Associations between food portion sizes, insulin resistance, VO2 max and metabolic syndrome in European adolescents: The HELENA study.

BACKGROUND AND AIMS: This study aims to examine the associations of food portion size (PS) with markers of insulin resistance (IR) and clustered of metabolic risk score in European adolescents. METHODS: A total of 495 adolescents (53.5% females) from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study were included. The association between PS from food groups and homeostasis model assessment of insulin resistance (HOMA-IR) index, VO2 max, and metabolic risk score was assessed by multilinear regression analysis adjusting for several confounders. Analysis of covariance (ANCOVA) was used to determine the mean differences of food PS from food groups by HOMA-IR cutoff categories by using maternal education as a covariable. RESULTS: Larger PS from vegetables in both gender and milk, yoghurt, and milk beverages in males were associated with higher VO2 max, while larger PS from margarines and vegetable oils were associated with lower VO2 max (p < 0.05). Males who consumed larger PS from fish and fish products; meat substitutes, nuts, and pulses; cakes, pies, and biscuits; and sugar, honey, jams, and chocolate have a higher metabolic risk score (p < 0.05). Males with lower HOMA-IR cutoff values consumed larger PS from vegetables, milk, yoghurt, and milk beverages (p < 0.05). Females with lower HOMA-IR cutoff values consumed larger PS from breakfast cereals, while those with higher HOMA-IR cutoff values consumed larger PS from butter and animal fats (p = 0.018). CONCLUSION: The results show that larger PS from dairy products, cereals, and high energy dense foods are a significant determinant of IR and VO2 max, and larger PS from food with higher content of sugar were associated with higher metabolic risk score.

Impact of different exercise training modalities on energy and nutrient intake and food consumption in sedentary middle-aged adults: a randomised controlled trial.

BACKGROUND: Exercise could influence energy and macronutrient intake, which could have an important role on body composition changes in response to exercise. The present study aimed to investigate the effects of different training modalities in energy and macronutrient intake, and whether changes in energy and macronutrient intake influences changes in body composition in response to different training modalities. METHODS: A 12-week randomised controlled trial was conducted. Eighty middle-aged sedentary adults were randomised to: (i) a control group; (ii) physical activity recommendation from the World Health Organization; (iii) high-intensity interval training; and (iv) whole-body electromyostimulation training. Dietary intake was assessed using the average of three 24-h recalls. RESULTS: High-intensity interval training and whole-body electromyostimulation training groups showed lower fibre intake and higher dietary energy density. Our results showed a negative association was found between changes in energy intake and changes in lean mass index. No association was found between changes in protein intake and changes in lean mass index. CONCLUSIONS: In conclusion, we observed a higher dietary energy density and lower fibre intake in high-intensity training groups.

Exercise training increases the S-Klotho plasma levels in sedentary middle-aged adults: A randomised controlled trial. The FIT-AGEING study.

This study aimed to investigate the effects of different training modalities on the soluble Klotho (S-Klotho) plasma levels in sedentary middle-aged adults. A total of 74 middle-aged adults (53.4 ± 5.0 years old; 52.7% women) were enrolled in the FIT-AGEING study. We conducted a 12-week randomised controlled trial. The participants were randomly assigned to 4 different groups: (i) a control group (no exercise), (ii) a physical activity recommendation from the World Health Organization group (PAR), (iii) a high intensity interval training group (HIIT), and (iv) a high intensity interval training group adding whole-body electromyostimulation training group (HIIT-EMS). S-Klotho plasma levels, anthropometric measurements, and body composition variables were measured before and after the intervention programme. All exercise training modalities induced an increase in the S-Klotho plasma levels (all P ≤ 0.019) without statistical differences between them (all P ≥ 0.696). We found a positive association between changes in lean mass index and changes in the S-Klotho plasma levels, whereas a negative association was reported between changes in fat mass outcomes and changes in the S-Klotho plasma levels after our intervention study. In conclusion, our results suggest that the link between exercise training and the increase in S-Klotho plasma levels could be mediated by a decrease of fat mass and an increase of lean mass.

Occupational allergy to Spagulax®(Plantago ovata seed).

SUMMARY: We report the case of a 36-year-old male pharmaceutical laboratory worker. On handling Spagulax® sachets whose content is a laxative called Plantago ovata, he immediately presented rhinoconjunctivitis. Methods. Specific allergy study included SDS-PAGE with Western Blot and specific nasal challenge to Plantago ovata extract. Results. Prick by prick for Spagulax® was negative. Total IgE: 126.5 U/mL. Western Blot recognized two proteins of 15 and 20 kDa in the extract of Plantago ovata and three proteins of 15, 18 and 50 kDa in the extract of Plantago lanceolata. Conclusions. We present a case of occupational allergy due to inhalation of and/or contact with Plantago ovata seeds.

Association of heart rate and blood pressure among European adolescents with usual food consumption: The HELENA study.

BACKGROUND AND AIM: In adults, there is some evidence that improving diet reduces blood pressure (BP) and the subsequent risk of cardiovascular diseases (CVDs). However, studies that analyse this association in adolescents are still scarce. The objective of the present study was to examine the associations between heart rate, systolic (SBP), diastolic (DBP) and mean arterial blood pressure (MAP) among European adolescents and usual intake of vegetables, fruits, dairy products, meat, fish, high-sugar foods and savoury snacks. METHODS AND RESULTS: In total, 2283 adolescents from the HELENA-study (12.5-17.5 years old; 1253 girls) were included. Dietary intake was assessed using two computerized 24-hour dietary recalls. Age, sex, body mass index, maternal educational level, physical activity and Tanner stage were considered as confounders. Associations were examined by mixed model analysis stratified by sex. Tests for trend were assessed by tertiles of intake while controlling for the aforementioned confounders. Dairy products and fish intake were negatively associated with BP and heart rate. Significant decreasing trends were observed for heart rate and BP across tertiles of dairy products, fish intake and high-sugar foods intake (p < 0.05). Significant increasing trends were observed for SBP and MAP across tertiles of savoury snack intake (p < 0.05). CONCLUSION: Significant but small inverse associations between fish and dairy products consumption with blood pressure and heart rate have been found in European adolescents. Dietary intervention studies are needed to explore these associations in the context of the modification of several risk factors for the prevention of cardiovascular diseases.

Cutaneous drug eruption induced by antihistamines.

Topical application of antihistamines commonly leads to sensitization for patients, but systemic administration of antihistamines rarely induces allergic hypersensitivity, which is mainly linked to phenothiazine-derived and piperazine-derived compounds. We report a 70-year-old woman whose medical history included lichen planus, and who was referred by the dermatology department of our hospital for suspected allergy to corticosteroids. The reason for referral was that on the fourth day of treatment with prednisone and hydroxyzine, the patient presented a bilateral highly pruritic palmar erythema that evolved to a generalized morbilliform rash with subsequent complete desquamation. At a later time, she took cetirizine for a cold, and developed palmar erythema and desquamation. Skin tests (prick and intradermal tests) were performed with steroids, and patch tests (read after 48 and 96 h) with corticosteroids and antihistamines. Controlled oral challenge tests were performed with prednisone and with an alternative antihistamine. Skin tests were negative for all corticosteroids. Patch tests were negative for all corticosteroids, but the antihistamine test was positive for hydroxyzine. Oral challenge with prednisone and dexchlorpheniramine was negative. The patient was diagnosed with cutaneous drug eruption from hydroxyzine and cetirizine. We consider it is important to assess every patient whose skin condition worsens after treatment with antihistamines, especially hydroxyzine, because it is known that antihistamines are often not recognised as the culprit in cases of cutaneous eruption.

Combined influence of healthy diet and active lifestyle on cardiovascular disease risk factors in adolescents.

To investigate the combined influence of diet quality and physical activity on cardiovascular disease (CVD) risk factors in adolescents, adolescents (n = 1513; 12.5-17.5 years) participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence study were studied. Dietary intake was registered using a 24-h recall and a diet quality index was calculated. Physical activity was assessed by accelerometry. Lifestyle groups were computed as: healthy diet and active, unhealthy diet but active, healthy diet but inactive, and unhealthy diet and inactive. CVD risk factor measurements included cardiorespiratory fitness, adiposity indicators, blood lipid profile, blood pressure, and insulin resistance. A CVD risk score was computed. The healthy diet and active group had a healthier cardiorespiratory profile, fat mass index (FMI), triglycerides, and high-density lipoprotein cholesterol (HDL-C) levels and total cholesterol (TC)/HDL-C ratio (all P ≤ 0.05). Overall, active adolescents showed higher cardiorespiratory fitness, lower FMI, TC/HDL-C ratio, and homeostasis model assessment index and healthier blood pressure than their inactive peers with either healthy or unhealthy diet (all P ≤ 0.05). Healthy diet and active group had healthier CVD risk score compared with the inactive groups (all P ≤ 0.02). Thus, a combination of healthy diet and active lifestyle is associated with decreased CVD risk in adolescents. Moreover, an active lifestyle may reduce the adverse consequences of an unhealthy diet.

Allergy to goat and sheep cheese with tolerance to cow's milk and its derivatives.

OBJECTIVE: We present two adult and three paediatric patients who had allergic reactions after cheese ingestion and subsequently tolerated cow's milk derivatives. The objective of this study was to determine possible cross-reactivity between different types of cheese. METHODS: Skin tests were performed to cow's milk fractions, and prick-prick tests for goat, sheep and cow cheese. Specific IgE to the fractions of cow's milk and cow, sheep and goat cheese was analysed. The protein profile of cow, sheep and goat cheese extracts was determined by SDS-PAGE and the allergenic profile by immunoblot. Cross-reactivity was investigated by immunoblot inhibition. RESULTS: Skin tests were positive for casein in the patients. The prick-prick tests were positive for the three cheeses in patients 1 and 4, for goat and sheep cheese in patients 2 and 3, and for sheep cheese in patient 5. The specific IgE test was positive in patients 1, 3 and 4 for goat and sheep cheese, and negative in patients 2 and 5. Serum 3 and 4 clearly recognised goat and sheep cheese extracts. Goat casein was almost completely inhibited with sheep casein and partially inhibited with goat and sheep serum proteins, while there was no inhibition with cow cheese. Sheep casein was totally inhibited with sheep serum proteins. Sheep casein was inhibited with goat and cow caseins, suggesting cross-reactivity among the three types of cheese. CONCLUSIONS: We showed sensitisation to goat and sheep cheese in two patients, and only to sheep cheese in another two of the studied patients.

Physical activity attenuates the negative effect of low birth weight on leptin levels in European adolescents; the HELENA study.

We examined whether physical activity (PA) influences the association between birth weight and serum leptin in adolescents. The study comprised a total of 538 adolescents (315 girls), aged 12.5-17.49 years, born at term (≥ 37 weeks of gestation). We measured serum leptin levels and time engaged in moderate-vigorous PA (MVPA) by accelerometry. There was an interaction effect between birth weight and meeting the PA recommendations (60 min/day MVPA) on leptin levels in girls (P = 0.023) but not in boys (P = 0.809). Birth weight was negatively associated with leptin levels in girls not meeting the PA recommendations (i.e. more than 60 min/day of MVPA) (ß = -0.096, P = 0.009), whereas no significant association was observed in those meeting the PA recommendations (ß = -0.061, P = 0.433). In conclusion, meeting the PA recommendations may attenuate the negative effect of low birth weight on serum leptin levels in European female adolescents.

Adiposity and bone health in Spanish adolescents. The HELENA study.

UNLABELLED: While the association of lean mass (LM) with bone mass is well understood, the association of fat mass (FM) with bone mass is controversial. Our results support that adolescents with higher levels of adiposity have greater bone mass, but this association is fully explained by their higher levels of LM. INTRODUCTION: We aimed (1) to study the independent association of FM and LM with bone mass and (2) to study the differences in bone mass by weight status in adolescents, after controlling for relevant confounders, such as physical activity (PA), calcium intake, and LM. METHODS: Participants were 330 adolescents (167 boys, 12.5-17.5 years) from the HELENA study. The relationships of FM (DXA, n = 330; BodPod, n = 282) and LM (DXA, n = 330) with different bone variables (whole body, total hip, lumbar spine, and femoral neck) were analyzed by linear regression, and differences between weight status were analyzed by ANCOVA. RESULTS: Fat mass (DXA) was positively associated with bone variables in both sexes, after adjustment for height, calcium intake, and sexual maturation. Additional adjustment by PA slightly increases the associations. However, adjustment for LM inverted these associations. Similar results were obtained using BodPod instead of DXA for assessing FM. Overweight/obese adolescents had higher BMC than their non-overweight peers in most of regions studied. Additional adjustment for PA slightly increased the differences between weight status groups, while adjusting for LM inverted the associations. LM was strong and positively associated with all bone variables in both sexes. Additional adjustment for PA or FM did not change the results. CONCLUSIONS: Adolescents with higher levels of adiposity have greater bone mass, but this association is explained by their higher levels of LM.

Cardiorespiratory fitness and dietary intake in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence study.

The present study investigated the association between cardiorespiratory fitness (CRF) and dietary intake in European adolescents. The study comprised 1492 adolescents (770 females) from eight European cities participating in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study. CRF was assessed by the 20 m shuttle run test. Adolescents were grouped into low and high CRF levels according to the FITNESSGRAM Standards. Dietary intake was self-registered by the adolescents using a computer-based tool for 24 h dietary recalls (HELENA-Dietary Assessment Tool) on two non-consecutive days. Weight and height were measured, and BMI was calculated. Higher CRF was associated with higher total energy intake in boys (P = 0·003). No association was found between CRF and macronutrient intake (as percentage of energy), yet some positive associations were found with daily intake of bread/cereals in boys and dairy products in both boys and girls (all P < 0·003), regardless of centre, age and BMI. CRF was inversely related to sweetened beverage consumption in girls. These findings were overall consistent when CRF was analysed according to the FITNESSGRAM categories (high/low CRF). A high CRF was not related to compliance with dietary recommendations, except for sweetened beverages in girls (P = 0·002). In conclusion, a high CRF is associated with a higher intake of dairy products and bread/cereals, and a lower consumption of sweetened beverages, regardless of centre, age and BMI. The present findings contribute to the understanding of the relationships between dietary factors and physiological health indicators such as CRF.

Muscular strength and markers of insulin resistance in European adolescents: the HELENA Study.

The aim of the study was to examine the association of muscular strength with markers of insulin resistance in European adolescents. The study comprised a total of 1,053 adolescents (499 males; 12.5-17.5 years) from ten European cities participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Cross-Sectional Study. Muscular strength was measured by the handgrip strength and standing long jump tests. Cardiorespiratory fitness was measured by the 20-m shuttle run test. Fasting insulin and glucose were measured and the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) indices were calculated. Weight, height, waist circumference and skinfold thickness were measured, and body mass index (BMI) was calculated. In males, the handgrip strength and standing long jump tests were negatively associated with fasting insulin and HOMA (all P < 0.05) after controlling for pubertal status, country and BMI or waist circumference. When skinfold thickness was included in the model, the association became non-significant. In females, the standing long jump test was negatively associated with fasting insulin and HOMA (all P < 0.001) after controlling for pubertal status, country and surrogate markers of total or central body fat (BMI, waist circumference or skinfold thickness). Findings were retained in males, but not in females after controlling for cardiorespiratory fitness. The findings of the present study suggest that preventive strategies should focus not only on decreasing fatness and increasing cardiorespiratory fitness but also on enhancing muscular strength.

Criterion-related validity of field-based muscular fitness tests in youth.

AIM: The purpose of the present study was to analyze the association between isokinetic strength and field-based muscular fitness tests in youth. METHODS: One hundred twenty-six adolescents (14.4±1.7 y) participated in the study. Upper and lower body isokinetic strength were measured at preset angular velocities of 90 º/s and 60 º/s, respectively. Muscular fitness was also assessed by means of field-based tests: handgrip strength, bent and extended arm hang tests, standing long jump, squat jump, countermovement jump and Abalakov jump. Height, weight and skinfold thickness were used to estimate body composition. RESULTS: All field-based tests were significantly associated with isokinetic peak torque and power (P<0.001 in all cases). Handgrip strength and standing long jump showed the highest associations with the isokinetic parameters (0.61≤r≤0.87; 0.39≤R2≤0.76). Weight-bearing field tests increased on average 20 % their association (R2) with isokinetic parameters when standardized by individual's body weight (test score × weight), while the average increase was 16 % when standardized by fat-free mass (test score × fat-free mass). CONCLUSION: Handgrip strength and standing long jump tests seem to be the most valid field-based muscular fitness tests when compared to isokinetic strength. These tests can be useful to assess muscular fitness in young people when laboratory methods are not feasible.

Association of Energy and Macronutrients Intake with S-Klotho Plasma Levels in Middle-Aged Sedentary Adults: A Cross-Sectional Study.

BACKGROUND: The ageing process can be influenced by energy intake and different macronutrients within the diet. The soluble form of the α-Klotho gene (called S-Klotho) is widely considered as a powerful anti-ageing biomarker. OBJECTIVE: To analyze the association of energy, dietary energy density and macronutrient intake with S-Klotho plasma levels in middle-aged sedentary adults. METHODS: A total of 72 (52.8% women) middle-aged sedentary adults (53.7 ± 5.2 years old) participated in the study. Energy and macronutrients intake (i.e. fat, carbohydrate and protein) were assessed using three non-consecutive 24-h recalls. S-Klotho plasma levels were measured in the Ethylenediaminetetraacetic acid (EDTA) plasma using a solid-phase sandwich enzyme-linked immunosorbent assay. RESULTS: No association was observed between energy, dietary energy density or macronutrient intake and S-Klotho plasma levels in men (all P≥ 0.1). We found an inverse association between energy, protein and carbohydrate intake with S-Klotho plasma levels in women (all P≤0.043), which disappeared after controlling for age, lean mass index and sedentary time. An inverse association was observed between dietary energy density and S-Klotho plasma levels in women after controlling for covariates (all P≤0.05). CONCLUSION: In summary, the present study showed an inverse association of dietary energy density with S-Klotho plasma levels in middle-aged women. In addition, our data suggest that the associations between energy and macronutrient intake could be highly dependent on lean mass and sedentary time.

Association between the FTO rs9939609 polymorphism and leptin in European adolescents: a possible link with energy balance control. The HELENA study.

We examined the association between the FTO rs9939609 polymorphism and serum leptin concentrations in adolescents. The FTO rs9939609 polymorphism was genotyped, and fasting serum leptin and insulin were measured in 655 European adolescents (365 females) aged 14.6 ± 1.2 years. We measured weight, height, triceps and subscapular skinfolds and waist circumference, and body fat percentage was calculated. Sex, pubertal status, center, physical activity (accelerometry), total or central adiposity and serum insulin concentrations were entered as confounders in the analyses. The minor A allele of the FTO rs9939609 was significantly associated with higher serum leptin concentrations independently of potential confounders including adiposity (+3.9 ng ml(-1) per risk allele (95% confidence interval: 2.0, 5.9); adjusted P < 0.001). These findings could link the FTO gene with serum leptin and consequently with the control of energy balance. Leptin could be a possible intermediary contributing to the association between the FTO rs9939609 polymorphism and adiposity.

Effect of fitness and physical activity on bone mass in adolescents: the HELENA Study.

Our aim is to analyse the effect on bone mass of: (1) physical fitness performance on a specific group of physical activity (PA) and, (2) PA on a specific physical fitness performance group. Bone mineral content (BMC) by dual energy X-ray absorptiometry (DXA) and PA by accelerometers was assessed in 373 Spanish adolescents (182 males). Adolescents were classified as: active and non-active (≥60 or <60 min day(-1) of moderate-vigorous PA). Fitness was assessed through speed/agility, strength and cardiorespiratory tests. Adolescents were classified by tertiles (T1, T2 and T3). ANCOVA was used for the analysis with sex, height, lean mass, calcium intake and pubertal status as covariates. Adolescents with lower strength, speed/agility and cardiorespiratory fitness (CRF) showed lower BMC in the whole body and extremities compared with adolescents with better results in these tests, mainly those non-active adolescents. Non-active adolescents with high fitness levels showed higher BMC (whole body and upper limbs) than active ones. The conclusions included: (1) within the non-active group, lower levels of fitness were associated with lower BMC; this might be through PA or trough an effect of PA on muscle mass. (2) Non-active adolescents with high level of fitness in most fitness tests showed higher BMC than their active peers, in spite of their lower PA levels. These unexpected results could be influenced by several factors such as genetics, nutrition, type of exercise or sport, hormones and skeletal age.

Associations of muscular and cardiorespiratory fitness with total and central body fat in adolescents: the HELENA study.

OBJECTIVE: to examine the association of healthrelated physical fitness with total and central body fat in adolescents. PARTICIPANTS/METHODS: the present cross-sectional study comprises 363 Spanish adolescents (186 female participants) aged 12.5-17.5 years. We assessed fitness by the 20-m shuttle run test (cardiorespiratory fitness); the handgrip strength, the standing broad jump and the Abalakov tests (muscular strength); and the 4 × 10-m shuttle run test (speed-agility). Total body fat was measured by dual energy x-ray absorptiometry (DXA), BodPod and sum of six skinfolds, and central body fat was measured by DXA at three regions (R1, R2 and R3) and waist circumference. RESULTS: the Abalakov, the standing broad jump, the 4 × 10-m shuttle run and the 20-m shuttle run tests were negatively associated with all markers of total and central body fat in men and women after controlling for age, pubertal status and objectively assessed physical activity (p<0.01). Handgrip strength test was positively associated with waist circumference (p<0.01). CONCLUSIONS: lower body muscular strength and cardiorespiratory fitness are negatively and consistently associated with total and central body fat in adolescents, whereas levels of upper body muscular strength were superior in adolescents with higher levels of central body fat.

Physical fitness levels among European adolescents: the HELENA study.

OBJECTIVE: To report sex- and age-specific physical fitness levels in European adolescents. METHODS: A sample of 3428 adolescents (1845 girls) aged 12.5-17.49 years from 10 European cities in Austria, Belgium, France, Germany, Greece (an inland city and an island city), Hungary, Italy, Spain and Sweden was assessed in the Healthy Lifestyle in Europe by Nutrition in Adolescence study between 2006 and 2008. The authors assessed muscular fitness, speed/agility, flexibility and cardiorespiratory fitness using nine different fitness tests: handgrip, bent arm hang, standing long jump, Bosco jumps (squat jump, counter movement jump and Abalakov jump), 4×10-m shuttle run, back-saver sit and reach and 20-m shuttle run tests. RESULTS: The authors derived sex- and age-specific normative values for physical fitness in the European adolescents using the LMS statistical method and expressed as tabulated percentiles from 10 to 100 and as smoothed centile curves (P5, P25, P50, P75 and P95). The figures showed greater physical fitness in the boys, except for the flexibility test, and a trend towards increased physical fitness in the boys as their age increased, whereas the fitness levels in the girls were more stable across ages. CONCLUSIONS: The normative values hereby provided will enable evaluation and correct interpretation of European adolescents' fitness status.

Safety of specific immunotherapy using a depigmented and polymerised extract of Dermatophagoides pteronyssinus in children under five years of age.

BACKGROUND: Different opinion documents point to a patient age of under five years as a relative contraindication to specific immunotherapy, arguing that this age group has a greater risk of developing anaphylaxis, and that specially trained personnel are needed to deal with the problem if it occurs. However, insufficient evidence exists to support such an affirmation. PATIENTS AND METHODS: A retrospective follow-up observational study was made of patients aged 60 months or younger who had been subjected to specific immunotherapy. We included 77 children with a diagnosis of extrinsic bronchial asthma (n=68), extrinsic spasmodic cough (n=5) and allergic rhinitis (n=4) confirmed by clinical criteria and prick-test, with specific IgE positivity to Dermatophagoides pteronyssinus. All patients received specific immunotherapy with an extract of depigmented D. pteronyssinus polymerised with glutaraldehyde, involving an initial cluster protocol of two weeks and monthly maintenance doses. All observed adverse reactions were recorded, and classified according to European Academy of Allergy and Clinical Immunology (EAACI) criteria. RESULTS: A total of 1837 doses were administered to the 77 patients, with four adverse reactions being observed in three patients. Three reactions (0.16% of the administered doses) were local and immediate, while one was systemic and of grade 2 (0.05% of the administered doses) - consisting of an episode of nocturnal wheezing. CONCLUSIONS: Specific immunotherapy in children under five years of age with the extract used is safe. We consider that further studies are needed, involving other types of extracts, to allow reconsideration of the relative contraindication of patient age for the administration of immunotherapy.