In a comparative clinical study with progression-free survival (PFS) or overall survival (OS) as the end point, the hazard ratio (HR) is routinely used to design the study and to estimate the ...treatment effect at the end of the study. The clinical interpretation of the HR may not be straightforward, especially when the underlying model assumption is not valid. A robust procedure for study design and analysis that enables clinically meaningful interpretation of trial results is warranted.
To discuss issues of conventional trial design and analysis and to present alternatives to the HR using a recent immunotherapy study as an illustrative example.
By comparing 2 groups in a survival analysis, we discuss issues of using the HR and present the restricted mean survival time (RMST) as a summary measure of patients’ survival profile over time. We show how to use the difference or ratio in RMST between 2 groups as an alternative for designing and analyzing a clinical study with an immunotherapy study as an illustrative example.
Overall survival or PFS. Group contrast measures included HR, RMST difference or ratio, and the event rate difference.
For the illustrative example, the HR procedure indicates that nivolumab significantly prolonged patient OS and was numerically better than docetaxel for PFS. However, the median PFS time of docetaxel was significantly better than that of nivolumab. Therefore, it may be difficult to use median OS and/or PFS to interpret of the HR value clinically. On the other hand, using RMST difference, nivolumab was significantly better than docetaxel for both OS and PFS. We also provide details regarding design of a future study with RMST-based measures.
The design and analysis of a conventional cancer clinical trial can be improved by adopting a robust statistical procedure that enables clinically meaningful interpretations of the treatment effect. The RMST-based quantitative method may be used as a primary tool for future cancer trials or to help us to better understand the clinical interpretation of the HR even when its model assumption is plausible.
When transplanted into failing heart, autologous somatic tissue-derived cells yield functional recovery via paracrine effects that enhance native regeneration. However, the therapeutic effects are ...modest. We developed a method in which scaffold-free cell sheets are attached to the epicardial surface to maximize paracrine effects. This Phase I clinical trial tested whether transplanting autologous cell-sheets derived from skeletal muscle is feasible, safe, and effective for treating severe congestive heart failure.
Fifteen ischemic cardiomyopathy patients and 12 patients with dilated cardiomyopathy, who were in New York Heart Association functional class II or III and had been treated with the maximum medical and/or interventional therapies available, were enrolled. Scaffold-free cell sheets of 3 to 9×10
cells derived from autologous muscle were transplanted over the LV free wall via left thoracotomy, without additional interventional treatments. There were no procedure-related major complications during follow-up. The majority of the ischemic cardiomyopathy patients showed marked symptomatic improvement in New York Heart Association classification (pre: 2.9±0.5 versus 6 months: 2.1±0.4,
<0.01; 1 year: 1.9±0.3,
<0.01) and the Six-Minute Walk Test with significant reduction of serum brain natriuretic peptide level (pre: 308±72 pg/mL versus 6 months: 191±56 versus 1 year: 182±46,
<0.05), pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vein resistance, and left ventricular wall stress after transplantation instead of limited efficacy in dilated cardiomyopathy patients.
Cell-sheet transplantation as a sole therapy was feasible for treating cardiomyopathy. Promising results in the safety and functional recovery warrant further clinical follow-up and larger studies to confirm this treatment's efficacy for severe congestive heart failure.
URL: http://www.umin.ac.jp/english/. Unique identifier: UMIN000003273.
This retrospective study examined how a pharmacist-involved education program in a multidisciplinary team (PEMT) for oral mucositis (OM) affected head-and-neck cancer (HNC) patients receiving ...concurrent chemoradiotherapy (CCRT).
Total samples data of 53 patients during the stipulated timeframe were retrospectively collected from electronic medical records from February 2017 to January 2019. We compared the presence/absence of OM (OM: yes/no) between patients with and without PEMT (PEMT: yes/no) as the primary endpoint and OM severity as the secondary endpoint. The following information was surveyed: age, gender, weight loss, steroid or immunosuppressant use, hematological values (albumin, white blood cell count, blood platelets, and neutrophils), cancer grade, primary cancer site, type and use of mouthwash and moisturizer, opioid use (yes/no, days until the start of opioid use, and dose, switch to tape), and length of hospital day (LOD). The two groups were compared using Fisher's exact test for qualitative data and the Mann-Whitney U test for quantitative data, and a significance level of p<0.05 was set.
The group managed by PEMT had significantly lower weight loss and a significantly lower incidence of local anesthetic and opioid use and switch to tape compared with the group not managed by PEMT (p<0.05). The two groups showed no significant difference in OM (yes/no) or OM severity. The PEMT group had significantly shorter LOD at 57 (53-64) days compared with the non-PEMT group at 63.5 (57-68) days (p<0.05).
Our results showed that PEMT did not improve OM (yes/no) or OM severity in HNC patients undergoing CCRT. However, the PEMT group had a lower incidence of grades 3 and 4 OM than the non-PEMT group, although not significantly. In addition, PEMT contributed to oral pain relief and the lowering of the risk for OM by reduction in weight loss.
Breast milk contains numerous factors that are involved in the maturation of the immune system and development of the gut microbiota in infants. These factors include transforming growth factor-β1 ...and 2, immunoglobin A, and lactoferrin. Breast milk factors may also affect epidermal differentiation and the stratum corneum (SC) barrier in infants, but no studies examining these associations over time during infancy have been reported. In this single-center exploratory study, we measured the molecular components of the SC using confocal Raman spectroscopy at 0, 1, 2, 6, and 12 months of age in 39 infants born at our hospital. Breast milk factor concentrations from their mothers’ breast milk were determined. Correlation coefficients for the two datasets were estimated for each molecular component of the SC and breast milk factor at each age and SC depth. The results showed that breast milk factors and molecular components of the SC during infancy were partly correlated with infant age in months and SC depth, suggesting that breast milk factors influence the maturation of the SC components. These findings may improve understanding of the pathogenesis of skin diseases associated with skin barrier abnormalities.
The role of antibiotics in the treatment of Shiga toxin-producing Escherichia coli (STEC) infection is controversial.
To evaluate the association between treatment (antibiotics, antidiarrheal agents, ...and probiotics) for STEC infection and hemolytic uremic syndrome (HUS) development.
We performed a population-based matched case-control study using the data from the National Epidemiological Surveillance of Infectious Diseases (NESID) between January 1, 2017 and December 31, 2018. We identified all patients with STEC infection and HUS as cases and matched patients with STEC infection without HUS as controls, with a case-control a ratio of 1:5. Further medical information was obtained by a standardized questionnaire. Multivariable conditional logistic regression model was used.
7760 patients with STEC infection were registered in the NESID. 182 patients with HUS and 910 matched controls without HUS were selected. 90 patients with HUS (68 children and 22 adults) and 371 patients without HUS (266 children and 105 adults) were included in the main analysis. The matched ORs of any antibiotics and fosfomycin for HUS in children were 0.56 (95% CI 0.32-0.98), 0.58 (0.34-1.01). The matched ORs for HUS were 2.07 (1.07-4.03), 0.86 (0.46-1.61) in all ages treated with antidiarrheal agent and probiotics.
Antibiotics, especially fosfomycin, may prevent the development of HUS in children, while use of antidiarrheal agents should be avoided.
•No echo indices for early prediction of ductal surgery have been fully tested.•We conducted a post-hoc analysis using a database including 710 preterm infants.•This study identified the useful echo ...indices for early prediction of future ductal surgery.
There is inconsistent evidence suggesting the clinical relevance of the early detection of future needs of preterm patent ductus arteriosus (PDA) surgery. We tested the hypothesis that echocardiographic indices at 3 days of age predict the future need for PDA surgery.
We analyzed a database including the clinical and echocardiographic data of 710 preterm infants with gestational ages between 23 and 29 weeks in 34 Japanese neonatal intensive care units, and prospectively collected data over 14 months. The predictive or discriminative ability of each echocardiographic index at 3 days of age for future PDA surgical closure was evaluated using multivariable logistic regression analyses with adjustment for gestational age, sex, and small-for-gestational-age status, according to the areas under the receiver-operating characteristic curves (AUCs) of the models.
A total of 688 eligible patients (median gestational age: 26 weeks, body weight at birth: 843 g) were analyzed, of whom 77 (11%) underwent PDA surgery (median age: 21 days) after full consideration of clinical conditions. The AUC of PDA diameter (PDAd) was the largest, followed by that of the left pulmonary artery end-diastolic velocity (LPAedv). Compared with the ratio of left atrial-to-aorta diameter (AUC 0.76), PDAd (AUC 0.84, p < 0.001) and LPAedv (AUC 0.82, p = 0.003) were significantly better predictors of future PDA surgery.
Echocardiographic indices at 3 days of age, especially PDAd and LPAedv, may predict the future need for surgical closure of PDA in preterm infants.
Display omitted .
The level of child development may be associated with the risk of poor maternal health-related quality of life (HRQoL). The objective of this study was to describe the developmental characteristics ...of very low birth weight (VLBW) children at 2.5 years of age and to examine associations between maternal HRQoL and the degree of child development based on the Japanese version of Ages and Stages Questionnaire (J-ASQ-3).
A cross-sectional study was performed using the data from a nationwide prospective birth cohort study in Japan. Among a total of 104,062 fetal records, the VLBW infants (birth weight ≤ 1500 g) were analyzed using linear regression models, adjusted for potential covariates. Subgroup analysis was also conducted to assess the association between social connection or cooperation of the partner and maternal HRQoL by the level of child development.
The final study subjects included 357 VLBW children and mothers. The suspected developmental delays (SDDs) in at least two domains was significantly associated with lower maternal mental HRQoL regression coefficient -2.314 (95%CI: -4.065 to -0.564). There was no association between the status of child development and maternal physical HRQoL. After adjusting for child and maternal covariates, the maternal HRQoL was not significantly associated with child development. Amongst women who indicated having some social support, having a child with a SDD in two or more domains was negatively associated with mental HRQoL compared with women whose child was less developmental delay, regression coefficient -2.337 (95%CI: -3.961 to -0.714). Amongst women who indicated having partner's cooperation to child-rearing, having a child with a SDD in two or more domains was negatively associated with mental HRQoL compared with women whose child was less developmental delay, regression coefficient -3.785 (95%CI: -6.647 to -0.924).
Our findings indicate that the lower maternal mental HRQoL was independently associated with the SDDs evaluated by the J-ASQ-3, whereas there was no association after adjusting for covariates. Further research is warranted to elucidate the impact of social connection and partner's cooperation on maternal HRQoL and child development. This study urges that particular attention should be paid to mothers of VLBW children with SDDs and also to provide early intervention and continued support.
Capturing epidemiological signatures is essential to document burdens of disease and to design health care services, including prevention measures, clinical interventions, and policies. There are ...large geographical and ethnic variations in the epidemiology of allergic and immunological diseases. Various data are available from North America and Europe, but the epidemiology of allergic and immunological diseases in Asia is not well documented.
To characterize epidemiological signatures of allergic and immunological disease in young children in Japan.
This was a national, multicenter, prospective birth cohort study: Japan Environment and Children's Study (JECS). A general population of 103,060 women was enrolled during pregnancy. Allergic and immunological outcomes were assessed among young children using questionnaire data.
The prevalence of caregiver-reported immediate food allergy was 7.6%, 6.7%, and 4.9% at age 1, 2, and 3 years, respectively. Hen egg allergy was most common (5.4% prevalence at age 1 year) followed by allergies to cow milk and wheat. Several patterns of allergic symptom clusters were identified. Physician diagnosed, as reported by the caregiver, non-IgE mediated gastrointestinal food allergy affected 0.5% of infants. By contrast, caregiver-reported gastrointestinal food allergies affected 1.4% of children. Kawasaki disease affected 0.3% and 0.4% children, respectively, at age 1 and 3 years. Primary immunodeficiency disorders affected 0.005% children at age 3 years.
These data provide important epidemiological signatures of allergy and immunology in young Japanese children including the age-specific prevalence of allergic disease, Kawasaki disease, and primary immune deficiency.
The association between maternal diet during pregnancy and allergy in offspring remains contentious. Here, we examined the association between maternal intake of vegetables and related nutrients ...during pregnancy and allergic diseases in offspring at one year of age. A cohort of 80,270 pregnant women enrolled in the Japan Environment and Children's Study were asked to respond to a food frequency questionnaire during pregnancy and the International Study of Asthma and Allergies in Childhood questionnaire at one year postpartum. The women were categorized into quintiles according to the energy-adjusted maternal intake of vegetables and related nutrients. Using the categorizations as exposure variables, the adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were determined for the allergic outcomes, including asthma, wheeze, atopic dermatitis, eczema, and food allergy, in the offspring per quintile at one year of age. Of the 80,270 participants, 2,027 (2.5%), 15,617 (19.6%), 3,477 (4.3%), 14,929 (18.7%), 13,801 (17.2%), and 25,028 (31.3%) children experienced asthma, wheeze, atopic dermatitis, eczema, food allergy, and some form of allergic disease, respectively. The aORs of each quintile of maternal vegetable intake for all allergic outcomes were close to 1.0 compared to the lowest quintile. The lowest aOR was found in the association of maternal cruciferous vegetable intake with asthma (aOR: 0.82, 95% CI: 0.70-0.96) and highest was found in the association of maternal total vegetable intake with atopic dermatitis (aOR: 1.17, 95% CI: 1.04-1.31). The risk of allergic outcomes for the various nutrients related to vegetable consumption was close to 1.0. The maternal intake of vegetables and various related nutrients during pregnancy had little or no association with any of the allergic outcomes, including asthma, wheezing, atopic dermatitis, eczema, and food allergy, in offspring at one year.
ABSTRACT
Background
Physiological skin properties of neonates and infants change drastically after birth and are implicated in the onset of atopic dermatitis and other diseases. Studies have measured ...physiological skin properties in infants; however, how these properties change over time remains unclear. No reports have measured ceramide in the stratum corneum of infants using confocal Raman spectroscopy; hence, we used it to measure the physiological properties of the skin, including ceramide, in infants.
Materials and methods
The water content and other factors in the skin of infants aged 0, 1, and 6 months were measured. All measurements were performed five times indoors at 22 ± 2°C and 50% ± 10% relative humidity in the middle of the calf at 4‐µm distances, and their mean was calculated.
Results
The water content of the area between the skin surface and superficial layers was the lowest in newborns as compared with other ages, and the deeper the skin layer, the higher the water content. The stratum corneum, evaluated using confocal Raman spectroscopy, was the thickest in newborns and gradually thinned with age. Its water content was the lowest in newborns. The levels of natural moisturizing factor, ceramide, and cholesterol were higher in newborns and tended to decrease with age.
Conclusion
This report is the first to evaluate ceramide in the stratum corneum of infants using confocal Raman spectroscopy and could help in conducting subsequent longitudinal measurements of physiological skin properties in neonates and infants.
PDF
