School-based physical activity interventions: which intervention characteristics are associated with participation and retention? A meta-analysis.

OBJECTIVE: Many school-based intervention studies are conducted to increase students' physical activity (PA). Recruitment and retention problems potentially impact the robustness of RCT findings. We conducted a meta-analysis to summarize recruitment and retention rates in long-term secondary school-based PA intervention studies and examined associated participant and intervention characteristics. METHODS: Web of Science, Pubmed, Medline, and PsychInfo were searched until March 20th 2023. We included studies on secondary school-based PA interventions ≥12 weeks, aimed at typically developing adolescents. We abstracted number of schools and students invited, randomized, and participating at follow-up to calculate pooled recruitment and retention rates; participant and intervention characteristics were abstracted to execute subgroup or meta-regression analyses. RESULTS: Recruitment rates were 51% for invited schools and 80% for invited students, the retention for schools was almost 100% and for students 91%. Interventions with fixed and flexible components, executed in Asia and South America, and from later publication years had higher student recruitment rates. Students' retention rates were lower for interventions which had flexible components, were theory/model-based, used an accelerometer, had a longer intervention duration, and included more females. CONCLUSION: Recruitment and retention rates in school-based PA interventions are high. Some participant and intervention characteristics influence these rates: flexibility of the intervention, theory/model-based intervention, accelerometer use, intervention duration, continent, and number of females. Researchers should consider these characteristics in intervention development to achieve optimal balance between intervention effectiveness, recruitment, and retention.

Mycoplasma pneumoniae Compared to Streptococcus pneumoniae Avoids Induction of Proinflammatory Epithelial Cell Responses despite Robustly Inducing TLR2 Signaling.

Mycoplasma pneumoniae and Streptococcus pneumoniae are the most common bacterial causes of pneumonia in children. The clinical characteristics of pneumonia differ significantly between the two bacteria. We aimed to elucidate the differences in pathogenesis between M. pneumoniae and S. pneumoniae by characterizing the respiratory epithelial cell immune response to both pathogens. Using primary human bronchial epithelial cells in air-liquid interface cultures, we observed lower production of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in response to M. pneumoniae than to S. pneumoniae. In contrast to the differences in proinflammatory cytokine production, Toll-like receptor 2 (TLR2)-mediated signaling in response to M. pneumoniae was stronger than to S. pneumoniae. This difference largely depended on TLR1 and not TLR6. We found that M. pneumoniae, but not S. pneumoniae, also induced signaling of TLR10, a coreceptor of TLR2 that has inhibitory properties. M. pneumoniae-induced TLR10 signaling on airway epithelial cells was partially responsible for low IL-8 production, as blocking TLR10 by specific antibodies increased cytokine production. M. pneumoniae maintained Th2-associated cytokine production by epithelial cells, which concurs with the known association of M. pneumoniae infection with asthma. M. pneumoniae left IL-33 levels unchanged, whereas S. pneumoniae downregulated IL-33 production both under homeostatic and Th2-promoting conditions. By directly comparing M. pneumoniae and S. pneumoniae, we demonstrate that M. pneumoniae avoids induction of proinflammatory cytokine response despite its ability to induce robust TLR2 signaling. Our new findings suggest that this apparent paradox may be partially explained by M. pneumoniae-induced signaling of TLR2/TLR10.

Correction to: Exploring the association between whole blood Omega-3 Index, DHA, EPA, DPA, AA and n-6 DPA, and depression and self-esteem in adolescents of lower general secondary education.

The original version of this article unfortunately contained a mistake. Title was incorrect.

Multi-component meningococcal serogroup B (MenB)-4C vaccine induces effective opsonophagocytic killing in children with a complement deficiency.

Vaccination against meningococcal serogroup B is recommended for patients with a complement deficiency; however, although immunogenicity in this patient group has been shown, efficacy has not yet been established. In this study, we collected serum from children with a complement deficiency in the alternative pathway or in late terminal pathway before and after vaccination with multi-component meningococcal serogroup B (MenB)-4C. MenB-4C is a multi-component, protein-based vaccine against MenB consisting of factor H-binding protein, Neisserial heparin-binding protein, Neisserial adhesion A and outer membrane vesicles containing Porin A. We assessed the vaccine immunogenicity and vaccine-mediated protection by a whole cell enzyme-linked immunosorbent assay with Neisseria meningitidis serogroup B strains H44/76, 5/99 and NZ98/254, which shows that vaccination induced antibody titers against meningococcus. We show that the classical serum bactericidal activity assay with exogenous serum indicates the presence of vaccine-induced antibodies and capacity to activate complement-mediated pathogen lysis. However, in children with a late terminal pathway deficiency, no complement-mediated pathogen lysis was observed when autologous serum was applied in the serum bactericidal activity assay, demonstrating a lack of serum bactericidal activity in children with complement deficiencies. However, MenB-4C vaccination still induced effective complement-dependent opsonophagocytic killing against N. meningitidis serogroup B in reconstituted whole blood with autologous serum from children with an alternative pathway or late terminal pathway deficiency. These findings support the recommendation to vaccinate all complement-deficient children against MenB.

Exploring the association between whole blood Omega-3 Index, DHA, EPA, DHA, AA and n-6 DPA, and depression and self-esteem in adolescents of lower general secondary education.

PURPOSE: Depression is common in adolescents and long-chain polyunsaturated fatty acids (LCPUFA) are suggested to be associated with depression. However, research in adolescents is limited. Furthermore, self-esteem has never been studied in relation to LCPUFA. The objective here was to determine associations of depression and self-esteem with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), Omega-3 Index (O3I), n-6 docosapentaenoic acid (n-6 DPA, also called Osbond acid, ObA), n-3 docosapentaenoic acid (DPA), and arachidonic acid (AA) concentrations in blood of adolescents attending lower general secondary education (LGSE). METHODS: Baseline cross-sectional data from a krill oil supplementation trial in adolescents attending LGSE with an O3I ≤ 5% were analysed using regression models built with the BayesFactor package in R. Fatty acids and O3I were determined in blood. Participants filled out the Centre for Epidemiologic Studies Depression (CES-D) scale and the Rosenberg Self-Esteem scale (RSE). RESULTS: Scores indicative of depression (CES-D ≥ 16) were found in 29.4% of the respondents. Of all fatty acids, we found extreme evidence [Bayes factor (BF) > 100] for a weak negative association between ObA and depression score [- 0.16; 95% credible interval (CI) - 0.28 to - 0.04; BF10 = 245], and substantial evidence for a weak positive association between ObA and self-esteem score (0.09; 95% CI, - 0.03 to 0.20; BF10 = 4). When all fatty acids were put in one model as predictors of CES-D or RSE, all of the 95% CI contained 0, i.e., no significant association. CONCLUSION: No evidence was found for associations of DHA, EPA and O3I with depression or self-esteem scores in LGSE adolescents with O3I ≤ 5%. The associations of higher ObA status with lower depression and higher self-esteem scores warrant more research.

Bone augmentation followed by implant surgery in the edentulous mandible: A systematic review.

Long-standing loss of natural teeth in the mandible can lead to severe jaw atrophy and even mandibular fracture. There is no consensus on the best pre-prosthetic surgical treatment to reconstruct the atrophic edentulous mandible. The purpose of this review was to provide an overview of the existing literature and to give an evidence-based recommendation for bone grafting and future research. This systematic review was conducted according to the PRISMA statement. A literature search was performed in online databases Pubmed and Cochrane library for articles published between January 1980 and September 2017. The search was conducted using Medical Subject Heading terms: alveolar ridge augmentation; mouth, edentulous and mandible. Eligible articles were included according to in- and exclusion criteria and assessed on quality. Dental implant survival and bone stability were the primary outcomes. Secondary outcomes were complications. Twenty-four text articles matched the criteria and were included. Eleven articles were assessed to be of adequate quality for analysis. Graft stability seems to be higher in vertical distraction and tent-pole grafting, but as the dental implant survival is high (91.7% or higher) regardless of the procedure used for bone augmentation, this is of no clinical relevance. The survival rate of dental implants is high, regardless of the bone augmentation procedure used. High-quality clinical trials are needed to support the current evidence and guidelines on pre-implant bone grafting. Reporting of future research should include proper baseline characteristics and treatment description, as well as uniform outcome rendering.

The Healthy Primary School of the Future: study protocol of a quasi-experimental study.

BACKGROUND: Unhealthy lifestyles in early childhood are a major global health challenge. These lifestyles often persist from generation to generation and contribute to a vicious cycle of health-related and social problems. This design article presents a study evaluating the effects of two novel healthy school interventions. The main outcome measure will be changes in children's body mass index (BMI). In addition, lifestyle behaviours, academic achievement, child well-being, socio-economic differences, and societal costs will be examined. METHODS: In close collaboration with various stakeholders, a quasi-experimental study was developed, for which children of four intervention schools (n = 1200) in the southern part of the Netherlands are compared with children of four control schools (n = 1200) in the same region. The interventions started in November 2015. In two of the four intervention schools, a whole-school approach named 'The Healthy Primary School of the Future', is implemented with the aim of improving physical activity and dietary behaviour. For this intervention, pupils are offered an extended curriculum, including a healthy lunch, more physical exercises, and social and educational activities, next to the regular school curriculum. In the two other intervention schools, a physical-activity school approach called 'The Physical Activity School', is implemented, which is essentially similar to the other intervention, except that no lunch is provided. The interventions proceed during a period of 4 years. Apart from the effectiveness of both interventions, the process, the cost-effectiveness, and the expected legal implications are studied. Data collection is conducted within the school system. The baseline measurements started in September 2015 and yearly follow-up measurements are taking place until 2019. DISCUSSION: A whole-school approach is a new concept in the Netherlands. Due to its innovative, multifaceted nature and sound scientific foundation, these integrated programmes have the potential to form a template for primary schools worldwide. The effects of this approach may extend further than the outcomes associated with well-being and academic achievement, potentially impacting legal and cultural aspects in our society. TRIAL REGISTRATION: The study protocol was registered in the database ClinicalTrials.gov on 14-06-2016 with the reference number NCT02800616 .

Assessment of a molecular diagnostic platform for integrated isolation and quantification of mRNA in whole blood.

Implementation of point-of-care tests may facilitate the health management of infectious diseases by reducing the timeframe on pathogen identification and host response measurements, allowing for immediate diagnosis and guided clinical intervention. In this feasibility study, a novel totally integrated and fully automated real-time polymerase chain reaction (PCR) platform (Idylla™, Biocartis) was assessed to determine the mRNA expression levels of multiple genes from 1 mL of whole blood. To this purpose, a sample-in result-out assay, including mRNA extraction and RT-qPCR-based detection, was ported to the platform. The genes used (matrix metallopeptidase 9, olfactomedin 4, NB1 glycoprotein and lipocalin 2) were previously identified as predictive for severity of disease caused by infection with respiratory syncytial virus (RSV). The reproducibility and robustness of the prototype assay was determined using the blood samples of 21 healthy donors. The data showed that the Idylla™ platform allows for a fast and user-friendly determination of the relative expression levels of the four selected mRNA markers.

What makes fixation of femoral neck fractures fail? A systematic review and meta-analysis of risk factors.

INTRODUCTION: This systematic review aims to provide an overview of predictors for failure of treatment of displaced femoral neck fracture (dFNF) with internal fixation and quantify their risk of fixation failure in a meta-analysis. PATIENTS AND METHODS: PubMed, Embase, Web of Science, Cochrane Library, and EMCare were searched for original studies published from January 2000, including adult patients with an internally fixated dFNF, that reported data on predictors for fixation failure defined as revision surgery due to non-union, avascular femoral head necrosis or cut-out of implant. RevMan version 5 software was used to pool univariable Odds Ratio's (OR) for predictors of fixation failure by means of a random effects model. RESULTS: This review included 16 articles (15 articles cohort studies and one randomised trial). Twenty-four predictors for fixation failure were identified and analysed, 16 of which were evaluated in just one study. Data of 7 predictors were pooled in a meta-analysis. Female sex (OR 1.78, 95% confidence interval [CI] 1.26-2.52), smoking (OR 3.64, 95% CI 1.68-7.91), age >50 years (OR 3.64, 95% CI 1.68-7.91), inadequate fracture reduction (OR 2.28, 95% CI 1.62-3.22), fixation with cannulated screws (CS) or pins compared to fixed angle devices (OR 2.16, 95% CI 1.03-4.54) were identified as significant predictors for fixation failure. CONCLUSION: This study can help surgeons to choose the preferred treatment for patients with a dFNF and substantiate future algorithms and guidelines for treatment of FNF.

Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations.

OBJECTIVES: The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. METHODS: Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined. RESULTS: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01). CONCLUSION: We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.

Effective generation of tumor-infiltrating lymphocyte products from metastatic non-small-cell lung cancer (NSCLC) lesions irrespective of location and previous treatments.

Background: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Because current treatment regimens show limited success rates, alternative therapeutic approaches are needed. We recently showed that treatment-naïve, stage I/II primary NSCLC tumors contain a high percentage of tumor-reactive T cells, and that these tumor-reactive T cells can be effectively expanded and used for the generation of autologous tumor-infiltrating T cell (TIL) therapy. Whether these promising findings also hold true for metastatic lesions is unknown yet critical for translation into the clinic. Materials and methods: We studied the lymphocyte composition using flow cytometry from 27 metastatic NSCLC lesions obtained from different locations and from patients with different histories of treatment regimens. We determined the expansion capacity of TILs with the clinically approved protocol, and measured their capacity to produce the key pro-inflammatory cytokines interferon-γ, tumor necrosis factor and interleukin 2 and to express CD137 upon co-culture of expanded TILs with the autologous tumor digest. Results: The overall number and composition of lymphocyte infiltrates from the various metastatic lesions was by and large comparable to that of early-stage primary NSCLC tumors. We effectively expanded TILs from all metastatic NSCLC lesions to numbers that were compatible with TIL transfusion, irrespective of the location of the metastasis and of the previous treatment. Importantly, 16 of 21 (76%) tested TIL products displayed antitumoral activity, and several contained polyfunctional T cells. Conclusions: Metastatic NSCLC lesions constitute a viable source for the generation of tumor-reactive TIL products for therapeutic purposes irrespective of their location and the pre-treatment regimens.

A newly discovered human pneumovirus isolated from young children with respiratory tract disease.

From 28 young children in the Netherlands, we isolated a paramyxovirus that was identified as a tentative new member of the Metapneumovirus genus based on virological data, sequence homology and gene constellation. Previously, avian pneumovirus was the sole member of this recently assigned genus, hence the provisional name for the newly discovered virus: human metapneumovirus. The clinical symptoms of the children from whom the virus was isolated were similar to those caused by human respiratory syncytial virus infection, ranging from upper respiratory tract disease to severe bronchiolitis and pneumonia. Serological studies showed that by the age of five years, virtually all children in the Netherlands have been exposed to human metapneumovirus and that the virus has been circulating in humans for at least 50 years.

Intrinsic defects and dopants in LiNH2: a first-principles study.

The lithium amide (LiNH(2)) + lithium hydride (LiH) system is one of the most attractive light-weight materials options for hydrogen storage. Its dehydrogenation involves mass transport in the bulk (amide) crystal through lattice defects. We present a first-principles study of native point defects and dopants in LiNH(2) using density functional theory. We find that both Li-related defects (the positive interstitial Li(i)(+) and the negative vacancy V(Li)(-)) and H-related defects (H(i)(+) and V(H)(-)) are charged. Li-related defects are most abundant. Having diffusion barriers of 0.3-0.5 eV, they diffuse rapidly at moderate temperatures. V(H)(-) corresponds to the [NH](2-) ion. It is the dominant species available for proton transport with a diffusion barrier of ∼0.7 eV. The equilibrium concentration of H(i)(+), which corresponds to the NH(3) molecule, is negligible in bulk LiNH(2). Dopants such as Ti and Sc do not affect the concentration of intrinsic defects, whereas Mg and Ca can alter it by a moderate amount. Ti and Mg are easily incorporated into the LiNH(2) lattice, which may affect the crystal morphology on the nano-scale.

Host biomarkers and paediatric infectious diseases: from molecular profiles to clinical application.

Infectious diseases are an important cause of death among children under the age of 5 (Stein et al., 2004). Most of these deaths are caused by preventable or curable infections. Limited access to medical care, antibiotics, and vaccinations remains a major problem in developing countries. But infectious diseases also continue to be an important public health issue in developed countries. With the help of modern technologies, some infections have been effectively controlled; however, new diseases such as SARS and West Nile virus infections are constantly emerging. In addition, other diseases such as malaria, tuberculosis, and bacterial pneumonia are increasingly resistant to antimicrobial treatment.

'Nonagenarians' with a hip fracture: is a different orthogeriatric treatment strategy necessary?

Nonagenarians differ from patients aged 70-79 and 80-89 years in baseline characteristics, complication and mortality rates. Differences increased gradually with age. The results of this study can be used, in combination with the Almelo Hip Fracture Score, to deliver efficiently targeted orthogeriatric treatment to the right patient group. PURPOSE: In previous literature, elderly with a hip fracture are frequently defined as ≥ 70 years. However, given the ageing population and the rapidly increasing number of 'nonagenarians' (aged ≥ 90 years), the question rises whether this definition is still actual. The aim of this study is to determine whether nonagenarians show differences compared to patients aged 70-79 years and patients aged 80-89 years in terms of patient characteristics, complications and mortality rate. METHODS: From April 2008 until December 2016, hip fracture patients aged ≥ 70 years treated according to our orthogeriatric treatment model were included. Patients were divided into three different groups based on age at admission: 70-79 years, 80-89 years and ≥ 90 years. Patient characteristics, risk of early mortality, complications and outcomes were analysed. Risk factors for 30-day mortality in nonagenarians were determined. RESULTS: A total of 1587 patients were included: 465 patients aged 70-80 years, 867 patients aged 80-90 years and 255 patients aged ≥ 90 years. Nonagenarians were more often female and had a lower haemoglobin level at admission. Prefracture, they were more often living in a nursing home, were more dependent in activities of daily living and mobility and had a higher risk of early mortality calculated with the Almelo Hip Fracture Score (AHFS). Post-operative, nonagenarians suffer significantly more often from delirium and anaemia. The 30-day mortality and 1-year mortality were significantly higher. Differences increased gradually with age. CONCLUSION: Nonagenarians differ from patients aged 70-79 and 80-89 years in baseline characteristics, complication and mortality rates. Differences increased gradually with age. The results of this study can be used, in combination with the Almelo Hip Fracture Score, to deliver efficiently targeted orthogeriatric treatment to the right patient group.

COVID-19 response in low- and middle-income countries: Don't overlook the role of mobile phone communication.

Estimates of health capacities in the context of the coronavirus disease 2019 (COVID-19) pandemic indicate that most low- and middle-income countries (LMICs) are not operationally ready to manage this health emergency. Motivated by worldwide successes in other infectious disease epidemics and our experience in Sub-Saharan Africa, we support mobile phone communication to improve data collection and reporting, communication between healthcare workers, public health institutions, and patients, and the implementation of disease tracking and subsequent risk-stratified isolation measures. Programmatic action is needed for centrally coordinated reporting and communication systems facilitating mobile phones in crisis management plans for addressing the COVID-19 pandemic in LMICs. We summarize examples of worldwide mobile phone technology initiatives that have enhanced patient care and public health outcomes in previous epidemics and the current COVID-19 pandemic. In addition, we provide an overview of baseline conditions, including transparency about privacy guarantees, necessary for the successful use of mobile phones in assisting in the fight against COVID-19 spread.

Effect of one year krill oil supplementation on depressive symptoms and self-esteem of Dutch adolescents: A randomized controlled trial.

INTRODUCTION: Observational studies have shown a relationship between omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) and depression in adolescents. However, n-3 LCPUFA supplementation studies investigating the potential improvement in depressive feelings in adolescents from the general population are missing. METHODS: A one-year double-blind, randomized, placebo controlled krill oil supplementation trial was conducted in two cohorts. Cohort I started with 400 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or placebo, after three months this increased to 800 mg EPA and DHA per day, whilst cohort II started with this higher dose. Omega-3 Index (O3I) was monitored via finger-prick blood measurements. At baseline, six and 12 months participants completed the Centre for Epidemiologic Studies Depression Scale (CES-D) and the Rosenberg Self Esteem questionnaire (RSE). Adjusted mixed models were run with treatment allocation/O3I as predictor of CES-D and RSE scores. RESULTS: Both intention-to-treat and assessing the change in O3I analyses did not show significant effects on CES-D or RSE scores. CONCLUSION: There is no evidence for less depressive feelings, or higher self-esteem after one year of krill oil supplementation. However, due to a lack of adherence and drop-out issues, these results should be interpreted with caution.

Validation of 70-gene prognosis signature in node-negative breast cancer.

PURPOSE: The 70-gene prognosis signature (van't Veer et al., Nature 415(6871):530-536, 2002) may improve the selection of lymph node-negative breast cancer patients for adjuvant systemic therapy. Optimal validation of prognostic classifiers is of great importance and we therefore wished to evaluate the prognostic value of the 70-gene prognosis signature in a series of relatively recently diagnosed lymph node negative breast cancer patients. METHODS: We evaluated the 70-gene prognosis signature in an independent representative series of patients with invasive breast cancer (N = 123; <55 years; pT1-2N0; diagnosed between 1996 and 1999; median follow-up 5.8 years) by classifying these patients as having a good or poor prognosis signature. In addition, we updated the follow-up of the node-negative patients of the previously published validation-series (Van de Vijver et al., N Engl J Med 347(25):1999-2009, 2002; N = 151; median follow-up 10.2 years). The prognostic value of the 70-gene prognosis signature was compared with that of four commonly used clinicopathological risk indexes. The endpoints were distant metastasis (as first event) free percentage (DMFP) and overall survival (OS). RESULTS: The 5-year OS was 82 +/- 5% in poor (48%) and 97 +/- 2% in good prognosis signature (52%) patients (HR 3.4; 95% CI 1.2-9.6; P = 0.021). The 5-years DMFP was 78 +/- 6% in poor and 98 +/- 2% in good prognosis signature patients (HR 5.7; 95% CI 1.6-20; P = 0.007). In the updated series (N = 151; 60% poor vs. 40% good), the 10-year OS was 51 +/- 5% and 94 +/- 3% (HR 10.7; 95% CI 3.9-30; P < 0.01), respectively. The DMFP was 50 +/- 6% in poor and 86 +/- 5% in good prognosis signature patients (HR 5.5; 95% CI 2.5-12; P < 0.01). In multivariate analysis, the prognosis signature was a strong independent prognostic factor in both series, outperforming the clinicopathological risk indexes. CONCLUSION: The 70-gene prognosis signature is also an independent prognostic factor in node-negative breast cancer patients for women diagnosed in recent years.

Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).

BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. OBJECTIVE: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype-phenotype correlations in ICF patients. METHODS: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. RESULTS AND CONCLUSIONS: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n = 41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n = 39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype-phenotype correlation was found between patients with and without DNMT3B mutations.