Onset In Early Life Research Articles

Comparison of Longitudinal Outcomes in Children with Primary Ciliary Dyskinesia and Cystic Fibrosis.

Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are both genetic diseases of mucociliary clearance resulting in progressive lung disease with onset in early life. PCD is often considered to be milder in childhood than CF, based on minimal evidence. Similar to CF, genotype-phenotype associations exist in PCD: pathogenic variants in CCDC39 and CCDC40, causing inner dynein arm/microtubular defects (IDA/MTD) are associated with more severe disease. To compare longitudinal outcomes in matched children with PCD and CF. We hypothesized that children with PCD with IDA/MTD defects would have lower lung function but better nutritional indices than matched children with CF with minimal function genotypes (i.e., those associated with pancreatic insufficiency). Children with PCD enrolled in a prospective, multicenter, observational study were matched with CF patients from the CF Foundation Patient Registry by birth cohort, age, sex, race/ethnicity and year of study visit. The association of disease group overall and by severity class (PCD-IDA/MTD versus all other defects and CF-minimal versus residual function) with longitudinal outcomes up to age 17 was evaluated with cubic spline mixed effects models. Groups included 136 children with PCD (40 IDA/MTD, 96 other) and 476 with CF (446 minimal function, 30 residual function). Below age 14, the PCD group had similar or lower estimated mean FEV1 % predicted compared to CF (e.g., at age 10, -5.4 % predicted lower (95% CI: -7.7, -3.1)). Compared to the CF-minimal function (pancreatic insufficient) group, the PCD-IDA/MTD group had similar BMI; estimated mean FEV1 % predicted was significantly lower by age 10 (mean difference -10.6% (95% CI: -14.7, -6.4), increasing to -15.7% (95% CI: -20.3, -11.2) at age 14. The CF cohort had increased prevalence of Pseudomonas aeruginosa cultured on one or more occasions compared to children with PCD (67% vs 27%, p<0.001); there was no difference in prevalence of P. aeruginosa between children with PCD-IDA/MTD and PCD-other. In childhood, average lung function abnormalities in PCD are not milder than CF, particularly for those with IDA/MTD ciliary defects. New guidelines and treatments to improve outcomes in PCD are urgently needed.

Functioning and neurocognition in very early and early-life onset bipolar disorders: the moderating role of bipolar disorder type.

Defining homogeneous subgroups of bipolar disorder (BD) is a major goal in personalized psychiatry and research. According to the neurodevelopmental theory, age at onset may be a key variable. As potential trait markers of neurodevelopment, cognitive and functional impairment should be greater in the early form of the disease, particularly type 1 BD (BD I). The age at onset was assessed in a multicenter, observational sample of 4190 outpatients with BD. We used a battery of neuropsychological tests to assess six domains of cognition. Functioning was measured using the Functioning Assessment Short Test (FAST). We studied the potential moderation of the type of BD on the associations between the age at onset and cognitive and functioning in a subsample of 2072 euthymic participants, controlling for potential clinical and socio-demographic covariates. Multivariable analyses showed cognition to not be impaired in individuals with early (21-30years) and very early-life (before 14years) onset of BD. Functioning was equivalent between individuals with early and midlife-onset of BD II and NOS but better for individuals with early onset of BD I. In contrast, functioning was not worse in individuals with very early-onset BD I but worse in those with very early-onset BD II and NOS. Early-life onset BDs were not characterized by poorer cognition and functioning. Our results do not support the neurodevelopmental view that a worse cognitive prognosis characterizes early-life onset BD. This study suggests that functional remediation may be prioritized for individuals with midlife-onset BD I and very early life onset BD 2 and NOS.

The Italian breakthrough in CRISPR trials for rare diseases: a focus on beta-thalassemia and sickle cell disease treatment.

The development of gene therapy and the current advantageous method of clustered regularly interspaced short palindromic repeats (CRISPRs) has allowed the implementation of several clinical trials aimed at studying the possible efficacy of gene therapy for rare diseases. Rare diseases pose a global challenge, in that their collective impact on health systems is considerable, whereas their individually rare occurrence hinders research and development of efficient therapies. Despite the low prevalence of individual rare diseases, there are more than 7,000 defined rare diseases affecting 3.5–5.9% of the global population. Rare diseases are mostly chronic and approximately 80% are caused by genetic mutation with an early-life onset. In Italy, in 2021 were recorded more than 400,000 people with rare disease. Because of its location and history, Italy has an unfortunate statistic regarding the presence and prevalence of two rare genetic diseases, namely beta-thalassemia, of which there are about 90 million carriers worldwide, 400,000 of whom are actually affected, and sickle cell disease, with about 300 million carriers and 6.5 million people affected worldwide. Advancements in genomic studies allowed Italy to join clinical trials to study effective and resolving gene therapies for BT and SCD. This study reports on the impact of rare diseases in Italy, ongoing studies, and recent achievements in BT and SCD trials using the CRISPR method and remaining hurdles in the application of CRISPR technology to rare diseases, also taking a glimpse at the newest challenges and future opportunities in the genetic treatment for rare diseases.

Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

STAT6 (Signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning 3 continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies and anaphylaxis. The cases were either sporadic (7 kindreds) or followed an autosomal dominant inheritance pattern (3 kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Two Perspectives on Dravet Syndrome: Viewpoints from the Clinician and the Caregiver.

Dravet syndrome (DS) is a severe genetic epilepsy characterized by early-life onset, seizures, and neurodevelopmental delays that have major impacts on affected children. DS is an incurable condition that requires a lifelong multidisciplinary approach involving both clinical and caregiver support. A better understanding of the multiple perspectives involved in the care of patients is necessary for supporting the diagnosis, management, and treatment of DS. Here we describe the personal experiences of a caregiver and a clinician facing the challenges of diagnosing and treating a patient throughout the three phases of DS. During the initial phase, the main goals include establishing an accurate diagnosis, coordination of care, and communication between clinicians and caregivers. After a diagnosis is established, frequent seizures and developmental delays are a major concern in the second phase, which is very taxing on children and their caregivers, so caregivers require support and resources to advocate for safe and effective care. Seizures may improve in the third phase, but developmental, communication, and behavioral symptoms persist as caregivers navigate the eventual transition from pediatric to adult care. Optimal care for patients is provided when clinicians are well educated on the syndrome and collaboration is established between members of the medical team and family.

Epithelial cell responses to rhinovirus identify an early-life–onset asthma phenotype in adults

The study of pathogenic mechanisms in adult asthma is often marred by a lack of precise information about the natural history of the disease. Children who have persistent wheezing (PW) during the first 6 years of life and whose symptoms start before age 3 years (PW+) are much more likely to have wheezing illnesses due to rhinovirus (RV) in infancy and to have asthma into adult life than are those who do not have PW (PW-). Our aim was to determine whether nasal epithelial cells from PW+ asthmatic adults as compared with cells from PW- asthmatic adults show distinct biomechanistic processes activated by RV exposure. Air-liquid interface cultures derived from nasal epithelial cells of 36-year old participants with active asthma with and without a history of PW in childhood (10 PW+ participants and 20 PW- participants) from the Tucson Children's Respiratory Study were challenged with a human RV-A strain (RV-A16) or control, and their RNA was sequenced. A total of 35 differentially expressed genes involved in extracellular remodeling and angiogenesis distinguished the PW+ group from the PW- group at baseline and after RV-A stimulation. Notably, 22 transcriptomic pathways showed PW-by-RV interactions; the pathways were invariably overactivated in PW+ patients, and were involved in Toll-like receptor- and cytokine-mediated responses, remodeling, and angiogenic processes. Asthmatic adults with a history of persistent wheeze in the first 6 years of life have specific biomolecular alterations in response to RV-A that are not present in patients without such a history. Targeting these mechanisms may slow the progression of asthma in these patients.

Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids.

Neurodevelopmental disorders (NDDs) are a collection of diseases with early life onset that often present with developmental delay, cognitive deficits, and behavioral conditions. In some cases, severe outcomes such as brain malformations and intractable epilepsy can occur. The mutations underlying NDDs may be inherited or de novo, can be gain- or loss-of-function, and can affect one or more genes. Recent evidence indicates that brain somatic mutations contribute to several NDDs, in particular malformations of cortical development. While advances in sequencing technologies have enabled the detection of these somatic mutations, the mechanisms by which they alter brain development and function are not well understood due to limited model systems that recapitulate these events. Human brain organoids have emerged as powerful models to study the early developmental events of the human brain. Brain organoids capture the developmental progression of the human brain and contain human-enriched progenitor cell types. Advances in human stem cell and genome engineering provide an opportunity to model NDD-associated somatic mutations in brain organoids. These organoids can be tracked throughout development to understand the impact of somatic mutations on early human brain development and function. In this review, we discuss recent evidence that somatic mutations occur in the developing human brain, that they can lead to NDDs, and discuss how they could be modeled using human brain organoids.

Neck Circumference, a Screening Tool for Obesity in Newly Pubescent Children-A Case Study

“Childhood Obesity and its co-morbidities is considered as a prime health hitch that lay up consideration among the public health society. Obesity and above the over weight has bagged the fifth position in the global risk for mortality. The obesity shows a very early onset in life which has laid the utmost importance in the prevention of it among the children. Neck circumference is being considered as the marker of upper body subcutaneous tissue distribution.&#x0D; Aim: The main objective is to evaluate the association between neck circumference and obesity among the children.&#x0D; Methodology: This is a cross sectional study conducted between the periods of august 2019 - September 2019, among 150 male + 129 female students, aged 11 to 18 years. Anthropometric markers of obesity- body mass index (BMI), waist circumference (WC), Hip circumference (HC), waist hip ratio (WHR), neck circumference (NC) were collected. Pearson’s correlation coefficient was used to compute the neck circumference with other obesity indices.&#x0D; Results: The mean BMI was 27.70±1.27 kg/m² and 27.72±2.12 kg/m², mean neck circumference was 35.42±2.26 cm and 32.85±1.92 in above the over weight /obesity boys + girls respectively. The hip circumference in boys was found to be greater than girls, which is higher in above the over weight /obesity students with P&lt;0.001. Neck circumference shows a strong positive correlation with other anthropometric measures BMI, WC, HC in boys and girls (P&lt;0.001).&#x0D; Conclusion: The present study showed that the weight increase in school children and need to aware the parents.

Impaired metabolic health over-time and high abdominal fat are prospectively associated with high-sensitivity C-reactive protein in children: The IDEFICS study.

Metabolic risk and inflammatory state have an early life onset and are associated with future diseases. To assess the association between metabolic syndrome (MetS) and metabolic health with high-sensitive C-reactive protein (hsCRP), cross-sectionally and longitudinally, in children. 2913 European children (2-10 years) from eight countries from the IDEFICS study were investigated. Data were collected at baseline and 2 years later (follow-up). A MetS z-score was computed with waist circumference (WC), insulin resistance index, blood pressure, high-density lipoprotein cholesterol and triglycerides. Metabolically unhealthy (MU) status was assessed. Multi-level linear and logistic regressions were performed. Among the MetS markers, WC was more consistently associated with hsCRP cross-sectional and prospectively. Baseline MetS score was significantly associated with greater risk of high hsCRP at follow-up and with prevalence and incidence of hsCRP. Those children who became MU overtime were significantly (P < .05) associated with future higher levels of hsCRP, independently of weight status at baseline. Transition over time to a MU state was associated with higher levels of hsCRP at follow-up, independent of weight status at baseline. Screening of metabolic factors and routine measurement of WC are needed to prevent inflammatory status and related chronic diseases in children.

Long-Term Social Isolation Reduces Expression of the BDNF Precursor and Prolyl Endopeptidase in the Rat Brain

Early-life stress is a risk factor for the development of behavioral and cognitive disorders in humans and animals. Such stressful situations include social isolation in early postnatal ontogenesis. Behavioral and cognitive impairments associated with neuroplastic changes in brain structures. We have found that after ten weeks of social isolation, male Wistar rats show behavioral abnormalities and cognitive deficit, accompanied by an increase in the relative expression of gene encoding serine protease prolyl endopeptidase (PREP, EC 3.4.21.26) in the brain frontal cortex. The present study aimed to assess synaptophysin (SYP), brain-derived neurotrophic factor precursor (proBDNF), and PREP expression using Western blot in the brain structures – the hippocampus, frontal cortex, and striatum of the rats subjected to prolonged social isolation compared with group-housed animals. Twenty Wistar rats were used for this study (10 males and 10 females). Experimental animals (5 males and 5 females) were kept one per cage for nine months, starting from the age of one month. Ten-month-old socially isolated rats showed memory deficit in passive avoidance paradigm and Morris Water Maze and reactivity to novelty reduction. We used monoclonal antibodies for the Western blot analysis of the expression of SYP, proBDNF, and PREP in the rat brain structures. Social isolation caused a proBDNF expression reduction in the frontal cortex in females and a reduction in PREP expression in the striatum in males. These data suppose that neurotrophic factors and PREP are involved in the mechanisms of behavioral and cognitive impairments observed in the rats subjected to prolonged social isolation with an early life onset.

025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex

Abstract Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

Hypopigmented macules in neurofibromatosis type 1: A case control study

To the Editor: Neurofibromatosis type 1 (NF1) is an autosomal dominant, neurocutaneous disorder. In most cases, cutaneous pigmentary manifestations are the main diagnostic clue. NF1 is characterized by hyperpigmentation—café au lait macules (CALMs), skinfold freckling, and melanotic plexiform neurofibromas. However, hypopigmented lesions have received little attention in patients with NF1. Riccardi1Riccardi V.M. Neurofibromatosis and Albright's syndrome.Dermatol Clin. 1987; 5: 193-203Abstract Full Text PDF PubMed Google Scholar described the presence of hypopigmented macules (HMs) in approximately 2% to 3% of patients with NF1 in 1987. Studies regarding the physiopathology of HM in NF1 are lacking. This study aimed to characterize the prevalence of HMs in our pediatric patients diagnosed with NF1. A case-control prospective study design was used to compare the prevalence of HMs in 108 patients diagnosed with NF1 (younger than 18 years) and 137 healthy age-matched control individuals. All patients included in the cases cohort had a confirmed diagnosis of NF1. We required a third National Institutes of Health criterion or genetic testing in children who exclusively showed CALMs and skinfold freckling. The patients were enrolled from October 2014 to January 2017. We also assessed the number, location, size, and morphology of HMs in our patients. Well-circumscribed lesions, those with early onset in life, and stable hypomelanosis were considered HMs. Patients with postinflammatory hypomelanosis and other possible causes of hypopigmentation as well as vitiligo or nevus anemicus (NA) were excluded. All HMs became erythematous after rubbing, unlike NA. All participants signed informed consent. We observed that 13.9% (n = 15) of patients showed HMs. In the control group 4.4% (n = 6) children presented with HMs. The prevalence of HMs in the cases group was significantly higher than in the control group (Pearson chi-square test P value = .008). Demographic and clinical characteristics are shown in Table I. The HM sizes ranged from 0.5 to 9 cm, and all presented with well-defined or sharp margins (Fig 1 and Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/6w3g76nyxr.2). Parents recalled the presence of HMs from birth in 4 (22.2%) children.Table IDemographic and clinical characteristicsClinical featuresPatients with NF1 (N = 108)Control individuals (N = 137)HMs, n (%)15 (13.9)6 (4.4)Age when HMs first noticed, y Mean4.24.7 Range0-103-13Sex, n (%)P = .132P = 1 Male9 (60)3 (50) Female6 (40)3 (50)Distribution Solitary, n (%)12 (80)6 (100) Range1-2 Mean ± SD1.2 ± 0.41Location, n (%) Thorax6 (40)3 (50) Legs5 (33.3)1 (16.6) Abdominal3 (20)0 Arms2 (13.3)1 (16.6) Lumbar1 (6.6)1 (16.6) Neck1 (6.6)0Size, cm, n (%) <14 (22.2)2 (33.3) 1-513 (72.2)4 (66.6) >51 (5.6)0Morphology, n (%) Ash-leaf6 (33.3)0 Rounded5 (27.8)3 (50) Oval5 (27.8)3 (50) Polygonal2 (11.1)0HM, Hypopigmented macule; SD, standard deviation. Open table in a new tab HM, Hypopigmented macule; SD, standard deviation. Although CALMs are present in almost all patients with NF1, the prevalence of circumscribed hypomelanosis has not been characterized. The differential diagnosis for HMs included tuberous sclerosis complex (TSC) hypomelanotic macules, NA, vitiligo, pityriasis alba, postinflammatory hypopigmentation, and piebaldism. The simultaneous occurrence of NF1 and TSC in a single individual is extremely rare,2Samanta D. Bosanko K.B. Zarate Y.A. An infant with ash-leaf and café au lait spots: a case of double phakomatosis.Acta Neurol Belg. 2016; 117: 323-324Crossref PubMed Scopus (1) Google Scholar and our patients did not show other signs of TSC. The HMs observed in patients with NF1 fulfilled the Coupe clinical diagnostic criteria and could be considered nevus depigmentosus (ND).3Coupe R.L. Unilateral systematized achromic naevus.Dermatology. 1967; 134: 19-35Crossref Scopus (40) Google Scholar,4Kim S.K. Kang H.Y. Lee E.S. Kim Y.C. Clinical and histopathologic characteristics of nevus depigmentosus.J Am Acad Dermatol. 2006; 55: 423-428Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar ND is the best characterized congenital, stable throughout life, well-circumscribed hypopigmented lesion.3Coupe R.L. Unilateral systematized achromic naevus.Dermatology. 1967; 134: 19-35Crossref Scopus (40) Google Scholar ND occurs in approximately 0.4% to 0.7% of infants,5Baselga E. Disorders of hypopigmentation.in: Schachner L.A. Hansen R.C. Pediatric Dermatology. 4th ed. Mosby Elsevier, Philadelphia, PA2012: 719-722Google Scholar so the HM prevalence in our series (13.9%) was higher than expected. Thus, our results suggest a statistical relationship between NF1 and HMs (P < .008). However, the pathophysiologic explanation of the higher prevalence of HMs in the NF1 population remains unknown. We conclude that HMs are a common finding in NF1. This finding could be either a coincidence or truly associated with NF1. Basic research investigations are needed to achieve a better knowledge of HM physiopathology.

Variable immunodeficiency study: Evaluation of two European cohorts within a variety of clinical phenotypes

IntroductionGiven the wide heterogeneity of common variable immunodeficiency (CVID), several groups have proposed clinical and immunological classifications to better define follow-up and prognostic algorithms. The present study aims to validate recent clinical and laboratory algorithms, based on different combinations of CVID biomarkers, to provide more personalized treatment and follow-up strategies. MethodsWe analysed clinical and immunological features of 80 patients with suspected or diagnosed CVID, in two reference centres of Portugal and Spain. Clinical manifestations were categorized into clinical phenotyping proposed by Chapel et al. [1] that included cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications. Results76% of patients in our cohort entered one of the four categories of clinical phenotyping, without overlap (cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications). The most prominent phenotype was “cytopenia” (40%) followed by “polyclonal lymphocytic infiltration” (19%). The remaining 24% patients of our cohort had overlap of 2 clinical phenotypes (cytopenia and unexplained enteropathy mainly). A delay of CVID diagnosis in more than 6 years presented 3.7-fold higher risk of developing lymphoproliferation and/or malignancy (p < 0.05), and was associated with increased CD8+CD45RO + T-lymphocytes (p < 0.05). An association between decreased switched-memory B cells with lymphoproliferation and malignancy was observed (p < 0.03 and p < 0.05, respectively). CD4 + T-lymphocytopenia correlated with autoimmune phenotype, with 30% prevalence (p < 0.05). HLA-DR7 expression was related to CVID onset in early life in our patients (13 vs 25 years), and DQ2.5 or DQ2.2 with unexplained enteropathy (p < 0.05). ConclusionsThe phenotypic and genetic study is crucial for an adequate clinical orientation of CVID patients. In these two independent cohorts of patients, classification based in clinical and laboratory algorithms, provides more personalized treatment and follow-up strategies.

The association between Open Dialogue to young Danes in acute psychiatric crisis and their use of health care and social services: A retrospective register-based cohort study

BackgroundAlthough most mental disorders have their onset in early life, the mental health needs of young people are often not addressed adequately. Open Dialogue is a need-adapted approach that mobilizes psychosocial resources in a crisis struck person’s social network. Open Dialogue is organised as a series of network meetings and seeks to promote collaborative integrated care, and a non-directive psychotherapeutic stance. Its effectiveness for young people has not previously been assessed. ObjectivesThe aim of the study was to examine whether a Danish Open Dialogue approach directed at young people, who sought help from Child and Adolescent Mental Health Services, reduced their utilisation of psychiatric and other health services, compared to peers receiving usual psychiatric treatment. DesignA retrospective register-based cohort study. MethodsUsing clinical and national register data, a cohort of patients aged 14–19 years (n = 503) enrolled from one region during 2000 to 2015 were compared to a matched comparison group from two other regions using propensity scores. Utilisation of psychiatric health services, GP services, and social markers were assessed after 1, 2, 5 and 10 year of follow-up using logistic and Poisson regression models. ResultsPatients receiving Open Dialogue intervention had more psychiatric outpatient treatments at one year of follow-up (RR = 1.2, CI: 1.1–1.4) than the comparison group, but not at subsequent follow-ups. Recipients of the intervention had fewer emergency psychiatric treatments (1 year follow-up: RR = 0.2, CI: 0.1-0.5; 10 years follow-up: RR = 0.5, CI: 0.3-0.8) and less use of general practitioner services (1 year follow-up: RR = 0.90, CI: 0.82-0.99; 10 years follow-up: RR = 0.85, CI: 0.78-0.92). There was no significant reduction in the number of psychiatric hospitalisation contacts or treatment days. ConclusionsOpen Dialogue was significantly associated with some reduced risks of utilising health care services. These mixed results should be tested in a randomized design.

Carrier screening. Disease prevention vs cost effectiveness

Patients come to fertility specialists to increase the probability of having a healthy child. According to the Online Mendelian Inheritance of Man there are nearly 24,000 heritable disease and phenotypes with which physicians and patients must contend. The American College of Obstetricians and Gynecologists have recently published committee opinions which add expanded carrier screening as an acceptable and recommended method of preconception screening. This allows traditional methods of ethnic based screening to be supplanted by more universal methods. In the face of data which shows that self-reported ethnicity can change with time and is impacted by the individual's culture, religion, language, behavior and psychology, this takes an uncertain factor off the table for patients and providers. Further, in the era of increased cost efficiency in genomic medicine, expanded carrier screening presents an increasingly cost effective method of preconception counseling. The curation of these panels needs to be an area of great focus and continued maintenance. It is recommended that these conditions have a carrier frequency of >1:100, have a well-defined phenotype, have a detrimental effect on quality of life, cause cognitive or physical impairment, require surgical or medical intervention, and have early onset in life. As we continue to discover new genetic causes of disease these panels will inevitably evolve. The identification of carrier status in couples allows for enhanced clinical decisions to be made. This includes options such as preimplantation genetic diagnosis, use of donor gametes, adoptions, or even a discussion about discontinuing effort to build a family. Traditionally utilization of PGD in at risk couples has been low given the limits of IVF including time, low success rates, high cost, and multiple gestation risk. However, with modern IVF, many of these concerns are greatly diminished allowing for more access to couples to this technology. For the clinician, this paradigm which avoids the need for ethnic based assessment allows for improved liability coverage and presents a cost effective approach to care when the cost of traditional screening methods in addition to the healthcare savings when heretofore undiagnosed carrier states result in an affected child are calculated. Reducing the burden to both patients and providers will likely lead to continued increased utilization in preconception care.

Ankylosing Spondylitis and Pregnancy: A Literature Review.

Ankylosing Spondylitis (AS) is the prototype of a group of systemic rheumatic diseases collectively referred to as Spondylarthitides (SpA). It has now become clear that AS is not as rare as previously thought and, although it has an early onset in life affecting patients in their reproductive years, it has not been proved to adversely affect fertility in females. The aim of this review is to summarize all the recent data on AS and pregnancy in terms of fertility, disease course and pregnancy outcome from a clinical perspective. A literature research was conducted based on the following medical databases: Pubmed/ Medline and the Cochrane Library. We searched for randomized controlled studies, casecontrol studies, cohort studies, patient and drug registers in relation to pregnancy and AS. The existing data do not support a causal relationship between AS and infertility. The state of pregnancy is not associated with reduced disease activity in patients with AS. Additionally, AS tends to adversely affect health-related quality of life during pregnancy, in comparison with normal population and patients with rheumatoid arthritis. As far as the obstetrical outcome is concerned, there is no consensus on the significant association between AS and specific pregnancy, delivery and fetal complications. Previous studies are highly heterogenous and mainly retrospective and thus, the existing data are controversial and inconclusive. Subsequent studies are required to enlighten our knowledge on the interaction between AS and pregnancy.

Using consented health record linkage in a longitudinal cohort study

ABSTRACT&#x0D; ObjectivesThe aim of this project is to address important issues relevant to children’s health This will be done by enhancing information collected in the longitudinal, UK-wide Millennium Cohort Study (MCS) by linking participating children to their routine health records. These issues include: health service implications of early life onset of obesity and overweight; timeliness of immunisations; association of infections with asthma and allergic disorders in childhood; and burden of disease due to childhood injuries.&#x0D; ApproachThe MCS comprises information on the social, economic and health-related circumstances of children surveyed at ages 9 months, 3, 5, 7, 11 and 14 years. At the age 7 interview, 12517 (89.1%) of the 14043 adults with parental responsibility consented for information from their child’s routine heath records to be released to the MCS (a).&#x0D; Routine health records have been requested for Wales, England and Scotland to be linked to MCS responses within the Secure Anonymised Information Linkage Databank at Swansea University. Data will be analysed using weights for non-response, non-consent and non-linkage and the linkage reported according to the RECORD guidelines (b).&#x0D; ResultsTo date, all 1881 MCS children with valid consent who live or have lived in Wales have been linked by assigning an Anonymous Linking Field (ALF) to each individual which can be mapped across multiple datasets without risk of identification (c). Of these children, 1365 (72.3%) had experienced at least one hospital admission by the age of 14 years. Risk of admission by each of the survey ages for boys and girls separately will be calculated adjusting for non-response at different sweeps. These children have also been linked to their immunisation records (n = 1872), Emergency Department attendances (n = 1276), and available GP records (n = 1151) to enable analyses in fulfilment of the project objectives.&#x0D; ConclusionsRoutine health records are a potentially valuable enhancement to longitudinal studies, allowing evaluation of questions of relevance to public health and health services, and the completeness and consistency of records from these different sources to be addressed.&#x0D; Referencesa. Shepherd, P. (2013) Consent to linkage to child health data ISBN 978-1-906929-59-6b. Benchimol, E.I. et al (2015) DOI: 10.1371/journal.pmed.1001885 c. Ford, D.V. et al (2009) DOI: 10.1186/1472-6963-9-157

Interventions in the health and non-health sectors aimed at promoting mental health

The impact of social determinants on women's mental health is becoming clearer worldwide. Poverty, violence and communal insecurity are among the main challenges to women's mental health and the health of their families. Depression is one of the most common mental disorders experienced by women. It typically has an early onset in life and is more frequently found in women made vulnerable by trauma.Improving mental health for women and girls requires early intervention for depression and other mental disorders; with gender sensitive clinical care and support for recovery in primary health care, and mother, child and reproductive health settings. Early intervention in primary health care and collaboration with patients and family carers encourage integration of mental health with the health care system, in turn protective of human rights.In addition, gender equity and observance of human rights need to be embedded in policy and practice in health and non-health sectors to ensure that women's mental health is promoted and mental illnesses adequately prevented and treated. Effective promotion of mental health and prevention of mental disorders is possible in countries of all income levels.Disclosure of interestThe author has not supplied his declaration of competing interest.

Familial Hemophagocytic Lymphohistiocytosis (FHL), Report of two Unique Cases

Familial hemophagocytic lymphohistiocytosis (FHLH) is a rare genetic disorder associated with early onset in life with overwhelming activation of T lymphocytes and macrophages invariably leading to death. We present two cases of FHLH admitted to our hospital at different points of time. First child presented with multiple episodes of GTCS and high grade fever. There was a history of sibling death before. He was having hepatosplenomegaly with leucopenia, hyper-triglyceridemia, hyper-ferritinemia and bone marrow revealed abundant hemophagocytes in smear. Second case was a 6 month male with complaint of (Generalised Tonic Clonic Seizure (GTCS) with past history of repeated attacks of acute Respiratory Infection and neuroinfection. Previous sibling died in similar presentation. He was having hepatosplenomegaly, leucopenia, hyper triglyceridemia, hyper ferritinemia with abundant hemophagocytes in bone marrow smear. Both the cases were diagnosed as FHLH and treated according to protocol.Nepal Paediatr Soc 2015;35(3):283-286