanical ventilation (MV) were assigned to the early tracheostomy group, whereas those who underwent tracheostomy after 14 days of MV were included in the late tracheostomy group. Clinical outcomes, including mortality, duration of MV, length of ICU and hospital stays, and incidence of ventilator-associated pneumonia (VAP) were compared between the groups. RESULTS: Of the 111 pediatric patients, 61 and 50 were included in the early and late tracheostomy groups, respectively. Total MV duration and the length of ICU and hospital stay were significantly longer in the late tracheostomy group than in the early tracheostomy group (all P < 0.01). The VAP rate per 1000 ventilator days before tracheostomy was 2.6 and 3.8 in the early and late tracheostomy groups, respectively. There were no significant differences in mortality rate between the groups. No severe complications were associated with tracheostomy itself. CONCLUSIONS: Tracheostomy performed within 14 days after the initiation of MV was associated with reduced duration of MV and length of ICU and hospital stay. Although there was no effect on mortality rate, children may benefit from early tracheostomy without severe complications.

Ultrasound assessment of gastric volume in children after drinking carbohydrate-containing fluids.

BACKGROUND: Gastric ultrasound is a valid tool for non-invasive assessment of the nature and volume of gastric contents in adults and children. Perioperative fasting guidelines recommend oral carbohydrates up to 2 h before elective surgery. We evaluated gastric volume in children using ultrasound before and after drinking carbohydrate fluids before surgery. METHODS: Paediatric patients younger than 18 yr old undergoing elective surgery were enrolled. Initial ultrasound assessment of gastric volume was performed after fasting for 8 h. Two hours before surgery, patients were given carbohydrate drinks: 15 ml kg(-1) for patients younger than 3 yr old and 10 ml kg(-1) for those more than 3 yr old. Before induction of general anaesthesia, the gastric volume was reassessed. Parental satisfaction scores (0=totally satisfied, 10=totally dissatisfied) and complications were recorded. RESULTS: Of the 86 enrolled patients, 79 completed the study; three refused to ingest the requested volume, and surgery was delayed for more than 2 h in four patients. The mean (sd) of the initial and second ultrasound measurements were 2.09 (0.97) and 1.85 (0.94) cm(2), respectively (P=0.01; mean difference 0.24 cm(2), 95% confidence interval 0.06-0.43). The median (interquartile range) satisfaction score was 2.4 (0-6). Two instances of postoperative vomiting and one instance of postoperative nausea occurred. CONCLUSIONS: Carbohydrate fluids ingested 2 h before surgery reduced the gastric volume and did not cause serious complications in paediatric patients. Parents were satisfied with the preoperative carbohydrate drink. Children may benefit from drinking carbohydrate fluids up to 2 h before elective surgery. CLINICAL TRIAL REGISTRATION: cris.nih.go.kr (KCT0001546).

[Cognitive Behavioral Therapy and Assertive Community Treatment Reduces Days in Hospital and Delays Hospital Admission in Severe Psychotic Disorders]. / Kognitive Verhaltenstherapie und Assertive Community Treatment reduzieren die Anzahl stationärer Tage und verlängern die Zeit bis zu einer stationären Aufnahme bei schweren psychotischen Störungen.

The primary aim of this study was to assess the effectiveness of integrated home treatment (IV, i. e. intensive cognitive behavioral therapy and pharmacotherapy provided within a framework of assertive community treatment) in individuals with severe mental disorders (n = 13) within the German healthcare system. A treatment-as-usual group (TAU, n = 13) was identified by propensity score matching. Symptoms (CGI), functioning (GAF) and service engagement (SES) were assessed. Quality of life (MSLQ-R) was rated by the IV patients. A reduction of days spent in hospital [IV: 2.3 (6.1); TAU: 33.6 (53.6); Z = 45; p = 0.044], time to admission (IV: 384 days 95% CI 309 - 459.1; TAU: 234.9 days 95% CI 127.2 - 342.5; log rank: Chi-square = 4.31, p < 0.05), severity of the illness (p < 0.01), positive symptoms (p < 0.001), and cognitive symptoms (p < 0.05), as well as functioning (p < 0.05) and service engagement (p < 0.05) was observed in IV patients. Despite differences on a descriptive level, differences in total admissions (IV: 15.3%; TAU: 53.8%; odds ratio = 0.155, 95% CI 0.0243 - 1.00) were not significant. A methodological limitation is that symptom ratings were not performed by independent and blinded raters.

Intralymphatic treatment of flagellin-ovalbumin mixture reduced allergic inflammation in murine model of allergic rhinitis.

BACKGROUND: Bacterial flagellin, a Toll-like receptor 5 agonist, is used as an adjuvant for immunomodulation. In this study, we aimed to evaluate the effect and its mechanism following intralymphatic administration of OVA-flagellin (FlaB) mixture in the mouse model of allergic rhinitis. MATERIALS AND METHODS: BALB/c mice were sensitized with OVA and treated with an OVA-FlaB mixture via intranasal, sublingual, and intralymphatic routes to evaluate the effect of each treatment. Several parameters for allergic inflammation and its underlying mechanisms were then evaluated. RESULTS: Intralymphatic injection of the OVA-FlaB mixture reduced symptom scores, eosinophil infiltration in the nasal mucosa, and total and OVA-specific IgE levels more significantly than intranasal and sublingual administration. Systemic cytokine (IL-4, IL-5, IL-6, IL-17, and IFN-γ) production and local cytokine (IL-4 and IL-5) production were also reduced significantly after intralymphatic injection with OVA-FlaB. Double intralymphatic injection of the mixture was more effective than single injection. Moreover, the expression of innate cytokines such as IL-25 and IL-33 in nasal epithelial cells was reduced, and the expression of chemokines such as CCL24 (eotaxin-2), CXCL1, and CXCL2 was decreased in the nasal mucosa, suggesting the underlying mechanism for intralymphatic administration of the OVA-FlaB mixture. CONCLUSION: Intralymphatic administration of an OVA-FlaB mixture was more effective in alleviating allergic inflammation than intranasal and sublingual administration in a mouse model of allergic rhinitis. This effect may be attributed to the reduced expression of innate cytokines and chemokines. This treatment modality can be considered as a new therapeutic method and agent.

Utility of component analyses in subjects undergoing sublingual immunotherapy for peanut allergy.

BACKGROUND: Sublingual immunotherapy (SLIT) with peanut changes clinical and immune responses in most peanut-allergic individuals, but the response is highly variable. OBJECTIVE: We sought to examine the component-specific effects of peanut SLIT and determine whether peanut component testing could predict the outcome of a double-blind, placebo-controlled food challenge (DBPCFC) after 12 months of peanut SLIT. METHODS: We included 33 subjects who underwent peanut SLIT with a DBPCFC of 2500 mg of peanut protein performed after 12 months of therapy. Plasma samples from baseline and after 12 months of peanut SLIT were assayed using ImmunoCAP for IgE and IgG4 against whole peanut, Ara h 1, Ara h 2, Ara h 3, Ara h 8, and Ara h 9. RESULTS: Following 12 months of SLIT, 10 subjects (30%) passed the DBPCFC without symptoms and were considered desensitized. Subjects that failed the DBPCFC tolerated a median of 460 mg peanut protein (range: 10-1710 mg). The desensitized group had significantly lower baseline levels of IgE against peanut (median 40.8 vs. 231 kUA /L, P = 0.0082), Ara h 2 (median 17 vs. 113 kUA /L, P = 0.0082), and Ara h 3 (median 0.3 vs. 8.5 kUA /L, P = 0.0396). ROC curves indicated that baseline IgE against peanut and Ara h 2 were equally effective at discriminating between the two groups (AUC = 0.7957, P = 0.007752 for both). CONCLUSION AND CLINICAL RELEVANCE: In this cohort of subjects undergoing SLIT for peanut allergy, lower baseline levels of IgE against Ara h 2, Ara h 3, and peanut were associated with successful desensitization.

Development of operational immunologic tolerance with neonatal gene transfer in nonhuman primates: preliminary studies.

Achieving persistent expression is a prerequisite for effective genetic therapies for inherited disorders. These proof-of-concept studies focused on adeno-associated virus (AAV) administration to newborn monkeys. Serotype rh10 AAV expressing ovalbumin and green fluorescent protein (GFP) was administered intravenously at birth and compared with vehicle controls. At 4 months postnatal age, a second injection was administered intramuscularly, followed by vaccination at 1 year of age with ovalbumin and GFP. Ovalbumin was highest 2 weeks post administration in the treated monkey, which declined but remained detectable thereafter; controls demonstrated no expression. Long-term AAV genome copies were present in myocytes. At 4 weeks, neutralizing antibodies to rh10 were present in the experimental animal only. With AAV9 administration at 4 months, controls showed transient ovalbumin expression that disappeared with the development of strong anti-ovalbumin and anti-GFP antibodies. In contrast, increased and maintained ovalbumin expression was noted in the monkey administered AAV at birth, without antibody development. After vaccination, the experimental monkey maintained levels of ovalbumin without antibodies, whereas controls demonstrated high levels of antibodies. These preliminary studies suggest that newborn AAV administration expressing secreted and intracellular xenogenic proteins may result in persistent expression in muscle, and subsequent vector administration can result in augmented expression without humoral immune responses.