Parents' experience of the communication process of positivity at newborn screening for metabolic diseases: A qualitative study.

BACKGROUND: The process of receiving a communication of positivity for metabolic diseases at expanded newborn screening (ENBS) is extremely articulated, involves a variety of actors (parents, maternal and child departments, clinical centres and laboratories) and is open to a variety of outcomes from false positive to true positive cases. Receiving communication of positivity can be highly stressful for parents and requires an adequate communication process to give clear and reliable information without causing excessive worry. This qualitative study describes the parents' experience of receiving a communication of positivity to metabolic diseases at ENBS, and their assessment of the quality of the communication process and steps, with the main aim to identify the process' strengths and weaknesses and to advance tailored recommendations to improve the communication process. METHOD: Fourteen in-depth, semi-structured phone interviews were conducted with parents whose children resulted positive to the ENBS. As part of the ENBS communication process, parents received a first phone call communication of positivity and a second in-person communication at metabolic clinical centres (MCC). The framework analysis method was used to organize the data and identify emerging themes. RESULTS: Parents were largely dissatisfied with the quality and depth of the information received and with the way the healthcare staff delivered the first communication phone call, which failed to create a caring, empathic and safe setting. Many parents tried to reduce the uncertainty by searching online information or consulting with other providers. Nevertheless, the majority of parents described the in-person visit at MCC as clear, welcoming and reassuring. CONCLUSION: More efforts are needed to improve the quality of the communication process of the ENBS. Guidelines, recommendations and standard scripts to communicate positivity are needed along with programmes and educational resources to train tailored communication skills.

Exosomal MicroRNAs as Potential Biomarkers of Hepatic Injury and Kidney Disease in Glycogen Storage Disease Type Ia Patients.

Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α). Affected individuals develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma and kidney failure. The purpose of this study was to identify potential biomarkers of the evolution of the disease in GSDIa patients. To this end, we analyzed the expression of exosomal microRNAs (Exo-miRs) in the plasma exosomes of 45 patients aged 6 to 63 years. Plasma from age-matched normal individuals were used as controls. We found that the altered expression of several Exo-miRs correlates with the pathologic state of the patients and might help to monitor the progression of the disease and the development of late GSDIa-associated complications.

Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients.

INTRODUCTION: 6-Pyruvoyl-tetrahydropterin synthase deficiency (PTPSd) is a rare autosomal recessive disorder of synthesis of biogenic amines, which is characterized by variable neurological impairment and hyperphenylalaninemia. We aimed to assess the long-term clinical outcome of this disorder and the factors affecting it. METHODS: At total of 28 PTPSd patients (aged 19.9 ±â€¯10.9 years) underwent clinical (neurological and psychiatric) and neuropsychological assessment (BRIEF, VABS-II, and IQ). Based on CSF homovanillic (HVA) and 5-hydroxyindolacetic acid (5-HIAA) and pterin concentrations at diagnosis, patients were classified as having either a severe [SF; low level of CSF, HVA, and 5-HIAA with altered neopterin/biopterin (Neo/Bio)] or mild form (MF; normal HVA and 5-HIAA with altered Neo/Bio) of PTPSd. RESULTS: Approximately 36% of patients had MF PTPSd. At the last examination, 43% of patients had movement disorders (2 MF, 10 SF), 43% of patients had variable degrees of intellectual disability (SF only), 39% met the criteria for a psychiatric disorder (3 MF, 9 SF). Applying a linear regression model, we found that HVA and phenylalanine levels at birth had a significant influence on IQ, BRIEF, and VABS-II variability. Lastly, 5-HIAA further contributed to VABS-II variability. The disease showed a self-limiting clinical course and its treatment, although delayed, is effective in improving the neurological status. CONCLUSIONS: Neurodevelopmental impairment due to PTPSd shows a self-limiting course. A continuous improvement in the neurological condition has been observed in patients receiving treatment, even when delayed. The severity of brain biogenic amine depletion at diagnosis predicts neurological and psychiatric outcomes.

Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020.

Data on features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adolescents are scarce. We report preliminary results of an Italian multicentre study comprising 168 laboratory-confirmed paediatric cases (median: 2.3 years, range: 1 day-17.7 years, 55.9% males), of which 67.9% were hospitalised and 19.6% had comorbidities. Fever was the most common symptom, gastrointestinal manifestations were frequent; two children required intensive care, five had seizures, 49 received experimental treatments and all recovered.

Cow's Milk Consumption and Health: A Health Professional's Guide.

The most recent scientific evidence supports the consumption of cow's milk and dairy products as part of a balanced diet. However, these days, the public and practicing physicans are exposed to a stream of inconsistent (and often misleading) information regarding the relationship between cow's milk intake and health in the lay press and in the media. The purpose of this article, in this context, is to facilitate doctor-patient communication on this topic, providing physicians with a series of structured answers to frequently asked patient questions. The answers range from milk and milk-derived products' nutritional function across the life span, to their relationship with diseases such as osteoporosis and cancer, to lactose intolerance and milk allergy, and have been prepared by a panel of experts from the Italian medical and nutritional scientific community. When consumed according to appropriate national guidelines, milk and its derivatives contribute essential micro- and macronutrients to the diet, especially in infancy and childhood where bone mass growth is in a critical phase. Furthermore, preliminary evidence suggests potentially protective effects of milk against overweight, obesity, diabetes, and cardiovascular disease, while no clear data suggest a significant association between milk intake and cancer. Overall, current scientific literature suggests that an appropriate consumption of milk and its derivatives, according to available nutritional guidelines, may be beneficial across all age groups, with the exception of specific medical conditions such as lactose intolerance or milk protein allergy. Key teaching points: Milk and its derivatives contribute essential micro and macronutrients to the diet, when consumed according to appropriate national guidelines, especially in infancy and childhood where bone mass growth is in a critical phase. Preliminary evidence suggests potentially protective effects of milk against overweight, obesity, diabetes and cardiovascular disease No clear data are available about the association between milk intake and cancer. Current scientific literature suggests that an appropriate consumption of milk and its derivatives may be beneficial at all ages, with the exception of specific medical conditions such as lactose intolerance or milk protein allergy.

Early varicocelectomy by percutaneous scleroembolization improves seminiferous tubules spermatozoa release in the adolescent phase of testicular growth.

Varicocele is a rather common andrological condition in adolescents, which can adversely affect testicular growth and seminal parameters, leading to infertility in about 20% of adults. The aim of this study was to investigate if treating varicocele before the age of 18 is a beneficial option to improve testicular hypotrophy and seminal parameters and if minimally invasive techniques could be an appropriate treatment choice for adolescent varicocele associated with spermatic vein reflux. A percutaneous scleroembolization was performed in sixty-four consecutive young patients (13-19 years old) with left varicocele, preceded by a fluoroscopy. In thirty-four of them, semen samples were also collected. We examined semen samples and testicles dimensions before and after percutaneous varicocelectomy, compared to a nonoperated control group, with a six-month follow-up. Total sperm count and sperm morphology were significantly increased in the intervention group. Left testicular volume significantly increased in both groups, while only correction of varicocele improved spermatozoa release per unit of testis volume. We conclude that early varicocelectomy by percutaneous scleroembolization significantly ameliorates seminiferous tubules activity in the critical adolescent phase of testicular growth. It is suggested that adolescents should be; offered varicocele repair as soon as possible in order to improve reproductive potential.

Epigenetic Effects of n-3 LCPUFAs: A Role in Pediatric Metabolic Syndrome.

Childhood obesity represents an important public health issue worldwide and is strongly linked to metabolic alterations such as hypertension, insulin resistance, and dyslipidemia. The constellation of these conditions is commonly known as Metabolic Syndrome (MetS). Metabolic syndrome is not just a simple cluster of metabolic complications due to excess of adipose tissue, but is considered a risk factor for cardiovascular diseases. Evidence from several human and animal studies suggests that environmental and nutritional exposure during pregnancy may affect the newborn development and future health through epigenetic changes, playing a potential role in determining obesity and obesity-related complications. Understanding how nutritional epigenetic mechanisms contribute to the "transgenerational risk" for obesity and metabolic dysfunction is crucial in order to develop early prevention strategies for children's health. Nutrigenetics is the science that studies the role of nutrients in gene expression. Long Chain Polyunsaturated Fatty Acids (LCPUFAs) are known for their health benefits, especially in relation to their ability to modulate inflammation and improve some obesity-associated comorbidities, mainly by decreasing plasma triglycerides. Recent nutrigenetic research is focusing on the potential role of LCPUFAs in influencing epigenetic markers. In this review, we present the most recent updates about the possible interaction between n-3 LCPUFAs and epigenetic pathways in metabolic syndrome. Literature from MEDLINE® and the Cochrane database between May 2005 and December 2018 has been scanned.

Predictability and inconsistencies in the cognitive outcome of early treated PKU patients.

Long-term cognitive outcome and treatment of adult early treated (ET)PKU patients is a main issue in PKU research. We questioned whether the intellectual development of ETPKU patients is stable and to what extent its variation may be predicted by the quality of metabolic control. The aims of the present longitudinal retrospective study were to assess in young adult ETPKU patients: i) the relationship between IQ and metabolic control during the first two decades of life; and ii) the intra- and interindividual variability in the developmental trajectory which cannot be predicted by the disease's biomarkers. We collected biochemical data from 65 ETPKU patients (diagnostic blood Phe > 360 µmol/l) who were assessed twice for IQ (Wechsler Intelligence Scale) during their lifetime (mean age: 10.2 and 19.6 years, respectively). Results show that in ETPKU patients IQ over the second decade of life remained stable in about half of the patients (51%); while the rest experienced a gain (7 to 15 points) or loss (7 to 28 points) in IQ scores (23 and 26% respectively) whatever the quality of metabolic control was. The main factor affecting the second IQ was the value of the first IQ (p < 0.000) whose effect overruled that of the markers of metabolic control. Looking at the developmental trajectory of our ETPKU patients, the present study disclosed a remarkable interindividual variability in their cognitive outcome and also an inconsistent linkage between cognitive performances and biochemical control, thus supporting the hypothesis of an individual resilience or vulnerability to Phe in young adult ETPKU.

Duration of exclusive breastfeeding and wheezing in the first year of life: A longitudinal study.

INTRODUCTION: Wheezing is the most common symptom associated with asthma in young children. There is a lack of well-designed prospective studies on the relationship of exclusive breastfeeding with wheezing in infants. This prospective cohort study investigated whether a relationship exists of exclusive breastfeeding with wheezing at 12 months of age. MATERIALS AND METHODS: A series of 1632 mother-infant pairs were sequentially recruited. Mothers were trained at hospital on breastfeeding practices and how to recognise wheezing. At hospital discharge they received a calendar-diary to record the date at stopping breastfeeding and at onset of wheezing. Data were collected by telephone interviews through 12 months post-delivery. Breastfeeding was in accordance with the World Health Organisation and wheezing with the International Classification of Diseases (ICD-10-CM code R06.2). RESULTS: At 12 months 1522 mother-infant pairs were participating. Breastfeeding started in 95.9% of them and was exclusive in 86.1%. The incidence of wheezing ever and recurrent wheezing at 12 months of age was 33.7% and 10.0%, respectively. Duration of exclusive breastfeeding was shorter in wheezing than non-wheezing infants (median 2.6 months vs. 4.1 months, P<0.001). After adjustment for confounders each month of exclusive breastfeeding reduced the risk of wheezing ever by 11% and of recurrent wheezing by 15%, at 12 months of age. CONCLUSION: Longer duration of exclusive breastfeeding reduces the risk of wheezing throughout the first 12 months of life. These findings would be relevant to all healthcare operators and mothers, also to improve their awareness about the best feeding practices for the infant's health.

Serum salicylic acid and fruit and vegetable consumption in obese and normal-weight children: a pilot-study.

Salicylic acid (SA), a phenolic compound produced by plants, may play a beneficial role on health. This pilot study evaluated whether there might be an association between serum SA and fruit and vegetable (FV) consumption in obese and normal-weight children. Thirty-four obese children (17 boys and 17 girls) and 34 normal-weight children were recruited. Dietary intake was evaluated by the 7-day dietary record. Serum SA was measured using gas chromatography-mass spectrometry method. FV intake in obese and normal-weight children was not different between groups (175.00 (97.66) g versus 192.29 (90.54) g, p = .455). Obese children had lower serum SA than normal-weight children [mean difference, -0.025; 95% CI (-0.044; -0.006) µmol/L]. Serum SA was not associated with daily intake of FV in obese (p = .111) and normal-weight (p = .092) children. Further studies are needed to evaluate the role of FV on serum SA, taking into account also the quantity and the type.

Atopic dermatitis: recent insight on pathogenesis and novel therapeutic target.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. It affects infancy, but it is also highly prevalent in adults and it is one of the disease burdens for the patients and their families. Nowadays, AD is recognized as a heterogenous disease with different subtypes with variable clinical manifestations which is affected by the impairments of the skin barrier. The severity of AD dictates the level of treatment. Current AD treatment focuses on restoration of the barrier function, mainly through the use of moisturizers and corticosteroids to control the inflammation, topical calcineurin inhibitors, and immunosuppresive drugs in the most severe cases. However, targeted disease-modifying therapies are under investigation. The most recent findings on the skin microbial dysbiosis is a promising future direction for the development of new treatments. We need to improve the understanding of the complex microbiome-host interactions, the role of autoimmunity, the comparative effectiveness of therapies and the ways to appropriately implement the educational strategies.

Docosahexaenoic Acid Levels in Blood and Metabolic Syndrome in Obese Children: Is There a Link?

Prevalence of metabolic syndrome is increasing in the pediatric population. Considering the different existing criteria to define metabolic syndrome, the use of the International Diabetes Federation (IDF) criteria has been suggested in children. Docosahexaenoic acid (DHA) has been associated with beneficial effects on health. The evidence about the relationship of DHA status in blood and components of the metabolic syndrome is unclear. This review discusses the possible association between DHA content in plasma and erythrocytes and components of the metabolic syndrome included in the IDF criteria (obesity, alteration of glucose metabolism, blood lipid profile, and blood pressure) and non-alcoholic fatty liver disease in obese children. The current evidence is inconsistent and no definitive conclusion can be drawn in the pediatric population. Well-designed longitudinal and powered trials need to clarify the possible association between blood DHA status and metabolic syndrome.

Radiological contrast media in the breastfeeding woman: a position paper of the Italian Society of Radiology (SIRM), the Italian Society of Paediatrics (SIP), the Italian Society of Neonatology (SIN) and the Task Force on Breastfeeding, Ministry of Health, Italy.

OBJECTIVES: Breastfeeding is a well-recognised investment in the health of the mother-infant dyad. Nevertheless, many professionals still advise breastfeeding mothers to temporarily discontinue breastfeeding after contrast media imaging. Therefore, we performed this review to provide health professionals with basic knowledge and skills for appropriate use of contrast media. METHODS: A joint working group of the Italian Society of Radiology (SIRM), Italian Society of Paediatrics (SIP), Italian Society of Neonatology (SIN) and Task Force on Breastfeeding, Ministry of Health, Italy prepared a review of the relevant medical literature on the safety profile of contrast media for the nursing infant/child. RESULTS: Breastfeeding is safe for the nursing infant of any post-conceptional age after administration of the majority of radiological contrast media to the mother; only gadolinium-based agents considered at high risk of nephrogenic systemic fibrosis (gadopentetate dimeglumine, gadodiamide, gadoversetamide) should be avoided in the breastfeeding woman as a precaution; there is no need to temporarily discontinue breastfeeding or to express and discard breast milk following the administration of contrast media assessed as compatible with breastfeeding. CONCLUSIONS: Breastfeeding women should receive unambiguous professional advice and clear encouragement to continue breastfeeding after imaging with the compatible contrast media. KEY POINTS: • Breastfeeding is a well-known investment in the health of the mother-infant dyad. • Breastfeeding is safe after administration of contrast media to the mother. • There is no need to temporarily discontinue breastfeeding following administration of contrast media.

Blood lipids profile in hyperlipidemic children undergoing different dietary long chain polyunsaturated supplementations: a preliminary clinical trial.

The aim of this preliminary study was to explore the effect size of different dietary long chain polyunsaturated supplementations on blood lipid profile in children with primary hyperlipidemia. Thirty-six children (8-13 years) were recruited. After an 8-week stabilization period on the Step I diet, they were randomized to additionally receive for a 16-week period one capsule (500 mg) daily of docosahexaenoic acid (DHA) alone or a DHA plus eicosapentaenoic acid (EPA) mixture (45.6% DHA; 41.6% EPA) or wheat germ oil (control). An effect size (as percentage change from baseline) of +8%, -12% and -16% for high-density lipoprotein cholesterol (HDL-C), total cholesterol/HDL-C ratio and triglycerides was observed in children supplemented with DHA, compared to +2%, -8% and -12%, respectively, in children supplemented with DHA plus EPA. This preliminary study suggests powered trials appear feasible and are warranted to evaluate efficacy of n-3 long-chain polyunsaturated fatty acid dietary supplementations on the blood lipid profile of children with primary hyperlipidemia.

Plant Sterols and Stanols for Pediatric Patients with Increased Cardiovascular Risk.

The atherosclerotic process begins in childhood and progresses throughout adult age. Hypercholesterolemia, especially familial hypercholesterolemia (FH) and metabolic dysfunctions linked to weight excess and obesity, are the main atherosclerosis risk factors in pediatric patients and can be detected and treated starting from childhood. Nutritional intervention and a healthy-heart lifestyle are cornerstones and first-line treatments, with which, if necessary, drug therapy should be associated. For several years, functional foods enriched with plant sterols and stanols have been studied in the treatment of hypercholesterolemia, mainly as nutritional complements that can reduce LDL cholesterol; however, there is a lack of randomized controlled trials defining their long-term efficacy and safety, especially in pediatric age. This review aims to evaluate what the main published studies on sterols and stanols in pediatric subjects with dyslipidemia have taught us, providing an updated picture of the possible use of these dietary supplements in children and adolescents with dyslipidemia and increased cardiovascular risk. Nowadays, we can state that plant sterols and stanols should be considered as a valuable therapy in pediatric patients with hypercholesterolemia, bearing in mind that nutritional and lifestyle counseling and, when necessary, pharmacologic therapy, are the cornerstones of the treatment in developmental age.

Diet and Lipid-Lowering Nutraceuticals in Pediatric Patients with Familial Hypercholesterolemia.

Familial hypercholesterolemia is a genetically determined disease characterized by elevated plasma total and LDL cholesterol levels from the very first years of life, leading to early atherosclerosis. Nutritional intervention is the first-line treatment, complemented with nutraceuticals and drug therapy when necessary. Nutraceuticals with a lipid-lowering effect have been extensively studied in the past few decades, and have been recently included in international guidelines as a complement to nutritional and pharmacological treatment in subjects with dyslipidemia. In this review, we explore current nutritional interventions for dyslipidemia in childhood, with a specific focus on the main nutraceuticals studied for treating severe dyslipidemia in pediatric patients. Additionally, we briefly describe their primary mechanisms of action and highlight the advantages and risks associated with the use of lipid-lowering nutraceuticals in childhood.

Nutritional Treatment of Hypertriglyceridemia in Childhood: From Healthy-Heart Counselling to Life-Saving Diet.

Hypertriglyceridemia is a lipid disorder with a varying prevalence; it is very common if we consider triglyceride plasma values slightly above the threshold, whereas it is extremely rare if only severely elevated triglyceride levels are considered. In most cases, severe forms of hypertriglyceridemia are caused by genetic mutations in the genes that regulate triglyceride metabolism, thus leading to extreme triglyceride plasma values and acute pancreatitis risk. Secondary forms of hypertriglyceridemia are usually less severe and are mainly associated with weight excess, but they can also be linked to liver, kidney, endocrinologic, or autoimmune diseases or to some class of drugs. Nutritional intervention is the milestone treatment for patients with hypertriglyceridemia and it has to be modulated on the underlying cause and on triglyceride plasma levels. In pediatric patients, nutritional intervention must be tailored according to specific age-related energy, growth and neurodevelopment requests. Nutritional intervention is extremely strict in case of severe hypertriglyceridemia, whereas it is similar to good healthy nutritional habits counselling for mild forms, mainly related to wrong habits and lifestyles, and to secondary causes. The aim of this narrative review is to define different nutritional intervention for various forms of hypertriglyceridemia in children and adolescents.

Dietary intervention for children and adolescents with familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is a frequent genetic disorder characterised by high plasma levels of total and LDL-cholesterol and premature atherosclerosis. If left untreated, affected subjects have a high risk of cardiovascular disease, as they are exposed to very high levels of LDL-cholesterol from birth. Healthy dietary habits and lifestyle are the first treatment option and, if started from childhood, represent a milestone in the prevention of atherosclerotic disease, both as a starting point and in combination with drug therapy. In this work, based on the main consensus documents available so far, we have evaluated the most up-to-date indications of the dietetic-nutritional intervention for the treatment of FH, delving into the peculiar aspects of the diet of the child/adolescent affected by FH. After an analysis of the macro- and micronutrients and the most common dietary patterns currently recommended, we highlighted some practical aspects, some frequent errors and some risks we could fall into when dealing with paediatric nutritional treatment. In conclusion, the dietary intervention for the child/adolescent with FH is a complex task, that should be individualised and tailored taking into account, first of all, the nutritional adequacy for growth and development, but also the multiple aspects linked to the child/adolescent's age, tastes and preferences, the family they belong to, the socio-economic context and the Country they live in.

Low bone mineralization in phenylketonuria may be due to undiagnosed metabolic acidosis.

Background: Dietary intervention is to date the mainstay treatment to prevent toxic phenylalanine (Phe) accumulation in PKU patients. Despite success preventing central nervous system damage, there is increasing evidence of possible other unfavorable outcomes affecting other systems, e.g. kidney and bone; underlying mechanisms are yet to be fully elucidated. Methods: This observational, cross-sectional and descriptive study investigated 20 adult with PKU evaluating biochemical parameters, BMD measurements and extrapolating data from 3-days food records and protein substitutes (PS) and special low protein foods (SLPF) composition. Results: Blood gas venous analysis (VBG) indices were indicative of metabolic acidosis in 60% of PKU patients and VBG pH significantly correlated with BMD's Z-score (p-value = 0.022) even if its overall mean was in range (-1.29). Low bone mineral density for chronological age (Z-score < - 2.0) was found in 4 patients (20%). Indices of kidney function were not impaired. All used PS had a moderate excess of acidity, while SLPF were alkalizing and type/variety of consumed vegetables did not determine significant changes in acid-base equilibrium. Total intakes of potassium and magnesium were lower than expected. Discussion: PKU patients seem to be at risk of metabolic acidosis, directly linked to possible low bone mineralization. This may be related to the acidic composition of PS, potentially capable of acidifying the entire diet. Reported low intakes of potassium and magnesium may be relevant to these observations. Further studies are needed to better address these topics.

Hyperphenylalaninemias genotyping: Results of over 60 years of history in Lombardy, Italy.

BACKGROUND: Hyperphenylalaninemias (HPA) are due to several gene mutations, of which the PAH gene is the most frequently involved. Prevalence and incidence of disease vary between populations, with genotype/phenotype correlations not always capable to correctly predict disease severity. The aim of this study was to give an overview of PAH mutations among one of the largest cohort of patients among Europe, born in Lombardy (Italy) starting from late 1970 s and including over a 60 years of activity; furthermore, to evaluate and discuss identified genotype/phenotype correlations and related reliability. PATIENTS/METHODS: Eight hundred and twenty-six HPA patients in current follow-up at the San Paolo Hospital in Milan (Italy) were retrospectively reviewed, including molecular results and allelic phenotype and genotype values (attributed on the basis of the APV/GPV system) to verify genotype-phenotype correlations. RESULTS: A total of 166 different PAH variants were reviewed; of those, seven variants were identified as not previously described in literature. Most frequently reported variant was p.Ala403Val, followed by p.Arg261Gln, p.Val245Ala, IVS10-11 g>a, p.Tyr414Cys and p.Leu48Ser. Phenotype prediction, based on APV/GPV, matched the actual phenotype in most cases, but not always. CONCLUSION/DISCUSSION: The cohort of patients included in this study constitute a representative sample of the HPA population worldwide. Studies on this sample may allow to improve clinical and genetic evaluation performances for affected patients, consequently to develop personalized medicine interventions and provide more precise indications on the correct treatment approach based on the accumulated evidence, also in light of a prognostically reliable but not always conclusive APV/GPV system.