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Neurotrophins (NTs) are four small proteins produced by both neuronal and non-neuronal cells; they include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). NTs can exert their action through both genomic and non-genomic mechanisms by interacting with specific receptors. Initial studies on NTs have identified them only as functional molecules of the nervous system. However, recent research have shown that some tissues and organs (such as the lungs, skin, and skeletal and smooth muscle) as well as some structural cells can secrete and respond to NTs. In addition, NTs perform several roles in normal and pathological conditions at different anatomical sites, in both fetal and postnatal life. During pregnancy, NTs are produced by the mother, placenta, and fetus. They play a pivotal role in the pre-implantation process and in placental and embryonic development; they are also involved in the development of the brain and respiratory system. In the postnatal period, it appears that NTs are associated with some diseases, such as sudden infant death syndrome (SIDS), asthma, congenital central hypoventilation syndrome (CCHS), and bronchopulmonary dysplasia (BPD).

Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.

BACKGROUND: Menstrual symptoms are predominantly studied among adults but may occur directly after menarche. Adolescent menstrual healthcare, however, faces specific obstacles and more research into menstrual symptoms as a determinant of adolescent well-being is therefore advocated. OBJECTIVE: This study aimed to investigate menstrual symptoms and their impact on everyday life and well-being among postmenarchal adolescents. STUDY DESIGN: A survey was delivered to a random sample of 1644 schoolgirls, drawn from a population-based project involving 116 lower secondary education schools (7th and 8th grade) in Stockholm, Sweden. Menstrual symptoms (ie, dysmenorrhea, heavy bleeding, irregular periods, mood disturbance, other general symptoms) were investigated through multiple choice questions and defined according to their impact on everyday life as mild (seldom affected), moderate (affected but possible to cope) and severe (affected and difficult to cope). Subjective well-being was measured with the World Health Organization Five Well-Being index. Postmenarchal respondents were eligible for analysis; those with incomplete outcome data or using hormonal contraception were excluded. The frequency and severity of symptoms across different postmenarchal years (1st, 2nd, 3rd, 4th, or 5th+ year after menarche) were studied with Chi-square and Kendall's tau statistics. Analysis of variance was used to study the association between menstrual symptoms and World Health Organization Five Well-Being index scores. A composite menstrual health index variable was obtained through principal component analysis and used to study the overall impact of menstrual symptoms on well-being in regression analyses. RESULTS: Of 1100 postmenarchal girls (mean age, 14.1±0.7 years), 93.2% reported menstrual symptoms, 81.3% had at least 1 moderate symptom and 31.3% had at least 1 severe symptom. The most frequent symptoms were dysmenorrhea (80.4%) and mood disturbance (81.1%), followed by irregular periods (67.9%), heavy bleeding (60.4%), and other general symptoms (60.4%). Throughout postmenarchal years, there was a significant increase in frequency and severity (P

We report a case of a 40-day-old patient admitted to the neonatal and paediatric intensive care unit for severe cardiovascular failure with an initial sinus rhythm. The first diagnostic hypothesis was septic shock, thus antibiotics, fluid resuscitation, inotropic drugs and ventilatory supportwere immediately started. After achieving haemodynamic stability, a new cardiovascular failure occurred with supraventricular tachycardia (SVT), making diagnosis of cardiogenic shock. Cardiogenic shock should be considered, although it is a rare cause of shock in children. SVT may be a cause of cardiogenic shock, therefore it should be diagnosed whit the aid of a cardiorespiratory monitor, which represents a useful device in the differential diagnosis of the various types of shock.

Abstract Conservative management of endometrial cancer (CMEC) is viable for women with early-stage disease wishing to preserve fertility, but there is poor knowledge regarding clinicians’ attitudes towards treatment or guidelines adherence. This 55-item survey study investigated CMEC-related experience, practice and attitudes among clinically active Swedish gynecologists and gynecological oncologists, focusing on reproductive eligibility criteria. The survey consisted of a general and two specific subsets, selectively delivered to clinicians active in infertility (subset A) and endometrial cancer (subset B) care. Answers from 218 clinicians were included. More than half agreed on CMEC whereas only 5% explicitly disagreed. The majority supported a fertility work-up to substantiate reasonable chances to pregnancy and live birth. Most disagreed about CMEC in case of previous unsuccessful fertility treatments, while more than 1/3 disagreed about CMEC in known fertility problems, recurrent miscarriages or previous children. Over 50% of respondents in subset A (n = 107) found it applicable with fertility investigations such as ovarian reserve testing or, in case of male partner, semen analysis. Respondents in subset B (n = 165) agreed on items based on existing recommendations regarding the oncological management of CMEC, including the use of continuous progestins, hysteroscopic resection of macroscopic lesions, control biopsy with curettage or hysteroscopy after 6 months of treatment, pursuing pregnancy as soon as possible after complete response, and performing a hysterectomy once live birth is achieved. While many clinicians were familiar with CMEC, the overall experience is limited. Fertility specialists seem less involved than oncologists in patient care but there is broad support for fertility-related eligibility criteria.

Abstract Oocytes can be effectively cryopreserved and stored for future use in in-vitro fertilisation. Oocyte cryopreservation (OC) can therefore mitigate different threats to female fertility, but attitudes and policies often seem more favourable in medical rather than age-related fertility preservation scenarios. The value of OC for potential candidates may be perceived differently depending on the indications, although relevant empirical data are lacking. An adequately powered sample of Swedish female university students (n = 270; median age 25; range 19–35) were randomly delivered a medical (n = 130) or age-related (n = 140) fertility preservation scenario within an online survey. Sociodemographic factors, reproductive experiences, and awareness about OC were not significantly different between the groups. Differences in four outcomes were studied: proportions of respondents (1) positive to the use of OC, (2) positive to public funding for OC, or (3) open to considering OC; and (4) willingness-to-pay (WTP) for OC, measured in thousand Swedish krona (K SEK) through contingent valuation. There were no significant differences in the proportions of respondents positive to the use of OC (medical: 96%; age-related: 93%) or open to consider it (medical: 90%; age-related: 88%) in each scenario. However, public funding had significantly greater support in the medical scenario (85%) than in the age-related one (64%). The median WTP (45 K SEK ≈ 4.15 K EUR) approximated the current Swedish market price for a single elective cycle and was not significantly different between the scenarios (Cliff’s delta − 0.009; 95%CI − 0.146, 0.128). These findings suggest that it may be inappropriate to justify counselling and priority policies only on the assumption that fertility preservation with OC for medical indications is more beneficial to women than when the same technique is used for age-related reasons. However, it would be interesting to investigate further why public funding appears more debatable than the treatment itself.

Pleural empyema, a severe complication of bacterial pneumonia, is a rare entity in the neonatal period. Treatment with systemic antibiotics and tube drainage may fail because of the thick viscous fluid, bacterial products with fibrin deposition, and multiple involvement. Intrapleural fibrinolytic therapy with urokinase is an effective and non-invasive treatment option that avoids surgical intervention, although its use in neonates has not been studied extensively. In this report, we describe the case of a 39-day-old male newborn with pneumonia and pleural empyema, treated successfully with antibiotics, chest tube drainage and intrapleuralurokinase.

Background: Despite the increasing interest in biologics for the management of allergic diseases, sparse real-world data are still available in the pediatric population. This study aimed to evaluate the early real-life efficacy and safety of omalizumab for patients with moderate-to-severe asthma and chronic spontaneous urticaria (CSU), and Dupilumab for patients with moderate-to-severe atopic dermatitis (AD). Methods: A prospective study enrolling children aged 6–18 years was designed to assess the efficacy and safety of biologic drugs at 16 weeks of treatment (T1). The effectiveness was measured using validated questionnaires (ACQ-5 for asthma, UAS7 for CSU, and EASI score for AD). Secondary outcome measures included reductions in inhaled corticosteroid (ICS) dosages, asthma-related hospitalizations/exacerbations, and quality of life (QoL) indicators (iNRS, sNRS, DLQI/cDLQI) for CSU and AD. Safety was expressed according to the descriptions of adverse events provided by EMA and FDA. Results: The study cohort consisted of eighteen children (mean age 12.9 ± 3.4 years). The omalizumab treatment significantly reduced ACQ-5 and UAS7 scores (p = 0.002 and p < 0.001, respectively). In patients with asthma, decreased ICS dosage and hospitalization/exacerbation rates were observed. QoL parameters significantly improved in CSU and AD patients. No severe adverse events were reported for either treatment. Conclusions: Our findings validate omalizumab and dupilumab as effective and safe therapeutic options for managing moderate-to-severe allergic diseases in children and adolescents.

Cough is one of the most common reasons leading to pediatric consultations, negatively impacting the quality of life of patients and caregivers. It is defined as a sudden and forceful expulsion of air from the lungs through the mouth, typically triggered by irritation or the stimulation of sensory nerves in the respiratory tract. This reflex is controlled by a neural pathway that includes sensory receptors, afferent nerves, the brainstem's cough center, efferent nerves, and the muscles involved in coughing. Based on its duration, cough in children may be classified as acute, lasting less than four weeks, and chronic, persisting for more than four weeks. Neuromodulators have shown promise in reducing the frequency and severity of cough by modulating the neural pathways involved in the cough reflex, although they require careful monitoring and patient selection to optimize the outcomes. This review aims to examine the rationale for using neuromodulators in the management of cough in children. [ABSTRACT FROM AUTHOR]

Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders. [ABSTRACT FROM AUTHOR]

Respiratory diseases (RDs) constitute a common public health problem both in industrialized and developing countries. The comprehension of the pathophysiological mechanisms underlying these conditions and the development of new therapeutic strategies are critical for improving the quality of life of affected patients. β2-adrenergic receptor (β2AR) and transient receptor potential vanilloid 1 (TRPV1) are both involved in physiological responses in the airways. β2AR is implicated in bronchodilation, mucociliary clearance, and anti-inflammatory effects, while TRPV1 is involved in the mediation of pain and cough reflexes. In RDs, such as respiratory infections, asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, the concentration and expression of these receptors can be altered, leading to significant consequences. In this review, we provided an update on the literature about the role of β2AR and TRPV1 in these conditions. We reported how the diminished or defective expression of β2AR during viral infections or prolonged therapy with β2-agonists can increase the severity of these pathologies and impact the prognosis. Conversely, the role of TRPV1 was pivotal in neuroinflammation, and its modulation could lead to innovative treatment strategies in specific patients. We indicate future perspectives and potential personalized treatments in RDs through a comprehensive analysis of the roles of these receptors in the physiological and pathological mechanisms of these pathologies. [ABSTRACT FROM AUTHOR]

NR5A1 gene mutations are associated principally to 46,XY DSD (Disorders of Sex Development), with an extensive range of phenotypic variability in patients, comprising gonadal dysgenesis and male infertility. NR5A1 gene plays a crucial role in reproduction, steroidogenesis, and sexual differentiation. The present case describes an Italian male adolescent with ambiguous genitalia at birth and a 46,XY karyotype who was investigated for DSD genetic panel conditions due to slow pubertal progression. A heterozygous variant in NR5A1 (NM_004959.4: c.937CT, p.Arg313Cys) was identified in this patient and in his father. The same variant was previously described in other studies showing the wide heterogeneity of genotype-phenotype correlation in DSD patients.

Sleep is a fundamental biological necessity, the lack of which has severe repercussions on the mental and physical well-being in individuals of all ages. The phrase “sleep-disordered breathing (SDB)” indicates a wide array of conditions characterized by snoring and/or respiratory distress due to increased upper airway resistance and pharyngeal collapsibility; these range from primary snoring to obstructive sleep apnea (OSA) and occur in all age groups. In the general pediatric population, the prevalence of OSA varies between 2% and 5%, but in some particular clinical conditions, it can be much higher. While adenotonsillar hypertrophy (“classic phenotype”) is the main cause of OSA in preschool age (3–5 years), obesity (“adult phenotype”) is the most common cause in adolescence. There is also a “congenital–structural” phenotype that is characterized by a high prevalence of OSA, appearing from the earliest ages of life, supported by morpho-structural abnormalities or craniofacial changes and associated with genetic syndromes such as Pierre Robin syndrome, Prader-Willi, achondroplasia, and Down syndrome. Neuromuscular disorders and lysosomal storage disorders are also frequently accompanied by a high prevalence of OSA in all life ages. Early recognition and proper treatment are crucial to avoid major neuro-cognitive, cardiovascular, and metabolic morbidities.

Following the recent acquisition of unprecedented anatomical details through state-of-the-art neuroimaging, stereotactic procedures such as microelectrode recording (MER) or deep brain stimulation (DBS) can now rely on direct and accurately individualized topographic targeting. Nevertheless, both modern brain atlases derived from appropriate histological techniques involving post-mortem studies of human brain tissue and the methods based on neuroimaging and functional information represent a valuable tool to avoid targeting errors due to imaging artifacts or insufficient anatomical details. Hence, they have thus far been considered a reference guide for functional neurosurgical procedures by neuroscientists and neurosurgeons. In fact, brain atlases, ranging from the ones based on histology and histochemistry to the probabilistic ones grounded on data derived from large clinical databases, are the result of a long and inspiring journey made possible thanks to genial intuitions of great minds in the field of neurosurgery and to the technical advancement of neuroimaging and computational science. The aim of this text is to review the principal characteristics highlighting the milestones of their evolution.

BackgroundSuicide is a leading cause of death among adolescents and more knowledge from high risk groups is needed in order to develop effective preventive strategies. The aim of this study was to evaluate the association between sexual minority status and suicidality in a multinational sample of European school pupils.MethodsA self-report questionnaire was delivered to 2046 adolescents (mean age 15.34±1.01; 56.3% females) recruited from 27 randomly selected schools in 6 European countries. Suicidal ideation, measured with the Paykel Suicide Scale (PSS), and lifetime suicide attempts were compared between heterosexual and sexual minority (i.e. those with a non-heterosexual orientation) youth. Poisson regression analyses studied the longitudinal association between sexual minority status and the rate of serious suicidal ideation, measured at three time-points during a 4-month period. Several variables, including alcohol and illegal drugs use, bullying, family interaction, school-related stress, economic status, and religiosity, were included in multivariable analysis. Sex-stratified analyses evaluated the association respectively among females and males.ResultsOf 1958 pupils included in analysis (mean age 15.35±1.00; females 56.8%), 214 (10.9%) were categorized as sexual minority youth (SMY). When compared to heterosexual youth (HSY), SMY were significantly more exposed to substance abuse, bullying, school-related stress, and lower economic status. SMY pupils had significantly higher suicidal ideation scores (pConclusionsEuropean sexual minority youth are a high-risk group for suicidality, independently from objective factors such as victimization or substance abuse. There is a need to develop primary and secondary preventive measures for sexual minority youth, including the management of context vulnerabilities and related distal stressors, before the establishment of proximal stressors. Context-targeting interventions may effectively focus on social and economic factors, as well as on the potentially different risk profile of female and male sexual minority youth.

Abstract in German Hintergrund Reproduktive und psychische Gesundheit sind Schlüsselbereiche des jugendlichen Wohlbefindens, aber mögliche Zusammenhänge sind kaum verstanden. Diese Querschnittsstudie untersuchte den Zusammenhang zwischen Psychopathologie und reproduktivem Gesundheitsrisiko bei europäischen Jugendlichen. Methoden: Im Rahmen des von der EU-Kommission geförderten Projektes "Saving and Empowering Young Lives in Europe" (SEYLE) wurden 12.395 Schüler von 179 zufällig ausgewählten Schulen in 11 europäischen Ländern mit einem strukturierten Fragebogen befragt. Der Fragebogen umfasste Fragen zur sexuellen Initiation und Risikofaktoren der reproduktiven Gesundheit, wie z. B. die Anzahl der Sexualpartner, Häufigkeit der Kondomnutzung und Schwangerschaften. Die psychopathologischen Auffälligkeiten wurden mit validierten Instrumenten und / oder Ad-hoc-Fragen evaluiert. Ergebnisse Von 11.406 Befragten (Median 15; Interquartilbereich [IQR] 14-15; 57% Mädchen) gaben 18,8% an sexuell aktiv geworden zu sein. Sechzig Prozent von ihnen berichteten auch mindestens einen reproduktiven Risikofaktor. Sexuelle Initiation war signifikant häufiger bei Schülern, die älter als 15 Jahre waren (38% versus 13,2% jüngeren Schülern) und bei Jungen (21,3% versus 16,9% Mädchen). Eine sexuelle Initiation lag auch häufiger bei Schülern mit Depressionen (Alter / Geschlechts-adjustiertes Odds Ratio [aOR] 1.871), Angstsymptomen (aOR 2.190), schweren Suizidgedanken (aOR 2.259), selbstverletzendem Verhalten (aOR 2.892) und Selbstmordversuchen (aOR 3.091) vor. Diese Assoziationen waren besonders ausgeprägt bei Schülern ≤15 Jahren und bei deutlich auffälliger Psychopathologie bei Schülern mit geringem nicht-sexuellem Risikoverhalten und beim weiblichen Geschlecht. Depressive Symptome (aOR 1.937), Angstsymptome (aOR 2.282), schwere Suizidgedanken (aOR 2.354), selbstverletzendes Verhalten (aOR 3.022) und Suizidversuche (aOR 3.284) waren mit einem erhöhten Risiko für die reproduktive Gesundheit verbunden - definiert durch eine steigende Anzahl von koexistierenden reproduktiven Risikofaktoren. Schlussfolgerungen Diese Ergebnisse deuten auf eine Beziehung zwischen Risiken für die psychische und reproduktive Gesundheit hin und unterstützen den Wert der domänenübergreifenden Zusammenarbeit bei der Gesundheit von Jugendlichen. Der Zusammenhang zwischen Psychopathologie und reproduktivem Gesundheitsrisiko sowie seine alters- und geschlechtsspezifischen Unterschiede und damit verbundenem Risikoverhalten sollten bei der Gestaltung gesundheitsfördernder oder krankheitsvorbeugender Maßnahmen für Jugendliche berücksichtigt werden.

Background: Despite the increasing interest in biologics for the management of allergic diseases, sparse real-world data are still available in the pediatric population. This study aimed to evaluate the early real-life efficacy and safety of omalizumab for patients with moderate-to-severe asthma and chronic spontaneous urticaria (CSU), and Dupilumab for patients with moderate-to-severe atopic dermatitis (AD). Methods: A prospective study enrolling children aged 6–18 years was designed to assess the efficacy and safety of biologic drugs at 16 weeks of treatment (T1). The effectiveness was measured using validated questionnaires (ACQ-5 for asthma, UAS7 for CSU, and EASI score for AD). Secondary outcome measures included reductions in inhaled corticosteroid (ICS) dosages, asthma-related hospitalizations/exacerbations, and quality of life (QoL) indicators (iNRS, sNRS, DLQI/cDLQI) for CSU and AD. Safety was expressed according to the descriptions of adverse events provided by EMA and FDA. Results: The study cohort consisted of eighteen children (mean age 12.9 ± 3.4 years). The omalizumab treatment significantly reduced ACQ-5 and UAS7 scores (p = 0.002 and p < 0.001, respectively). In patients with asthma, decreased ICS dosage and hospitalization/exacerbation rates were observed. QoL parameters significantly improved in CSU and AD patients. No severe adverse events were reported for either treatment. Conclusions: Our findings validate omalizumab and dupilumab as effective and safe therapeutic options for managing moderate-to-severe allergic diseases in children and adolescents. [ABSTRACT FROM AUTHOR]

Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder caused mainly by loss of function variants in the NHS gene. NHS is characterized by congenital cataracts, dental anomalies, and distinctive facial features, and a proportion of the affected individuals also present intellectual disability and congenital cardiopathies. Despite identification of at least 40 distinct hemizygous variants leading to NHS, genotype-phenotype correlations remain largely elusive. In this study, we describe a Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing (WES). The affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies. Furthermore, brain imaging showed corpus callosum anomalies and periventricular leukoencephalopathy. We expand the phenotypic and mutational NHS spectrum and review potential disease mechanisms underlying the central neurological anomalies and the potential neurodevelopmental features associated with NHS.

Cardiorenal syndrome (CRS) is defined as a disorder resulting from the abnormal interaction between the heart and kidney, in which acute or chronic dysfunction of one organ may lead to acute and/or chronic dysfunction of the other. The functional interplay between the heart and kidney is characterized by a complex bidirectional symbiotic interaction, regulated by a wide array of both genetic and environmental mechanisms. There are at least five known subtypes of CRS, based on the severity of clinical features and the degree of heart/renal failure. The fourth subtype (cardiorenal syndrome type 4 (CRS4)) is characterized by a primary chronic kidney disease (CKD), which in turn leads to a decreased cardiac function. Impairment of renal function is among the most important pathophysiological factors contributing to heart failure (HF) in the pediatric age group, and cardiovascular complications could be one of the most important causes of mortality in pediatric patients with advanced CKD. In this context, a loss of glomerular filtration rate directly correlates with both the progression of cardiovascular complications in CRS and the risk of HF. This review describes the interaction pathways between the heart and kidney and the recently identified pathophysiological mechanisms underlying pediatric CRS, with a special focus on CRS4, which encompasses both primary CKD and cardiovascular disease (CVD).

Sexuality is a physiological component of adolescent development, though early initiation is associated with reproductive health risk. This study aimed at identifying correlates and predictors of sexual initiation in a large multinational cohort of European adolescents.A questionnaire addressing socio-demographics, behaviours, mental health and sexual activity, was delivered to 11,110 adolescents recruited from 168 randomly selected schools in 10 European countries between 2009 and 2011. A follow-up questionnaire was delivered after 12 months. The longitudinal association of baseline risk behaviors, psychological attributes and contextual vulnerabilities, with sexual initiation during follow-up was evaluated through simple and multivariable age/sex stratified logistic regression. Multinomial logistic regression measured the association between predictors and sexual initiation with or without coexisting reproductive risk factors, such as multiple partners or infrequent condom use.Baseline sexual experience was reported by 19.2% of 10,757 respondents (median age 15; IQR 14-15; females 59.6%). This was significantly more frequent among pupils older than 15 (41%) and males (20.8%). Of 7,111 pupils without previous experience who were available at follow-up (response rate 81.8%), 17% reported sexual initiation, without differences between females and males. Baseline smoking (age/sex adjusted odds ratio [aOR] 3.63), alcohol use (aOR 2.95), illegal drugs use (aOR 2.72), and poor sleep (aOR 1.71) predicted sexual initiation. Stratified analyses showed a particularly strong association in case of younger and female pupils, and, among girls, when initiation was reported together with multiple partners and/or infrequent condom use. Externalizing (i.e. conduct and hyperactivity) symptoms independently predicted sexual initiation. Internalizing difficulties (i.e. emotional and peer problems) were negatively associated with early and risky sexual initiation among boys. Significant predictors included also being bullied, fighting, truancy, and low parental involvement.Adolescent sexual behaviours are related to non-sexual risk behaviours, psychological difficulties and contextual vulnerabilities. While gateway effects explain some associations, a comprehensive model is needed to understand adolescent sexual behaviours, their physical, mental, and social health outcomes, and their potential positive effects on wellbeing. Tailored interventions may need to consider younger girls as a particularly vulnerable group in view of a strong association between non-sexual and sexual behaviors.