Background
The objective was to evaluate the association between grass pollen exposure, allergy symptoms and impact on measured treatment effect after grass sublingual immunotherapy (SLIT)‐tablet ...treatment.
Methods
The association between grass pollen counts and total combined rhinoconjunctivitis symptom and medication score (TCS) was based on a post hoc analysis of data collected over six trials and seven grass pollen seasons across North America and Europe, including 2363 subjects treated with grass SLIT‐tablet or placebo. Daily pollen counts were obtained from centralized pollen databases. The effect of treatment on the relationship between the TCS and pollen counts was investigated, and the relative difference between grass SLIT‐tablet and placebo as a function of average grass pollen counts was modelled by linear regression.
Results
The magnitude of treatment effect based on TCS was greater with higher pollen exposure (P < 0.001). The relative treatment effect in terms of TCS for each trial was correlated with the average grass pollen exposure during the first period of the season, with predicted reduction in TCS = 12% + 0.35% × pollen count (slope significantly different from 0, P = 0.003; R2 = 0.66). Corresponding correlations to the entire grass pollen season and to the peak season were equally good, whereas there was a poor correlation between difference in measured efficacy and pollen exposure during the last part of the season.
Conclusions
In seasonal allergy trials with grass SLIT‐tablet, the observed treatment effect is highly dependent on pollen exposure with the magnitude being greater with higher pollen exposure. This is an important relationship to consider when interpreting individual clinical trial results.
Background. GII.4 is the predominant norovirus genotype worldwide. Challenge models involving humans have shown the association of human histo-blood group antigens (HBGAs) and susceptibility to ...infection with Norwalk virus (GLI norovirus), but the association of HBGAs and infection with other noroviruses is based on results of epidemiological studies. We performed the first GII.4 challenge study involving humans and prospectively evaluated the relationship between HBGAs and norovirus infection and associated illness. Methods. Forty healthy adults (23 secretors and 17 nonsecretors of HBGAs) were challenged with 5 × 10⁴ reverse-transcription polymerase chain reaction (RT-PCR) units of GII.4 norovirus. Subjects were assessed daily for clinical illness, and stool specimens were evaluated for norovirus by RT-PCR. Infection was defined by detection of norovirus and/or seroconversion to GII.4 antibody. Results. Of the 23 secretors, 16 (70%) were infected with norovirus, 13 (57%) became ill (characterized by vomiting and/or diarrhea), and 12 (52%) developed norovirus-associated illness. In contrast, only 1 nonsecretor (5.9%) became ill, and another nonsecretor shed virus for a single day (P<.001 for each variable, compared with secretors). Infection occurred in secretors regardless of ABO blood group. Illness was mild to moderate in severity and lasted 1-3 days. Conclusions. Secretor status determined the susceptibility to norovirus GII.4 challenge. This human challenge model should be useful for evaluating norovirus vaccines and antiviral agents.
Viral culture of urine or saliva has been the gold standard technique for the diagnosis of congenital cytomegalovirus (CMV) infection. Results of rapid culture and polymerase chain reaction (PCR) ...analysis of urine and saliva specimens from 80 children were compared to determine the clinical utility of a real-time PCR assay for diagnosis of congenital CMV infection. Results of urine PCR were positive in 98.8% of specimens. Three PCR-positive urine samples were culture negative. Results of saliva PCR and culture were concordant in 78 specimens (97.5%). Two PCR-positive saliva samples were culture negative. These findings demonstrate that PCR performs as well as rapid culture of urine or saliva specimens for diagnosing congenital CMV infection and saliva specimens are easier to collect. Because PCR also offers more rapid turn-around, is unlikely to be affected by storage and transport conditions, has lower cost, and may be adapted to high-throughput situations, it is well suited for targeted testing and large-scale screening for CMV.
Background
Lanadelumab demonstrated efficacy in preventing hereditary angioedema (HAE) attacks in the phase 3 HELP Study.
Objective
To assess time to onset of effect and long‐term efficacy of ...lanadelumab, based on exploratory findings from the HELP Study.
Methods
Eligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0‐69 findings using a Poisson regression model accounting for overdispersion. Least‐squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0‐69 versus steady state (days 70‐182) used a paired t test for continuous endpoints or Kappa statistics for categorical endpoints.
Results
One hundred twenty‐five patients were randomized and treated. During days 0‐69, mean monthly attack rate was significantly lower with lanadelumab (0.41‐0.76) vs placebo (2.04), including attacks requiring acute treatment (0.33‐0.61 vs 1.66) and moderate/severe attacks (0.31‐0.48 vs 1.33, all P ≤ .001). More patients receiving lanadelumab vs placebo were attack free (37.9%‐48.1% vs 7.3%) and responders (85.7%‐100% vs 26.8%). During steady state, the efficacy of lanadelumab vs placebo was similar or improved vs days 0‐69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable—HAE attack rate was consistently lower vs placebo, from the first 2 weeks of treatment through study end. Treatment emergent adverse events were comparable during days 0‐69 and 70‐182.
Conclusion
Protection with lanadelumab started from the first dose and continued throughout the entire study period.
During days 0‐69, lanadelumab‐treated patients had a significantly lower mean monthly hereditary angioedema (HAE) attack rate vs placebo and were more likely to be responders and attack free. Protection starts early and is sustained; during steady state, lanadelumab efficacy was similar or improved vs days 0‐69. Prophylactic agents with rapid onset, sustained effect, and convenient dosing frequency can improve HAE management plans. Abbreviations: HAE, hereditary angioedema; q2wks, every 2 weeks.
The Flt3 gene encodes a tyrosine kinase receptor that regulates proliferation and differentiation of hematopoietic stem cells. An internal tandem duplication of the Flt3 gene (Flt3/ITD) has been ...reported in acute myelogenous leukemia (AML) and may be associated with poor prognosis. We analyzed diagnostic bone marrow specimens from 91 pediatric patients with AML treated on Children's Cancer Group (CCG)-2891 for the presence of the Flt3/ITD and correlated its presence with clinical outcome. Fifteen of 91 samples (16.5%) were positive for the Flt3/ITD. Flt3/ITD-positive patients had a median diagnostic white count of 73 800 compared with 28 400 for the Flt3/ITD-negative patients (P = .05). The size of the duplication ranged from 21 to 174 base pairs (bp). Nucleotide sequencing of the abnormal polymerase chain reaction products demonstrated that all duplications involved exon 11 of theFlt3 gene and also preserved the reading frame. Lineage restriction analysis revealed that Flt3/ITD was not present in the lymphocytes, suggesting a lack of stem cell involvement for this mutation. None of the Flt3/ITD-positive patients had unfavorable cytogenetic markers, and there was no predominance of a particular FAB class. The remission induction rate was 40% in Flt3/ITD-positive patients compared with 74% in Flt3/ITD-negative ones (P = .005). The Kaplan-Meier estimates of event-free survival at 8 years for patients with and without Flt3/ITD were 7% and 44%, respectively (P = .002). Multivariate analysis demonstrated that presence of the Flt3/ITD was the single most significant, independent prognostic factor for poor outcome (P = .009) in pediatric AML.
(1-3)-β- d-glucan is a fungal cell wall component, suspected to cause respiratory symptoms in adults. However, very little is known on the possible health effects of (1-3)-β- d-glucan during infancy. ...We examined the association between (1-3)-β- d-glucan exposure and the prevalence of allergen sensitization and wheezing during the first year of life in a birth cohort of 574 infants born to atopic parents. Endotoxin exposure was included as a possible confounder. (1-3)-β- d-glucan and endotoxin exposures were measured in settled dust collected from infants' primary activity rooms. The primary outcomes at approximately age one included parental reports of recurrent wheezing and allergen sensitization evaluated by skin prick testing to a panel of 15 aeroallergens as well as milk and egg white. Exposure to high (1-3)-β- d-glucan concentration (within fourth quartile) was associated with reduced likelihood of both recurrent wheezing adjusted OR (aOR) = 0.39, 95% CI = 0.16-0.93 and recurrent wheezing combined with allergen sensitization (aOR = 0.13, 95% CI = 0.03-0.61). Similar trends were found between (1-3)-β- d-glucan concentrations and allergen sensitization (aOR = 0.57, 95% CI = 0.30-1.10). In contrast, recurrent wheezing with or without allergen sensitization was positively associated with low (1-3)-β- d-glucan exposure within the first quartile (aOR = 3.04, 95% CI = 1.25-7.38; aOR = 4.89, 95% CI = 1.02-23.57). There were no significant associations between endotoxin exposure and the studied health outcomes. This is the first study to report that indoor exposure to high levels of (1-3)-β- d-glucan (concentration >60 μg/g) is associated with decreased risk for recurrent wheezing among infants born to atopic parents. This effect was more pronounced in the subgroup of allergen-sensitized infants.
Background
An objective of the phase 3 HELP Study was to investigate the effect of lanadelumab on health‐related quality of life (HRQoL) in patients with hereditary angioedema (HAE).
Methods
Patients ...with HAE‐1/2 received either lanadelumab 150 mg every 4 weeks (q4wks; n = 28), 300 mg q4wks (n = 29), 300 mg every 2 weeks (q2wks; n = 27), or placebo (n = 41) for 26 weeks (days 0–182). The Angioedema Quality of Life Questionnaire (AE‐QoL) was administered monthly, consisting of four domain (functioning, fatigue/mood, fears/shame, nutrition) and total scores. The generic EQ‐5D‐5L questionnaire was administered on days 0, 98, and 182. Comparisons were made between placebo and (a) all lanadelumab‐treated patients and (b) individual lanadelumab groups for changes in scores (day 0–182) and proportions achieving the minimal clinically important difference (MCID, −6) in AE‐QoL total score.
Results
Compared with the placebo group, the lanadelumab total group demonstrated significantly greater improvements in AE‐QoL total and domain scores (mean change, −13.0 to −29.3; p < 0.05 for all); the largest improvement was in functioning. A significantly greater proportion of the lanadelumab total group achieved the MCID (70% vs 37%; p = 0.001). The lanadelumab 300 mg q2wks group had the highest proportion (81%; p = 0.001) and was 7.2 times more likely to achieve the MCID than the placebo group. Mean EQ‐5D‐5L scores at day 0 were high in all groups, indicating low impairment, with no significant changes at day 182.
Conclusion
Patients with HAE‐1/2 experienced significant and clinically meaningful improvements in HRQoL measured by AE‐QoL following lanadelumab treatment in the HELP Study.
In the phase 3 HELP Study, HRQoL (health‐related quality of life) of patients with HAE (hereditary angioedema)‐1/2 was evaluated using the angioedema‐specific AE‐QoL (Angioedema Quality of Life Questionnaire). After 26 weeks, lanadelumab‐treated patients experienced significantly greater HRQoL improvements than placebo‐treated patients. Patients receiving lanadelumab 300 mg q2wks (every 2 weeks) were most likely to see clinically meaningful benefit, with 81% reaching the MCID (minimal clinically important difference) and seven times greater odds vs placebo for this achievement.
Abbreviations: AE‐QoL, Angioedema Quality of Life Questionnaire; HAE, hereditary angioedema; HRQoL, health‐related quality of life; MCID, minimal clinically important difference; q2wks, every 2 weeks; q4wks, every 4 weeks.
Summary
Symptom and medication use are the key outcomes for assessing the efficacy of subcutaneous (SCIT) and sublingual allergen immunotherapy (SLIT). Our objective was to explore the similarities ...and differences between existing scoring mechanisms used in clinical trials of SLIT for seasonal allergens and characterize the impact that such differences may have on efficacy reporting. Randomized, double‐blind, placebo‐controlled clinical trials investigating the efficacy of SLIT for seasonal allergic rhinitis (2009–2013) were selected for review. Simulated and published data were used to demonstrate differences in scoring methods. Symptom and medication scoring methods across trials, although all designed to achieve the same objective, included important differences. The maximum daily symptom score (DSS) can vary widely depending on the number of symptoms assessed, and terminology of symptoms is not consistent. Similarly, daily medication scoring (DMS) methods differ greatly among studies and are dependent on medications allowed and weighting of scores assigned to each medication. When published DSS and DMS scores were used to calculate simulated daily combined scores (DCSs) based on various published methods, changes from placebo ranged from 19% to 29% when assuming all variables other than the DSS and DMS methods were equal. Variations in trial design, analysis, and seasonal characteristics also have effects on symptom and medication scoring outcomes. We identified multiple differences in trial scoring methods and design that make comparison among trials difficult. Symptom, medication, or combined scores cannot be indirectly compared among trials without taking the methods of scoring and other trial differences into account.
Cell-cell interactions mediated by Notch and its ligands are known to effect many cell fate decisions in both invertebrates and vertebrates. However, the mechanisms involved in ligand induced Notch ...activation are unknown. Recently it was shown that, in at least some cases, endocytosis of the extracellular domain of Notch and ligand by the signaling cell is required for signal induction in the receptive cell. These results imply that soluble ligands (ligand extracellular domains) although capable of binding Notch would be unlikely to activate it. To test the potential activity of soluble Notch ligands, we generated monomeric and dimeric forms of the Notch ligand Delta-1 by fusing the extracellular domain to either a series of myc epitopes (Delta-1(ext-myc)) or to the Fc portion of human IgG-1 (Delta-1(ext-IgG)), respectively. Notch activation, assayed by inhibition of differentiation in C2 myoblasts and by HES1 transactivation in U20S cells, occurred when either Delta-1(ext-myc) or Delta-1(ext-IgG) were first immobilized on the plastic surface. However, Notch was not activated by either monomeric or dimeric ligand in solution (non-immobilized). Furthermore, both non-immobilized Delta-1(ext-myc) and Delta-1(ext-IgG) blocked the effect of immobilized Delta. These results indicate that Delta-1 extracellular domain must be immobilized to induce Notch activation in C2 or U20S cells and that non-immobilized Delta-1 extracellular domain is inhibitory to Notch function. These results imply that ligand stabilization may be essential for Notch activation.
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