Investigating the Relationship between Parental Education, Asthma and Rhinitis in Children Using Path Analysis.

Parental socioeconomic position (SEP) is a known determinant of a child's health. We aimed to investigate whether a low parental education, as proxy of SEP, has a direct effect on physician-diagnosed asthma, current asthma and current allergic rhinitis in children, or whether associations are mediated by exposure to other personal or environmental risk factors. This study was a secondary data analysis of two cross-sectional studies conducted in Italy in 2006. Data from 2687 adolescents (10-14 years) were analyzed by a path analysis model using generalized structural equation modelling. Significant direct effects were found between parental education and family characteristics (number of children (coefficient = 0.6229, p < 0.001) and crowding index (1.1263, p < 0.001)) as well as with exposure to passive smoke: during pregnancy (maternal: 0.4697, p < 0.001; paternal: 0.4854, p < 0.001), during the first two years of children's life (0.5897, p < 0.001) and currently (0.6998, p < 0.001). An indirect effect of parental education was found on physician-diagnosed asthma in children mediated by maternal smoking during pregnancy (0.2350, p < 0.05) and on current allergic rhinitis mediated by early environmental tobacco smoke (0.2002; p < 0.05). These results suggest the importance of promotion of ad-hoc health policies for promoting smoking cessation, especially during pregnancy.

Time of onset and/or diagnosis of ADHD in European children: a systematic review.

BACKGROUND: Attention-Deficit/ Hyperactivity Disorder (ADHD) is one of the most common childhood neurobehavioral conditions. Symptoms related to this disorder cause a significant impairment in school tasks and in the activities of children's daily lives; an early diagnosis and appropriate treatment could almost certainly help improve their outcomes. The current study, part of the Models Of Child Health Appraised (MOCHA) project, aims to explore the age at which children experience the onset or diagnosis of ADHD in European countries. METHODS: A systematic review was done examining the studies reporting the age of onset/diagnosis (AO/AD) of ADHD in European countries (28 European Member States plus 2 European Economic Area countries), published between January 1, 2010 and December 31, 2019. Of the 2276 identified studies, 44 met all the predefined criteria and were included in the review. RESULTS: The lowest mean AO in the children diagnosed with ADHD alone was 2.25 years and the highest was 7.5 years. It was 15.3 years in the children with ADHD and disruptive behaviour disorder. The mean AD ranges between 6.2 and 18.1 years. CONCLUSIONS: Our findings indicate that there is a wide variability in both the AO and AD of ADHD, and a too large distance between AO and AD. Since studies in the literature suggest that an early identification of ADHD symptoms may facilitate early referral and treatment, it would be important to understand the underlying reasons behind the wide variability found. TRIAL REGISTRATION: PROSPERO registration: CRD42017070631 .

Quality of child healthcare in European countries: common measures across international databases and national agencies.

BACKGROUND: The evaluation of child healthcare is not yet widely explored, especially from a cross-country comparison perspective. The routine adoption of measures by national assessment agencies is under-investigated. Though the guiding principles developed at international level call for a child-centric multi-dimensional evaluation of child care, its feasibility is hampered by the availability of robust and harmonized data. METHODS: To explore the data availability, international databases (IDBs) were scrutinized and measures dealing with child health-related issues were collated. In parallel, an ad hoc questionnaire was administrated to 30 Country Agents (CAs) to gather measures routinely adopted at local level. To facilitate the comparison of measures, a three-level conceptual map was developed. RESULTS: The IDBs yielded at 207 measures that pertained mainly to non-health determinants of health, whereas the 352 measures obtained from CAs focused on process and outcome. A set of 33 common measures that related to immunization, morbidity and mortality were identified. CONCLUSIONS: A limited set of measures used both in IDBs and at national level identify common areas of concerns that certainly capture crucial issues with child prevention and health outcomes. However, they are far from satisfying a child-centric multi-dimensional approach to the evaluation of child well-being and well-becoming. There is room for improvement at both international and national levels. IDBs should include and harmonize measures that concern the provision of child-centric services and encompass physical, social and mental development. At the national level, efforts towards the inclusion of measures that concern non-health determinants of health should be pursued.

Quality of life improvement in children with attention-deficit hyperactivity disorder reduces family's strain: A structural equation model approach.

OBJECTIVES: The objective of the study is to analyse how the quality of life of children diagnosed with attention-deficit/hyperactivity disorder (ADHD) impacts the relationship between disease severity and family burden. METHOD: The data collected by a longitudinal, observational study involving 1478 children with ADHD residing in 10 European countries (aged 6 to 18 years) were analysed to evaluate the relationships between ADHD severity, the children's quality of life and family burden. RESULTS: The disorder's severity directly and indirectly affected the children's health-related quality of life (HRQoL) and family burden. The degree of family burden was modulated by the children's HRQoL. CONCLUSIONS: One of the primary causes of the stress experienced by parents of children with ADHD is their perception of the child's reduced HRQoL and not the symptom severity itself. Efforts to minimize symptom severity cannot alone reduce family burden.

Variability in the assessment of children's primary healthcare in 30 European countries.

BACKGROUND: The high variability in the types and number of measures adopted to evaluate childcare across European countries makes it necessary to investigate country practices to identify trends in setting national priorities in the assessment of child well-being. OBJECTIVE: This paper intends to investigate country practices under the lens of variability to explore possible trends in setting national priority in the evaluation of childcare. In particular, it analyses variability considering to what extent this depends on the tendency of adopting a broad vision (i.e. selecting measures for a larger variety of aspects) or whether this is influenced by the choice of adopting an in-depth approach (i.e. using more measures to analyse a specific aspect). METHODS: An ad hoc questionnaire was administered to a national expert in each country and yielded 352 measures. To analyse variability, the breadth in the number of aspects considered was explored using a convergence index, while the depth in the distribution of measures in each aspect was investigated by computing a coefficient of variation. Countries were grouped by adopting a hierarchical clustering approach. RESULTS: There is a high variability across countries in the selection of measures that cover different aspects of childcare. Preferences in the distribution of measures are significant even at the domain level and in countries that use a limited number of measures and become more evident at the category and sub-category levels. The statistical analysis clusters countries in four main groups and two outliers. The in-depth distribution of measures focused on a specific aspect shows a homogeneous pattern, with the identification of two main groups of countries. CONCLUSIONS: A limited set of measures are shared across countries hampering a robust comparison of paediatric models. The selection of measures shows that the evaluation is closely related to national priorities as resulting from the number and types of measures adopted. Moreover, a range of a reasonable number of measures can be hypothesized to address the quality of childcare under a multi-dimensional perspective.

Salt-reduction strategies may compromise salt iodization programs: Learnings from South Africa and Ghana.

OBJECTIVES: Universal salt iodization has been adopted by many countries to address iodine deficiency. More recently, salt-reduction strategies have been widely implemented to meet global salt intake targets of <5 g/d. Compatibility of the two policies has yet to be demonstrated. This study compares urinary iodine excretion (UIE) according to 24-h urinary sodium excretion, between South Africa (SA) and Ghana; both countries have implemented universal salt iodization, but in Ghana no salt-reduction legislation has been implemented. METHODS: Participants from the World Health Organization's Study on Global Ageing and Adult Health Wave 3, with survey and valid 24-h urinary data (Ghana, n = 495; SA, n = 707), comprised the sample. Median 24-h UIE was compared across salt intake categories of <5, 5-9 and >9 g/d. RESULTS: In Ghana, median sodium excretion indicated a salt intake of 10.7 g/d (interquartile range [IQR] = 7.6), and median UIE was 182.4 µg/L (IQR = 162.5). In SA, both values were lower: median salt = 5.6 g/d (IQR = 5.0), median UIE = 100.2 µg/L (IQR = 129.6). UIE differed significantly across salt intake categories (P < 0.001) in both countries, with positive correlations observed in both-Ghana: r = 0.1501, P < 0.0011; South Africa: r = 0.4050, P < 0.0001. Participants with salt intakes <9 g/d in SA did not meet the World Health Organization's recommended iodine intake of 150 µg/d, but this was not the case in Ghana. CONCLUSIONS: Monitoring and surveillance of iodine status is recommended in countries that have introduced salt-reduction strategies, in order to prevent reemergence of iodine deficiency.

Determinants of change in blood pressure in Ghana: Longitudinal data from WHO-SAGE Waves 1-3.

The prevalence of hypertension is increasing in low- and middle-income countries, however statistics are generally derived from cross sectional surveys that utilize different methodologies and population samples. We investigated blood pressure (BP) changes over 11-12 years in a large cohort of adults aged 50 years and older (n = 820) included in the World Health Organization's Study on global AGEing and adult health (WHO-SAGE Ghana) Wave 1 (2007/8) with follow up in Wave 3 (2019). Participants' BP were measured in triplicate and a survey completed at both time points. Survey instruments collected information on sociodemographic characteristics, lifestyle, health behaviors and chronic conditions. While no significant difference was found in systolic BP between Waves 1 and 3, diastolic BP decreased by 9.7mmHg (mean = 88.6, 15.4 to 78.9, 13.6 respectively) and pulse pressure increased by 9.5mmHg (44.8, 13.7 to 54.3, 14.1). Awareness of hypertension increased by 37%, from (20% to 57%), but no differences were found for the proportion of hypertensives receiving treatment nor those that had controlled BP. Mixed effects modelling showed a decrease in diastolic BP was associated with increasing age, living in rural areas and having health insurance. Factors associated with an increased awareness of hypertension were residing in urban areas, having health insurance and increasing body mass index. While diagnosis of hypertension has improved over time in Ghana, there is an ongoing need to improve its treatment in older adults.

Survey of doctors' perception of professional values.

BACKGROUND: New challenges in the medical field of the third millennium emphasise the "humanization of medicine" leading to a redefinition of doctors' values, limits and roles. The study aims to assess whether there are different personality dimensions of physicians in relation to their perception of professional values and public expectations. METHODS: A questionnaire on the perception of professional values and the opinion on work in the medical field, work relationships and public expectations was administered to 374 doctors attending Continuing Medical Education courses. RESULTS: Two personality dimensions were identified: the first dimension (which we termed "Performance Attainment") is associated preeminently with values of competence, advocacy, confidentiality, spirit of enquiry, integrity, responsibility and commitment; the second dimension (which we called "Personal Involvement") focuses on concern and compassion. The doctors that have more difficulty accepting judgements on their activity are those who think that "Performance attainment" is less important (ß = 6.01; p-value = 0.007). Instead, the doctors who believe "public expectation of the health system" is not high enough, tend to think that "Performance Attainment" is more important (ß = -6.08; p-value = 0.024). The less importance is given to the values of "Personal Involvement", the less is the doctor's perception of having a leading role in respect to other health professionals (ß = -2.37; p-value = 0.018). CONCLUSIONS: Our results demonstrate that there are two different attitudes in terms of recognition and selection of the essential values to better practice the medical profession. Whether the doctors attach more importance to one dimension or the other, they do not differ in our analysis for how they answered the questions about relationships with patients, colleagues or family commitments in the questionnaire, even if they work in different areas. This suggests that in our research there is no single personal attitude that characterizes "a good doctor".

Salt and potassium intake among adult Ghanaians: WHO-SAGE Ghana Wave 3.

Though Ghana has high hypertension prevalence, the country lacks current national salt consumption data required to build and enhance advocacy for salt reduction. We explored the characteristics of a randomly selected sub sample that had valid urine collection, along with matched survey, anthropometric and BP data (n = 839, mean age = 60y), from the World Health Organization's Study on global AGEing and adult health (WHO-SAGE), Ghana Wave 3, n = 3053). We also investigated the relationship between salt intake and blood pressure (BP) among the cohort. BP was measured in triplicate and 24 h urine was collected for the determination of urinary sodium (Na), potassium (K), creatinine (Cr) and iodine levels. Hypertension prevalence was 44.3%. Median salt intake was 8.3 g/day, higher in women compared to men (8.6, interquartile range (IQR) 7.5 g/day vs 7.5, IQR 7.4 g/day, p <  0.01), younger participants (18-49 y) compared to older ones (50+ y) (9.7, IQR 7.9 g/day vs 8.1, IQR 7.1 g/day, p <  0.01) and those with higher Body Mass Index (BMI) (> 30 kg/m2) compared to a healthy BMI (18.5-24.9 kg/m2) (10.04, IQR 5.1 g/day vs 6.2, IQR 5.6 g/day, p <  0.01). More than three quarters (77%, n = 647) of participants had salt intakes above the WHO maximum recommendation of 5 g/d, and nearly two thirds (65%, n = 548) had daily K intakes below the recommended level of 90 mmol. Dietary sodium to potassium (Na: K) ratios above 2 mmol/mmol were positively associated with increasing BP with age. Population-based interventions to reduce salt intake and increase K consumption are needed.

Old age and depression in Ghana: assessing and addressing diagnosis and treatment gaps.

Background: There is limited evidence about the prevalence of depression among older people in sub-Saharan Africa, about access to treatment or the potential efficacy of community-based interventions.Objective: Using nationally representative data from the WHO SAGE survey, we examine the prevalence of and factors associated with depression among people aged 50 and over in Ghana. Compare self-reported diagnosis and a symptom algorithm to assess treatment gaps and factors associated with the size of gap. Assess the feasibility of a small community-based intervention specifically for older people.Method: Prevalence and treatment data were taken from the WHO SAGE 2007 survey in Ghana, including 4,725 people aged 50 or over. Outcomes of interest were self-reported depression and diagnosis of depression derived from a symptom-based algorithm. The data were subjected to bivariate and multivariate analysis. In parallel, a pilot intervention was conducted with 35 older people, which included screening by a trained psychiatrist and follow-up group sessions of psychotherapy.Results: The symptomatic algorithm reported an overall rate of 9.2 per cent for the study population, with associations with female sex and older age. The treatment gap for these cases was found to be 83.0 per cent. The implementation of the pilot study was perceived as effective and replicable by stakeholders and there was some evidence of enhanced outcomes for people with mild depression.Conclusions: Large numbers of older people in Ghana experience depression, but very few have access to treatment. There is an urgent need to develop and validate community-based services for older people experiencing this condition.

Intra-individual biological variation in sweat chloride concentrations in CF, CFTR dysfunction, and healthy pediatric subjects.

BACKGROUND: The sweat test is one of the main diagnostic tools used in newborn screening programs and as a confirmatory test, in case of suspect of Cystic Fibrosis (CF). Since sweat chloride (Cl) concentration is also considered an appropriate parameter to explore the efficacy of CFTR modulators in clinical trials, it is crucial to evaluate the biological variability of this test in healthy and pathological conditions. The aim of this pilot study was to determine the intra-individual biological variability of sweat Cl, both in healthy individuals and CF patients and to assess its correlation with diet, season, and menstrual cycle. METHODS: Thirty-five out of 36 selected subjects (6-18 years) were enrolled by 2 CF care centers and assigned to 3 cohorts: CF, CFTR-related disorder (CFTR-RD) and healthy volunteers. Each participant was subjected to eight sweat tests in different conditions and time of the year. Data were analyzed using linear mixed effects models for repeated measures, taking also into account intra-individual correlations. RESULTS: We observed a high intra-individual variability of sweat Cl, with the lowest mean CV% values among CF patients (20.21 in CF, 29.74 in CFTR-RD, and 31.15 in healthy subjects). Gender and diet had no influence on sweat Cl variability, nor had pubertal age and menstrual phase. CONCLUSION: Results of this pilot study confirmed that sweat Cl variability is high in CF patients, although non-CF individuals displayed even higher mean CV% values. Season significantly influenced sweat test values only in CF patients, likely due to changes in their hydration status.

Quantitative Real Time PCR assessment of hormonal receptors and HER2 status on fine-needle aspiration pre-operatory specimens from a prospectively accrued cohort of women with suspect breast malignant lesions.

OBJECTIVES: Reliable assessment of estrogen, progesterone (ER and PR), and HER2 receptor status are essential in breast cancer (BC) treatment. Immunohistochemical methods are limited by intra- and inter-laboratory variability. Furthermore, current methods are not the ideal approach for reproducing the biological continuum of ER, PR, and HER2 receptor levels, due to their intrinsic, semi-quantitative nature, relying in part on subjective interpretation. METHODS: In the present study, we tested a molecular approach to define ER, PR, and HER2 status in fine-needle-aspirate (FNA) samples from patients with early BC. We performed flow cytometry analysis on 88 FNA specimens from suspect BC patients to determine cellularity. We used quantitative Real Time PCR (QRT-PCR) to assess ER, PR, HER2 status, and qPCR for HER2 gene copy number (GCN). RESULTS: ER and PR mRNA levels showed a highly significant correlation with IHC data on surgical samples. qPCR showed greater accuracy than IHC in defining HER2 status. QRT-PCR defined better than IHC the continuous spectrum of the expression of the assessed receptors. Moreover, PCR analysis demonstrated a strict correlation between HER2 status and higher levels of its transcript, correctly stratifying HER2+ and HER2- patients. Finally, there was a strongly significant agreement between HER2 GCN assessed on FNA specimens by qPCR and FISH data obtained on pathological tissue specimens. CONCLUSIONS: The present results support a comprehensive approach to determine ER, PR, and HER2 status by PCR (QRT-PCR and qPCR) in FNA specimens, with high relevance for therapeutic strategies like neoadjuvant treatment.

Evaluating treatment response of chronic myeloid leukemia: emerging science and technology.

Chronic myeloid leukemia (CML) is a hematological disease accounting for about 15-20% of all adult leukemias. The clinical and biologic advances achieved in such a malignancy, represent one of the best successes obtained by translational medicine. Indeed, identification of the fusion oncogene BCR-ABL has allowed using of small molecule inhibitors of its tyrosine kinase activity which, in turn, have literally revolutionized the treatment of CML. Importantly the successfully clinical management was also realized on appropriate diagnosis, disease monitoring as well as early identification of such mutations causing drug resistance. Notably the recent availability of refined laboratory equipments represented by the Next Generation Sequencing (NGS) and genomic analyses has further contributed to gain ground towards the cure of this tumor. These issues are discussed here together with an overview on how patients treated with tyrosine kinase inhibitors should be monitored.

Tracking molecular relapse of chronic myeloid leukemia by measuring Hedgehog signaling status.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of a leukemic stem cell (LSC) clone, carrying a Philadelphia translocation, able to overcome the non-malignant hematopoietic stem cells. The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib are gold-standard for CML treatment. Each shows an impressive rate of complete cytogenetic response in chronic phase (CP)-CML. However, relapse and treatment failure are major problems with long-term use of TKIs. A polymerase chain reaction (PCR) assay to detect the mRNA expression of BCR-ABL1 represents the main molecular approach to monitoring response to treatment. However, using this analysis it is currently not possible to prospectively identify patients whose disease will relapse due to LSC reappearance. The aim of our study was to investigate whether the mRNA expression analysis of two Hedgehog (Hh) stemness signaling molecules, Smoothened (SMO) and Patched-1 (PTCH1), could predict upcoming molecular relapse. At the time of diagnosis, patients with high Sokal risk (n = 12) showed higher and lower levels of SMO and PTCH1, respectively (p = 0.0132), compared with patients with different Sokal scores (p = 0.0316 for intermediate risk and p = 0.0340 for low risk). These data suggest that Hh signaling was functionally more active in this risk group at the time of diagnosis. Furthermore, the kinetics of Hh signaling activity during the individual medical history correlated with BCR-ABL1 mRNA level and with upcoming molecular relapse. Also, mutation analysis of BCR-ABL1 revealed that activation of Hh signaling precedes molecular relapse by several months, mostly in patients carrying the gatekeeper mutation T315I. Importantly, in vitro data showed a synergistic effect of chemical inhibitors of Hh signaling and TKIs in both wild-type and resistant (T315I) CML cell lines. Collectively our data show that monitoring Hh pathway activity contemporaneously with BCR-ABL1 mRNA level may improve the chance of early detection of patients who will experience a relapse (mainly in the high Sokal risk group), paving the way for an innovative management of this hematologic malignancy.

Engagement of CD31 delivers an activating signal that contributes to the survival of chronic lymphocytic leukaemia cells.

The present study showed that engagement of CD31 delivers a survival signal in chronic lymphocytic leukaemia (CLL) cells. We describe two groups of CLL, showing different kinetics of apoptosis in vitro and distinct ratios between anti-apoptotic and pro-apoptotic proteins: CLL-I displayed low Bcl-x(L) /Bax and Bcl-2/Bax ratio and underwent rapid apoptosis in vitro; CLL-II had high Bcl-x(L) /Bax and Bcl-2/Bax ratio and were resistant to apoptosis for several days. Nurse-like cells, expressing vimentin, CD68 and CD31 were detected mainly in CLL-II cultures. Of note, CD31 cross-linking, obtained with a specific monoclonal antibody (mAb), induced phosphatidylinositol-3-kinase-dependent Akt phosphorylation and nuclear translocation of the nuclear factor-kBp65 and p52 subunits in both CLL groups, leading to upregulation of Bcl-2 and Bcl-x(L) transcription and increased cell survival. Binding to CD31(+) stable transfectants, could also deliver an anti-apoptotic signal in B cells of both CLL-I and CLL-II, increasing the Bcl-2 and Bcl-x(L) protein content, regardless the expression of CD38. On the other hand, the addition of the F(ab')2 (that is unable to oligomerize the target molecule) of the anti-CD31 mAb prevented these effects. These data suggest that the CD31 adhesion system may play a role also in vivo in maintaining CLL survival.

Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as alpha-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies.

Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.

Ras-induced resistance to lapatinib is overcome by MEK inhibition.

Lapatinib, a dual HER2 and EGFR tyrosine kinase inhibitor is highly active in HER2+ breast cancer. However, its efficacy is limited by either primary or acquired resistance. Although mutations in ras genes are rarely found in breast cancer, H-ras overexpression is frequently observed. Moreover, genetic alterations that do not directly involve ras such as Brk amplification, ultimately result in increased ras signaling. Using SKBR3 cells, a HER2+ breast cancer cell line that is naturally devoid of mutations in PI3KCA, PTEN, BRAF, and ras we show that both H-ras overexpression and expression of an oncogenic ras allele (ras V12) reduce susceptibility to lapatinib in analogy to what observed with activating PI3KCA mutations and with a constitutively active form of Akt. Importantly, we found that resistance to lapatinib due to ras overexpression or to ras V12 is overcome by MEK inhibition with U0126, suggesting a key role for the MEK-Erk pathway in ras-induced resistance. Similar results were obtained in BT474 cells, another HER+ breast cancer cell line. Therefore, our data indicate that overexpressed/mutated ras may act as a biological modifier of the response to lapatinib. Combining MEK inhibitors with lapatinib may help overcome this form of resistance and increase the efficacy of lapatinib in these tumors.