A pilot study, a specially designed pillow may prevent developmental plagiocephaly by reducing pressure from the infant head

Developmental plagiocephaly (DP) has been an increasing problem since the successful “back to sleep campaign”. The referrals for DP have increased by >400% during the years 2004 to 2008. Many infants spend less time in the prone position nowadays and some of the risk factors for DP are as follows: less than 3 times per day for the tummy time, torticollis and slow achievement of motor milestones. There is a need for better information to the parents but also for other strategies to prevent DP. The aim of this study was to investigate the effect of a special pillow and thus to reduce pressure on the infant head. Method: infants aged zero to two months were included in the study. They were randomized to either intervention group or control group. Head shape was investigated on two occasions, on the second occasion motor development, mobility and muscle function of the neck were also investigated. The parents were asked about tummy time and sleep position. All infants were investigated by the same physical therapist, blinded to group belonging. Result: seven infants had CVAI >3.5 on the last assessment, five of these had not used any method to reduce pressure. Fishers exact test showed a tendency where infants with reduced pressure on the head had less DP (P 0.08). Paired t test showed significant decrease in CVAI for the infants who had had reduced pressure on the head (P 0.01). Among these infants the CVAI was zero for 47% in the last assessment. For the infants who had not had a reduction of pressure on the head, there was no indication of a decrease of CVAI (P 0.45), and only 12% of these infants had a CVAI that was zero in the last assessment. Conclusion: this pilot study shows that a specially designed pillow may prevent DP in young infants. However, a larger sample is needed to confirm or disprove this. The study is planned to go on until there are 200 participants.

A Specially Designed Pillow Can Decrease Developmental Plagiocephaly in Young Infants

Developmental plagiocephaly (DP) has been an increasing problem since the successful “back to sleep campaign”. The referrals for DP have increased by more than 400% during the years 2004 to 2008. Many infants spend less time in the prone position nowadays and some of the risk factors for DP are: tummy time less than 3 times per day, torticollis and slow achievement of motor milestones. Improved information for the parents is needed but also other strategies to prevent DP. This study is a continuum of an earlier pilot study;the aim was to investigate the effect of a pillow, designed to reduce pressure on the infant head. Method: Infants aged zero to two months were included in the study. They were randomized to either intervention group or control group. Head shape was investigated on two occasions, on the second occasion motor development, mobility and muscle function of the neck were also investigated. The parents were asked about tummy time and sleep position. All infants were investigated by the same physical therapist, blinded to group belonging. Result: Fishers exact test showed that it was more common with decreased CVAI among infants in the intervention group (P 0.001). Paired t test showed significant decrease in CVAI for the intervention group (P 0.002), but not for the control group (P 0.96). Conclusion: This study shows that a specially designed pillow can decrease DP in young infants.

A Clinical Analysis of Physical and Neurological Development in very Low Birth Weight Infants with MEIR(Massage,Exercises,Intelligence training,and Rehabilitation training)

Objective:This study aimed to investigate the application of MEIR(Massage,Exercises,Intelligence training,and Rehabilitation training)in Chinese VLBW infants and to observe its effects on infants’growth and deve1opment.Methods:Clinical data of 92 VLBW infants who were treated at the neonatal intensive care unit(NICU)of Loudi Centra1 Hospital were retrospectively analyzed.The patients were grouped as the MEIRgroup(n=47)and controls(n=45).Physical and neurodevelopment deve1opment were compared between the two groups.Results:There were differences in height and weight and head circumference between the two groups at all corrected ages(all P<0.05).Abnormal motions,reflexes,muscular tension,audio-visual reactions,and posture,and the total numbers of abnormalities of 3-,6-,9-and 12-corrected month-old infants in the MElRgroup were 1ower than in the control group(all P<0.05).The mental development index and psychomotor development index of 6-and 12-corrected month infants in the MEIR group were higher than in the control group(all P<0.05).Conclusion:MEIR could improve the physical and neurological developments of VLBW infants,reduce the incidence of adverse events,and improve their growth and development.

Influencing factors of the neurodevelopment of high-risk infants

Background High-risk infants refer to newborns exposed to high-risk factors in the prenatal, natal or postnatal period. High-risk infants are at high risk of developmental retardation, and early identification of developmental abnormalities plays a vital role in improving high-risk infants' quality of life.Aims To describe the neurodevelopment of high-risk infants aged less than 1 year old, and to analyse the incidences and influencing factors of neurodevelopmental abnormalities in order to provide a basis for neurodevelopment monitoring and management of highrisk infants.Methods High-risk infants born between January 2016 and December 2016 in the maternity and infant health hospitals of three districts in Shanghai were followed up.The Gesell Developmental Scale was used to assess the neurodevelopmental level at the time of recruitment(0-2 months) and at 9 months. Univariate and multivariate analyses of the influencing factors were conducted.Results 484 high-risk infants(male 51 %, female 49%)with an average gestation age of 36.5±2.2 weeks were recruited. At the time of recruitment, the average age was2.1(0.8) months, and the developmental quotient(DQ)scores of full-term high-risk infants in motor(t=3.542,p=0.001), cognitive(t=3.125, p=0.002), language(t=3.189, p=0.002) and social(t=3.316, p=0.001) areas were higher than those of preterm infants. The incidences of developmental abnormalities of full-term high-risk infants in motor(χ~2 =9.452, p=0.002), cognitive(χ~2=6.258, p=0.012), language(χ~2 =12.319, p =0.001) and social(χ~2 =6.811, p=0.009) areas were lower than the preterm infants. At 9 months, there was no difference in the DQ scores and incidences of developmental abnormalities in four areas between full-term and preterm high-risk infants, and the incidence of developmental abnormalities was around 10%.Conclusion The incidence of neurodevelopmental abnormalities in high-risk infants aged less than 1 year old is high. Preterm birth and parental bad habits are significant factors affecting the neurodevelopment.Monitoring and early interventions help to improve highrisk infants' neurodevelopment.

Development of PVEP in Infants and Children

The development of components of VEP was studied in 150 infants and children between 2 weeks and 9 years of age participated as subjects. Ten adult subjects, 25 ito 35 years of age were also studied. The results indicated that the VEP had a simple wave form, consisting of only a slowly rising positive wave to 140', 70' and 35' checks from infants of 2 to 8 weeks following birth. P_1 wave appeared in response to 17.5' check stimulus at 10 weeks following birth. The latencies of P_1 components shortened d...

Fractal description and quantitative analysis of normal brain development in infants

We examined the fractal pattern of cerebral computerized tomography images in 158 normal infants aged 0 3 years, based on the quantitative analysis of chaotic theory. Results showed that the fractal dimension of cerebral computerized tomography images in normal infants remained stable from 1.86-1.91. The normal distribution range in the neonatal period, 1-2 months old infants, 1-2 year old infants, and of 2-3 year old infants was 1.88 1.90 （mean： 1.891 3 ± 0.006 4）, 1.89-1.90 （mean： 1.892 7 ±0.004 5）, 1.86-1.90 （mean： 1.886 3 ± 0.008 5）, and 1.88-1.91 （mean： 1.895 8±0.008 3）, respectively. The spectrum width of the multifractal spectrum （△α） in normal infants was 1.4618. These data suggest that the spectral width parameters of the multifractal spectrum and the fractal dimension criteria in normal children may be useful as a practical specific parameter for assessing the fractal mode of brain development in normal infants.

Effect of Community Interventions on Intelligence Development of Infants

Objective To assess the interventions effect on intelligence of the infants through the community. Methods A total of 309 newborns and their families were recruited in Xuhui district, Shanghai. They were asked to fill out the baseline questionnaires. The newborns＇ intelligence quotients were measured by Developmental Screening Test for Child Under Six, and physical examinations were conducted at the same time. The newborns were randomly assigned to intervention group （156 cases） and control group （153 cases）. The infants and their families were followed up every 6 months. A questionnaire of follow-up was completed by face-to-face interview at the communities and infant intelligence quotients were measured and had their physical check-ups again at the end of the 6th month. Results After 6 months＇ intervention, the means of MI and DQ in the intervention group were respectively 5.96 and 9.80 higher than those in control group after adjustment of the baseline scores. Conclusion Early intelligence education in the community may promote the intelligence development of infants.

Role of Ultrasound in Evaluation of Developmental Dysplasia of the Hip in Infants

Background/Aim: The present study was directed to investigate the accuracy of ultrasound (USG) in early detection of developmental dysplasia of the hip (DDH) to prevent permanent complications. Material & Methods: A total of 276 infants was investigated;their ages range from 1 - 6 months. Patients referred from the clinic based on clinical assessment (mainly Barlo & Ortolani maneuvers). Then the patient’s hips were examined by expert radiologists in USG scan. After that, dynamic (coronal and transverse) & static ultrasound views evaluated by the same radiologist using Graf’s criteria. Infants with abnormal ultrasound findings suggestive of DDH were followed up after 4 - 6 weeks by the same investigator to monitor the progress. At the same time, the patient referred to a specialist for conservative management from the first positive findings. Results: Among the 276 referred patients, infants with normal stable hips (Graf Type I and Type II a+) were 221 (80%), 155 of them were female and 66 male infants. Infants with unstable hips based on Graf’s criteria (Type II a-, II b, II c and Type III a) were 55 (20%). Out of 55 with abnormal findings, the affected hips on both sides, right and left were: 5 cases (1.8%), 7 (2.5%) and 43 hips (15.5%) consecutively. Out of 55 infants affected;3 referred to tertiary centers for further surgical management while 52 managed conservatively. Conclusion: Delayed treatment rates of DDH and complications could be reduced by the usage of the USG after the first month of life. In addition to physical assessment, USG for high-risk infants will provide more accurate diagnosis and minimize complications.

Linear Mixed Model Analysis of Worldwide Longitudinal Infant Mortality Rate Data and Association with Human Development Index

A linear mixed model is used to determine the explaining infant mortality rate data of United Nations countries. The HDI （human development index） has a significant negative linear relationship with infant mortality rate. United Nations data shows that the infant mortality rate has a descending trend over the period 1990-2010. This study aims to assess the value of the HDI as a predictor of infant mortality rate. Findings in the paper suggest that significant percentage reductions in infant mortality might be possible for countries for controlling the HDI.

Association of maternal hypertensive disorders in pregnancy with infant neurodevelopment

Inconsistent findings have been reported regarding the associations between hypertensive disorders in pregnancy (HDP) and infant neurodevelopment. Leveraging data from the Jiangsu Birth Cohort, in the present study, we re-visited such associations in one-year-old infants from 2 576 singleton pregnancies and 261 twin pregnancies. We first assessed infant neurodevelopment by the Bayley Scales of Infant and Toddler Development Screening Test (the Third Edition), and then estimated its association with maternal HDP using general linear regression models and Poisson regression models. In singleton pregnancies, compared with mothers unexposed to HDP, infants born to mothers with chronic hypertension exhibited a lower score (β, −0.67;95% confidence interval [CI], −1.19-−0.15) and a higher risk of "non-optimal" gross motor development (risk ratio [RR], 2.21;95% CI, 1.02-4.79);in twin pregnancies, infants born to mothers with HDP exhibited lower scores in cognition (β, −0.49;95% CI, −0.96-−0.01), receptive communication (β, −0.55;95% CI, −1.03-−0.06), and gross motor (β, −0.44;95% CI, −0.86-−0.03), and at a higher risk of "non-optimal" gross motor development (RR, 2.12;95% CI, 1.16-3.88). These findings indicate that infants born to mothers with HDP may have inferior neurodevelopment outcomes at the age of one year.

Neurodevelopmental in Relation to Breastfeeding–Experiences among Hungarian Preterm Infants at 12 Months of Corrected Age:Empirical Study

Preterm and low birth weight infants are at higher risk of neurodevelopmental outcomes;breastfeeding offers sev-eral beneficial aspects for them.This study aimed to describe the average neurodevelopmental outcomes of pre-term infants and examine the associations between neurodevelopment and breastfeeding among Hungarian preterm infants at 12 months of corrected age.154 preterm infants with low birth weight(<2500 g)and their mothers were participated in this study.Bayley-III Screening Test(Bayley Scales of Infant and Toddler Develop-ment Screening Test,Third Edition)was administered to measure the cognitive,language and motor skills of infants;breastfeeding data was obtained through parental anamnesis.To analyze data,independent sample t-test or the Welch t-test,Mann-Whitney tests,Chi-square tests of independence and Spearman’s rank correlation test were used to.Concerning the risk of developmental delay,Receptive and Expressive language and Fine motor subscales were the lowest.Examination of the associations between breastfeeding and neurodevelopmental per-formance identified significantly higher cognitive(U=2047.5;P=0.023)andfine motor(U=2096.0;P=0.037)skills in infants who were breastfed.We found significant positive correlations between the duration of breastfeeding and cognitive,expressive language andfine motor skills.The study draws the attention to the importance of breastfeeding and early screening.Further research is required to examine the casual relationship between neurodevelopmental outcomes and breastfeeding.

Eeffect of super early comprehensive rehabilitationon neurodevelopmental prognosis of high-risk infants

Objective: To observe the effect of super-early comprehensive rehabilitation intervention on neurodevelopmental prognosis of premature high-risk infants;Methods: Premature high-risk infantsmet the inclusion criteria were divided into control group (n=30) and treatment group (n=30) according to parental willingness. The control group was given routine treatment, while the treatment group was treated with comprehensive rehabilitationon the basis of the control group. The course of treatment for both groups was 10 d. The changes of body weight, milk consumption, NBNA score, GMFM score and Gesell score were observed. Results:After treatment, the body weight and milk consumption of the treatment group increased significantly compared with those before treatment (P<0.01), which was significantly better than that of the control group (P<0.01);the NBNA score of the treatment group was higher than that of the control group at 40 weeks of gestational age (P<0.05), and the abnormal rate of NBNA was lower than that of the control group (P<0.01). The GMFM scores of A-energy and B-energy areas and the five dimensions of social adaptation, big exercise, fine exercise, language and personal social interaction in the treatment group increased significantly in 1 month, 2 months and 3 months after birth,which were significantly better than those in the control group (P<0.05 or P<0.01). Conclusion: Super-early comprehensive rehabilitation can improve the physical quality of high-risk infants and promote the development of the nervous system, with remarkable effect.

A specially designed pillow may be used as treatment for young infants with developmental plagiocephaly

Developmental plagiocephaly has increased since the back to sleep campaign and is nowadays a rather common condition in infants. Prevention is the best way to decrease this problem, therefore, tools for treatment are needed. This case description of two children who dropped out from a study of a specially designed pillow indicates that the Mimos pillow may work as the treatment in young infants with developmental plagiocephaly.

Early Intervention in the Neurodevelopment of Premature Infants during the First Six Months of Life

Objective: Measure the effects of Early Intervention ad modum Katona (EI-K) in high-risk premature infants by means of clinical, neurobehavioral, and neurophysiologic tests. Method: We used the Amiel-Tison neurologic examination, the Bayley Scale of Infant Behavior, and electroencephalography (EEG) recordings at 42 weeks of conceptional age, and after 6 months of treatment EI-K (n = 14) and compared these results with those of a group of infants without early intervention (nEI) (n = 11). Results: We found better performance of infants in EI-K than nEI group after 6 months of treatment in neurologic and behavioral examination measurements, but found no differences in EEG comparisons. Conclusion: Our data suggest significant benefit of the use of EI-K program over n-EI in the neurologic and neurobe-havior examinations of premature infants after 6 months of age.

Ultrasound measurement of the corpus callosum and neural development of premature infants

Length and thickness of 152 corpus callosa Using ultrasonic diagnostic equipment with a were measured in neonates within 24 hours ot b^rtn. neonatal brain-specific probe, corpus callosum length and thickness of the genu, body, and splenium were measured on the standard mid-sagittal plane, and the anteroposterior diameter of the genu was measured in the coronal plane. Results showed that corpus callosum length as well as thickness of the genu and splenium increased with gesta- tional age and birth weight, while other measures did not. These three factors on the standard mid-sagittal plane are therefore likely to be suitable for real-time evaluation of corpus callosum de- velopment in premature infants using cranial ultrasound. Further analysis revealed that thickness of the body and splenium and the anteroposterior diameter of the genu were greater in male infants than in female infants, suggesting that there are sex differences in corpus callosum size during the neonatal period. A second set of measurements were taken from 40 premature infants whose ges- tational age was 34 weeks or less. Corpus callosum measurements were corrected to a gestational age of 40 weeks, and infants were grouped for analysis depending on the outcome of a neonatal behavioral neurological assessment. Compared with infants with a normal neurological assessment, corpus callosum length and genu and splenium thicknesses were less in those with abnormalities, indicating that corpus callosum growth in premature infants is associated with neurobehavioral development during the early extrauterine stage.

Motor Development as a Potential Marker to Monitor Infantile Pompe Disease on Enzyme Replacement Therapy

After Enzyme Replacement Therapy (ERT) using recombinant human acid alpha-glucosidase (rhGAA), survival of Infantile Pompe Disease (IPD) patients through the first 18 months of age has been documented and acquisitions of motor development are an important outcome, but description of its course is scarce. Objective: To describe the motor development in an IPD patient and its correlation with clinical conditions during the first 18 months on ERT with rhGAA. Methods: By longitudinal observational study of an IPD case at early stage. Clinical and biochemical characteristics were obtained from patient records. Echocardiogram assessed cardiac indexes and the urinary biomarker—glucose tetrasaccharide (Glc4)—was obtained by HPLC/UV, following sample derivatization with butyl 4-amino benzoate and analysis on a C18 stationary phase column. Motor skills were evaluated with Alberta Infant of Motor Scale (AIMS) and motor delay was considered as motor percentile (p) below 10. Descriptive statistical analysis was carried out and t-test was used to calculate the differences among means, with significance level defined as p value < 0.05. Results: After ERT beginning amelioration of the cardiomyopathy with reduced left ventricle mass index (LVMI) from the 2nd month onwards was observed, but above the upper normal limit for healthy children and CRIM-positive IPD patients. Although GAA antibodies level remained above the recommended titers and fluctuating elevation of Glc4 quantified, motor development analysis showed an ascendant curve expected for age within achievement of independent ambulation. Motor delay after pneumonia and maintenance of hypotonia were noted. Variation of Glc4 appeared long after a transitory intercurrence. Conclusion: In an IPD case, motor development can have normal evolution despite hypotonia. Motor analysis seems to be sensitive to follow-up clinical intercurrences. To elucidate the interaction among prognostic factors and outcomes, further clinical studies need to be conducted.

Influencing factors of colostrum exposure to low-level lead and their relationship with early neural development of infants

BACKGROUND： Exposure to low-level lead has a toxic effect on the development of neonates, which has attracted wide attention. Colostrum lead level can be used as the indication of lead exposure. OBJECTIVE： To observe the relationship of colostrum lead level and the neurobehavioral development of infants. DESIGN： A prospective control observation. SETTING： Center for Maternal and Child Health, Shanxi Provincial Children＇s Hospital. PARTICIPANTS： Totally 128 neonates of full-term normal delivery, 76 male and 52 female, from Shanxi Provincial Maternal and Child Health Center and Jiexiu Maternal and Child Health Center were involved in this study. All the involved neonates had no peripartal ischemic/hypoxic history or fetus intrauterine developmental lag. Pregnant women had no various acute and chronic diseases in pregnancy, family history of neurological disease or occupational lead exposure. 128 portions of colostrum sample of full-term normal delivery were collected. Informed consents of detected items were obtained from the puerperants and their relatives. METHODS： ① Experimental grouping： Lead level in the colostrum was determined by atomic absorption spectrometry. According to lead level in the colostrum, the neonates were classified into two exposure groups of greater than or equal to 0.24 μmol/L in a high-level lead group and less than 0.24 μ mol/L in a low-level lead group. ② Experimental evaluation： Mental developmental index （MDI） and psychological developmental index （PDI） of 3-month-old infants were evaluated with Bayley Scales of Infant Development （BSID）. The relationships of MDI, PDI and colostrum lead level were performed correlation regression analysis; The relationship of colostrum lead level and development was performed multi-factor analysis with family environment and health questionnaires. MAIN OUTCOME MEASURES： ① Evaluation results of MDI and PDI. ② Multi-factor analysis results. RESULTS： Totally 128 neonates were involved in the study. Ten and eleven neonates were lost due to emigration in the high-level lead group and low-level lead group respectively, and the other 107 neonates participated in the final analysis. ① MDI and PDI in the high-level lead group were significantly lower than those in the low-level lead group, respectively （P 〈 0.01）; Regression analysis results showed that two developmental indexes were statistically negatively correlated with colostrum lead level （regression equation y = 1.9＋0.01x1,-0.04x2,＋0.04x3,＋0.03x4）. ② Four variables of the factors included by family environment and health questionnaires were taken into equation. Large maternal age, irrational dietary pattern in pregnancy and pollution degree of habitation environment in pregnancy were the risk factors of colostrum lead level （partial regression coefficien t =0.598 4,0.426 8,0.306 7,P 〈 0.05-0.01）, and calcium supplementation in pregnancy was a protective factor （partial regression coefficien t =-0.455 8, P 〈 0.01）. CONCLUSION： High colostrum lead level will have adverse effects on the early development of neonates; Large maternal age, irrational dietary pattern in pregnancy and pollution degree of habitation environment in pregnancy are the risk factors of colostrum lead level, and calcium supplementation in pregnancy was a protective factor.

The association between folic acid supplementation,maternal folate during pregnancy and intelligence development in infants:a prospective cohort study

Objective The study aimed to explore the association between folic acid supplementation,maternal nutritional levels during pregnancy and intelligence development of infants.Method This was a prospective cohort study,mothers and their offspring in Jurong Maternal and Child Health Hospital were followed up through pregnancy up to 1 year.The basic information of pregnant women was obtained through questionnaire survey,including pregnancy lifestyle,marital status,vitamin and mineral supplements during pregnancy.Blood samples of pregnant women were collected on admission,serum folate,vitamin B12 and homocysteine concentrations were determined.Maternal postpartum colostrum was collected and the concentrations of folate and vitamin B12 in colostrum were determined.Pregnant women(n=478)and their corresponding infants were followed up and the Developmental Screen Test scores were recorded at 1,3,6,8 and 12 months of age.Results Compared with the normal group,infants in the low serum folate group had a score of 0.12 points lower in the intellectual energy zone(95%CI:-0.23–-0.01,P=0.04),and infants with the high homocysteine level scored 1.30 points lower than the lower-level group(95%CI:-2.52–-0.08,P=0.04).In the colostrum low-vitamin B12 level group,infants scored 0.10 points lower(95%CI:-1.84–-0.02,P=0.02)in the social adaptation zone compared to the normal group.Conclusion In conclusion,folic acid supplementation in the pre-pregnancy supplementation group and the post-pregnancy supplementation group may be not associated with infant mental development.In addition,maternal folate and homocysteine may be related to the intellectual development of infants.The level of vitamin B_(12)in colostrum may be associated with infants’social adaptive capacity.This result may be caused by individual differences in folate and homocysteine metabolism in pregnant women.

THE DEVELOPMENT OF A MANIKIN TO SIMULATE THE THERMAL PHYSIOLOGY OF PREMATURE INFANTS

This paper describes a manikin (also known as mannequin) to simulate the thermal physiology of premature infants and experiments performed on it.The performance of the manikin is shown to compare well with that a selection of premature infants in terms of their rate of heat loss.

Psychomotor Development of Low Birth Weight Infants at the “Mère-Enfant” University Hospital Centre (UHC) of Libreville

Introduction: Low birth weight is a key indicator of newborn health. The objective of this study was to contribute to the reduction of low birth weight-related morbidity and mortality. Patients and Methods: cohort study conducted from January 2019 to July 2020 at the “Mère-Enfant” University Hospital Centre (UHC) of Libreville. All newborns with a birth weight 2500 g were included. The clinical data of patients were studied. They were followed over a period of 12 months and assessed psychomotorly by the Brunet-Lézine scale. Results: 1260/9035 births of low birth weight (14.0%) were observed, and 300 among them were included. The mortality rate was 27.0% (81) and 219 were followed for 12 months. The sex ratio was 0.8, the average birth weight was 2008.6 ± 215.2 g. The average gestational age was 34 ± 12 weeks with 75.3% prematurity. An infant disease was observed in 61.6% of cases and respiratory pathologies were more observed except at 3 months of age where the proportion of digestive pathologies was 20.5%. At the time of the last consultation at 12 months of life, 76.2% of infants had no pathology. The quotients of postural development, language and coordination were normal (between 110 - 70) respectively in 75.4%, 99.1% and 68% of cases at the age of 12 months. The psychomotor development quotient was correlated with the birth weight in the language area r = 0.15 (p = 0.024), posture r = 0.15 (p = 0.015) and coordination r = 0.15 (p = 0.026) respectively. Conclusion: Low birth weight is a public health problem at UHCME-JEF. Despite the fact that psychomotor development can be said to be satisfactory, many efforts remain to be made to reduce low birth weight levels and improve survival.