Human regulatory T cells locally differentiate and are functionally heterogeneous within the inflamed arthritic joint.

Objective: Tregs are crucial for immune regulation, and environment-driven adaptation of effector (e)Tregs is essential for local functioning. However, the extent of human Treg heterogeneity in inflammatory settings is unclear. Methods: We combined single-cell RNA- and TCR-sequencing on Tregs derived from three to six patients with juvenile idiopathic arthritis (JIA) to investigate the functional heterogeneity of human synovial fluid (SF)-derived Tregs from inflamed joints. Confirmation and suppressive function of the identified Treg clusters was assessed by flow cytometry. Results: Four Treg clusters were identified; incoming, activated eTregs with either a dominant suppressive or cytotoxic profile, and GPR56+CD161+CXCL13+ Tregs. Pseudotime analysis showed differentiation towards either classical eTreg profiles or GPR56+CD161+CXCL13+ Tregs supported by TCR data. Despite its most differentiated phenotype, GPR56+CD161+CXCL13+ Tregs were shown to be suppressive. Furthermore, BATF was identified as an overarching eTreg regulator, with the novel Treg-associated regulon BHLHE40 driving differentiation towards GPR56+CD161+CXCL13+ Tregs, and JAZF1 towards classical eTregs. Conclusion: Our study reveals a heterogeneous population of Tregs at the site of inflammation in JIA. SF Treg differentiate to a classical eTreg profile with a more dominant suppressive or cytotoxic profile that share a similar TCR repertoire, or towards GPR56+CD161+CXCL13+ Tregs with a more distinct TCR repertoire. Genes characterising GPR56+CD161+CXCL13+ Tregs were also mirrored in other T-cell subsets in both the tumor and the autoimmune setting. Finally, the identified key regulators driving SF Treg adaptation may be interesting targets for autoimmunity or tumor interventions.

T cell interaction with activated endothelial cells primes for tissue-residency.

Tissue-resident memory T cells (TRM) are suspected drivers of chronic inflammation, but their induction remains unclear. Since endothelial cells (EC) are obligate interaction partners for T cells trafficking into inflamed tissues, they may play a role in TRM development. Here, we used an in vitro co-culture system of human cytokine-activated EC and FACS-sorted T cells to study the effect of EC on T(RM) cell differentiation. T cell phenotypes were assessed by flow cytometry, including proliferation measured by CellTrace Violet dilution assay. Soluble mediators were analyzed by multiplex immunoassay. Co-culture of T cells with cytokine-activated, but not resting EC induced CD69 expression without activation (CD25, Ki67) or proliferation. The dynamic of CD69 expression induced by EC was distinct from that induced by TCR triggering, with rapid induction and stable expression over 7 days. CD69 induction by activated EC was higher in memory than naive T cells, and most pronounced in CD8+ effector memory T cells. Early CD69 induction was mostly mediated by IL-15, whereas later effects were also mediated by interactions with ICAM-1 and/or VCAM-1. CD69+ T cells displayed a phenotype associated with tissue-residency, with increased CD49a, CD103, CXCR6, PD-1 and CD57 expression, and decreased CD62L and S1PR1. EC-induced CD69+ T cells were poised for high production of pro-inflammatory cytokines and showed increased expression of T-helper 1 transcription factor T-bet. Our findings demonstrate that activated EC can induce functional specialization in T cells with sustained CD69 expression, increased cytokine response and a phenotypic profile reminiscent of TRM. Interaction with activated EC during transmigration into (inflamed) tissues thus contributes to TRM-residency priming.

Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response.

OBJECTIVE: JDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes as a novel IFN-inducible biomarker for disease activity monitoring and prediction of treatment response in patients with JDM. METHODS: Siglec-1 was measured by flow cytometry on circulating monocytes of 21 newly diagnosed JDM patients before start of treatment and, for 10 of these, also during follow-up. The expression levels of five type I IFN-stimulated genes, MX1, IFI44, IFI44L, LY6E and IFIT3, were measured by RT-qPCR to determine the IFN signature and calculate an IFN score. IFN-inducible plasma proteins CXCL10 and galectin-9 were measured by multiplex immunoassay. RESULTS: Siglec-1 and IFN score were increased in JDM patients compared with controls and correlated with clinical disease activity. Stratification of patients by Siglec-1 expression at diagnosis identified those with high Siglec-1 expression as having a higher risk of requiring treatment intensification within the first 3 months after diagnosis (55% vs 0% of patients, P = 0.01). Siglec-1 expression strongly correlated with plasma levels of previously validated biomarkers CXCL10 (rs = 0.81, P < 0.0001) and galectin-9 (rs = 0.83, P < 0.0001), and was superior to the IFN score in predicting treatment response (area under the curve 0.87 vs 0.53, P = 0.01). CONCLUSION: Siglec-1 on monocytes is a novel IFN-inducible biomarker in JDM that correlates with clinical disease activity and identifies patients at risk for a suboptimal treatment response. Further studies are required to validate these findings and their clinical potential.

Comparing machine learning to a rule-based approach for predicting suicidal behavior among adolescents: Results from a longitudinal population-based survey.

INTRODUCTION: Suicidal thoughts and suicide attempts are one of the most prominent public health concerns in adolescents and therefore early detection is important to initiate preventive interventions and closer monitoring. METHOD: We examined whether the Machine Learning models Random Forest and Lasso Regression better predict future suicidal behavior than a simple decision rule that classifies every adolescent with history of suicide ideation at baseline as at risk (current practice). We used data from a general population of students in second and fourth year of secondary education in Amsterdam, the Netherlands. RESULTS: Both the Random Forest and the Lasso Regression resulted in slightly better prediction. The AUC of the Random Forest (0.79) and Lasso regression (0.76) were both higher than the AUC of the decision rule (0.64). The Random Forest achieved slightly (but non-significantly) higher sensitivity than the decision rule (0.37 versus 0.34), with the same specificity (0.94). With Lasso Regression the sensitivity increased significantly (0.52), but at the expense of the specificity (0.85). LIMITATIONS: The loss of cases after merging the data, the use of self-reported data, confidential data collection and the use of only four questions to measure suicidal behavior. CONCLUSIONS: This is the first study applying Machine Learning techniques to predict future suicidal behavior on survey data collected in a general population of adolescents. Our study showed that integrating machine learning techniques in screening practice will result in a small improvement in the ability to predict suicide. The models need to be further optimized to improve accuracy.

Chronically Activated T-cells Retain Their Inflammatory Properties in Common Variable Immunodeficiency.

PURPOSE: Immune dysregulation complications cause significant morbidity and mortality in common variable immunodeficiency (CVID), but the underlying pathophysiology is poorly understood. While CVID is primarily considered a B-cell defect, resulting in the characteristic hypogammaglobulinemia, T-cells may also contribute to immune dysregulation complications. Here, we aim to further characterize T-cell activation and regulation in CVID with immune dysregulation (CVIDid). METHODS: Flow cytometry was performed to investigate T-cell differentiation, activation and intracellular cytokine production, negative regulators of immune activation, regulatory T-cells (Treg), and homing markers in 12 healthy controls, 12 CVID patients with infections only (CVIDio), and 20 CVIDid patients. RESULTS: Both CD4 + and CD8 + T-cells in CVIDid showed an increased activation profile (HLA-DR + , Ki67 + , IFNγ +) when compared to CVIDio, with concomitant upregulation of negative regulators of immune activation PD1, LAG3, CTLA4, and TIGIT. PD1 + and LAG3 + subpopulations contained equal or increased frequencies of cells with the capacity to produce IFNγ, Ki67, and/or GzmB. The expression of PD1 correlated with serum levels of CXCL9, 10, and 11. Treg frequencies were normal to high in CVIDid, but CVIDid Tregs had reduced CTLA-4 expression, especially on CD27 + effector Tregs. Increased migratory capacity to inflamed and mucosal tissue was also observed in CVIDid T-cells. CONCLUSION: CVIDid was characterized by chronic activation of peripheral T-cells with preserved inflammatory potential rather than functional exhaustion, and increased tissue migratory capacity. While Treg numbers were normal in CVIDid Tregs, low levels of CTLA-4 indicate possible Treg dysfunction. Combined studies of T-cell dysfunction and circulating inflammatory proteins may direct future treatment strategies.

Improvement in left ventricular ejection fraction after pharmacological up-titration in new-onset heart failure with reduced ejection fraction.

OBJECTIVE: Recent studies have reported suboptimal up-titration of heart failure (HF) therapies in patients with heart failure and a reduced ejection fraction (HFrEF). Here, we report on the achieved doses after nurse-led up-titration, reasons for not achieving the target dose, subsequent changes in left ventricular ejection fraction (LVEF), and mortality. METHODS: From 2012 to 2018, 378 HFrEF patients with a recent (< 3 months) diagnosis of HF were referred to a specialised HF-nurse led clinic for protocolised up-titration of guideline-directed medical therapy (GDMT). The achieved doses of GDMT at 9 months were recorded, as well as reasons for not achieving the optimal dose in all patients. Echocardiography was performed at baseline and after up-titration in 278 patients. RESULTS: Of 345 HFrEF patients with a follow-up visit after 9 months, 69% reached ≥ 50% of the recommended dose of renin-angiotensin-system (RAS) inhibitors, 73% reached ≥ 50% of the recommended dose of beta-blockers and 77% reached ≥ 50% of the recommended dose of mineralocorticoid receptor antagonists. The main reasons for not reaching the target dose were hypotension (RAS inhibitors and beta-blockers), bradycardia (beta-blockers) and renal dysfunction (RAS inhibitors). During a median follow-up of 9 months, mean LVEF increased from 27.6% at baseline to 38.8% at follow-up. Each 5% increase in LVEF was associated with an adjusted hazard ratio of 0.84 (0.75-0.94, p = 0.002) for mortality and 0.85 (0.78-0.94, p = 0.001) for the combined endpoint of mortality and/or HF hospitalisation after a mean follow-up of 3.3 years. CONCLUSIONS: This study shows that protocolised up-titration in a nurse-led HF clinic leads to high doses of GDMT and improvement of LVEF in patients with new-onset HFrEF.

Psychometric properties of the Dutch-Flemish PROMIS® pediatric item banks Anxiety and Depressive Symptoms in a general population.

PURPOSE: This study aims to validate the Dutch-Flemish PROMIS pediatric item banks v2.0 Anxiety and Depressive Symptoms, the short forms 8a, and computerized adaptive tests (CATs) in a general Dutch population and to provide reference data. METHODS: Participants (N = 2,893, aged 8-18), recruited by two internet survey providers, completed both item banks. These item banks were assessed on unidimensionality, local independence, monotonicity, Graded Response Model (GRM) item fit, and differential item functioning (DIF) for gender, age group, region, ethnicity, and language. The short forms and CATs were assessed on reliability and construct validity compared to the Revised Child Anxiety and Depression Scale short version (RCADS-22) subscales. Reference scores were calculated. RESULTS: Both item banks showed sufficient unidimensionality, local independence, monotonicity, and GRM item fit, except for three Depressive Symptoms items that showed insufficient GRM item fit. No DIF was found when using ordinal regression analyses, except for two Depressive Symptoms items that showed DIF for language; all items showed DIF for language when using IRT PRO, except for one Anxiety item. Both short forms and CATs revealed sufficient reliability for moderate and severe levels of anxiety and depression, as well as high positive correlations with corresponding RCADS-22 subscales and slightly lower correlations with non-corresponding RCADS-22 subscales. CONCLUSION: The Dutch-Flemish PROMIS pediatric item banks v2.0 Anxiety and Depressive Symptoms, the short forms 8a and CATs are useful to assess and monitor anxiety and depression in a general population. Reference data are presented.

Patterns and predictors of burn scar outcome in the first 12 months after burn: The patient's perspective.

OBJECTIVE: This study aimed to provide insight into the patterns and factors that predict burn scar outcomes at 3, 6 and 12 months after burn. METHODS: The Patient and Observer Scar Assessment Scale (POSAS) was used to assess the scar formation of each patient. Structural equation modelling was used. The predictor variables used in this study were sex, three age categories, TBSA, depth of the wound and cause of the burn. RESULTS: The POSAS patient total and individual item scores demonstrated a statistically significant decrease in the first 12 months after burn, except for the relief item. Male patients had a lower total and items scores (better scar quality) for pain and pruritus compared with female patients. Full thickness burns had a higher scores for pruritus, pliability, thickness and relief compared to the partial-thickness burns. Ages younger than 5 years, higher TBSA values and flame burns were predictors of various POSAS items at 3 and 6 months after burn. CONCLUSION: The POSAS patient total and individual item scores demonstrated a statistically significant improvement in the scar quality in the first 12 months after burn, except for the relief. Sex, age, depth of the wound, the percentage of TBSA and flame burns were predictors of various POSAS patient items at 3, 6 and 12 months after burn.

[A rare cause of abdominal pain in children]. / Een zeldzame oorzaak van buikpijn bij kinderen.

A 4-year-old boy was admitted to our hospital with abdominal pain, vomiting and weight loss. After a period of diarrhoea, he was now constipated. Micturition was painful but there were no abnormalities in the urine. Blood test showed no signs of infection or elevated liver enzymes. Signs of cholecystitis were seen on abdominal ultrasound, but this diagnosis was ignored because of the low incidence of cholecystitis in children and the absence of abnormal liver enzymes and infection parameters. Other diagnostic investigations were carried out, but no cause could be found for his symptoms. His condition worsened during the hospital stay, and liver enzymes and infection parameters became abnormal. An abdominal laparoscopy was finally performed, and a perforation in the presence of a necrotizing cholecystitis was seen. This case shows that one should never ignore a diagnostic report even if the diagnosis has low prevalence.

Heart failure patients' future expectations and their association with disease severity, quality of life, depressive symptoms and clinical outcomes.

BACKGROUND: Although treatment of heart failure (HF) patients has improved, prognosis still remains poor. Current HF Guidelines recommend communication about prognosis with all patients. Little is known about HF patients' awareness of their shortened life expectancy. AIM: To explore HF patients' future expectations and to examine whether these expectations are associated with disease severity, quality of life, depressive symptoms and clinical outcomes. METHOD: Patients randomised to the intervention groups of the COACH study, who were at the end of HF hospitalisation, were asked about their future expectations. Patients were divided into three groups: patients expecting improvement/stabilisation, patients expecting deterioration and those not knowing what to expect. Depressive symptoms were measured by CES-D and quality of life with the Ladder of Life and RAND-36. RESULTS: Six hundred and seventy eight patients (age 70 ± 12; 41% female patients; LVEF 33% ± 15) participated in the study. Most patients (56%, N = 380) expected improvement or stabilisation, 8% (N = 55) expected deterioration and 21% (N = 144) did not know what to expect for the future. Patients who expected to deteriorate were significantly older, experienced a lower quality of life and more depressive symptoms compared with patients in the other two groups. They also had a higher mortality rate, both after 18 and 36 months, and had more HF admissions. No association with severity of the disease (NYHA-class, LVEF, BNP levels) was found. CONCLUSION: Many hospitalised HF patients are not aware of their poor prognosis. Depressive symptoms, poor quality of life, increased mortality and rehospitalisation were related to expected deterioration. Improvement of communication about prognosis with HF patients is needed in the future.

Three-dimensional imaging: a novel, valid, and reliable technique for measuring wound surface area.

PURPOSE: The aim of this study was to investigate the validity and reliability of a novel three-dimensional imaging technique using Artec MHT™ 3D Scanner for measuring the wound surface area. METHODS: The validity was tested by measuring the surface area of 60 stickers (gold standard) on 20 volunteers. Stickers with standardized areas of 2590, 7875, and 15,540 mm2 were applied on the thorax, forearm, and thigh, respectively. For the reliability test, 58 burn wounds on 48 patients were assessed twice by two different observers with the Artec MHT™ 3D Scanner. Scanning, post-processing, and surface area measurements were performed by two clinicians. RESULTS: The results for the validity analysis showed an intraclass correlation coefficient of 0.99 and coefficient of variation of the thorax, forearm, and thigh were 1.1%, 0.9%, and 0.6%, respectively. The reliability analysis showed an intraclass correlation coefficient of 0.99, a coefficient of variation of 6.3%, and limits of agreement between measurements of two observers were calculated at 0 ± 0.17 × mean surface area. CONCLUSION: Three-dimensional imaging using the Artec MHT™ 3D Scanner is a valid and reliable method for measuring the wound surface area.

The effect of pre-operative blood withdrawal, with or without sequestration, on allogeneic blood product requirements.

UNLABELLED: A common effect of autologous blood withdrawal before cardiopulmonary bypass (CPB) is a decrease in haematocrit (Hct) and haemoglobin (Hb) content. A refinement of this technique is autologous blood withdrawal with the sequestration of platelet rich plasma (PRP) and red blood cells (RBCs). METHODS: One hundred and four patients were included in a randomized study stratified into three groups: the autologous blood withdrawal group (Group 1), the autologous blood withdrawal group with blood loss sequestration (Group 2) and the control group (Control group). In Group 1, the amount of withdrawn blood was transfused after CPB. In Group 2, the RBCs were transfused immediately after sequestration and the PRP was transfused after the termination of CPB. In the Control group, no autologous blood withdrawal was employed. The following variables were analysed: blood loss, blood products transfusion, fluid transfusion, diuresis, haematological and coagulation data and the duration of the operation and intensive care unit stay. RESULTS: We found no significant differences in peri-operative blood loss and transfused blood products among the three groups. There was a trend towards a lower amount of transfused fresh frozen plasma (FFP) for Group 1 (p =0.057) in the operation room (OR). The use of plasma expanders post-CPB was significantly higher in the Control group (p=0.024). RBCs coming from the auto-transfusion device were, for Group 1, significantly lower (p=0.007). The Hb and Hct values in Group 1, at start and end of CPB, were significantly lower (p=0.023-0.003 / 0.001-0.001, respectively). All other parameters were not significantly different. CONCLUSION: there were no significant differences between the study groups. This randomized trial shows that, although sequestration immediately after autologous blood withdrawal has no added value, autologous blood withdrawal in patients with a normal pre-operative Hb and Hct is simple, inexpensive and allows for autologous blood transfusion.

Increased maternal BMI is associated with infant wheezing in early life: a prospective cohort study.

Rates of obesity are increasing in women of child bearing age with negative impacts on maternal and offspring health. Emerging evidence suggests in utero origins of respiratory health in offspring of obese mothers but mechanisms are unknown. Changes in maternal cortisol levels are one potential factor as cortisol levels are altered in obesity and cortisol is separately implicated in development of offspring wheeze. We aimed to assess whether increased pre-pregnancy maternal body mass index (BMI) was associated with offspring early life wheezing, and whether this was mediated by altered cortisol levels in the mother. In a prospective community-based cohort (Amsterdam Born Children and their Development cohort), women completed questionnaires during pregnancy and at 3-5 months post-delivery regarding self-history of asthma and atopy, and of wheezing of their offspring (n=4860). Pre-pregnancy BMI was recorded and serum total cortisol levels were measured in a subset of women (n=2227) at their first antenatal visit. A total of 20.2% (n=984) women were overweight or obese and 10.3% reported wheezing in their offspring. Maternal BMI was associated with offspring wheezing (1 unit (kg/m2) increase, OR: 1.03; 95% CI: 1.00-1.05), after correction for confounders. Although maternal cortisol levels were lower in overweight mothers and those with a history of asthma, maternal cortisol levels did not mediate the increased offspring wheezing. Pre-pregnancy BMI impacts on baby wheezing, which is not mediated by lower cortisol levels. As the prevalence of obesity in women of child-bearing age is increasing, further studies are needed to investigate modifiable maternal factors to avoid risk of wheezing in young children.

Reconstructive surgery after burns: a 10-year follow-up study.

BACKGROUND: There is minimal insight into the prevalence of reconstructive surgery after burns. The objective of this study was to analyse the prevalence, predictors, indications, techniques and medical costs of reconstructive surgery after burns. METHODS: A retrospective cohort study was conducted in the three Dutch burn centres. Patients with acute burns, admitted from January 1998 until December 2001, were included. Data on patient and injury characteristics and reconstructive surgery details were collected in a 10-year follow-up period. RESULTS: In 13.0% (n=229/1768) of the patients with burns, reconstructive surgery was performed during the 10-year follow-up period. Mean number of reconstructive procedure per patient were 3.6 (range 1-25). Frequently reconstructed locations were hands and head/neck. The most important indication was scar contracture and the most applied technique was release plus random flaps/skin grafting. Mean medical costs of reconstructive surgery per patient over 10-years were €8342. CONCLUSIONS: With this study we elucidated the reconstructive needs of patients after burns. The data presented can be used as reference in future studies that aim to improve scar quality of burns and decrease the need for reconstructive surgery.

Optimal treatment of partial thickness burns in children: a systematic review.

A large part of the patient population of a burn centre consists of children, most of whom are younger than four years. The majority of these young children suffer from superficial and deep partial thickness scald burns that may easily deepen to full thickness burns. A proper wound therapy, that prevents infection and ensures a moist wound condition, might prevent the deterioration of the wound. Therefore, we performed a systematic review of wound management and dressing materials to select the best treatment option for children with burns. A search in Medline and Embase revealed 51 articles for a critical appraisal. The articles were divided into randomized controlled trials, cohort studies and a group of case-reports. Total appraisal did not differ much amongst the groups; the level of evidence was highest in the randomized controlled trials and lowest in the case-reports. In 16 out of 34 comparative studies, silver sulfadiazine or a silver sulfadiazine/chlorhexidine-gluconate combination was the standard of wound care treatment. The competitor dressing was Biobrane(®) in six studies and amnion membrane in three. Tulle gauze, or tulle gauze impregnated with an antibacterial addition were the standard of care treatment in seven studies. In general, membranous dressings like Biobrane(®) and amnion membrane performed better than the standard of care on epithelialization rate, length of hospital stay and pain for treatment of partial thickness burns in children. However, hardly any of the studies investigated long-term results like scar formation.

Self-reported versus 'true' adherence in heart failure patients: a study using the Medication Event Monitoring System.

BACKGROUND: Adherence to (non)pharmacological treatment is important in heart failure (HF) patients, since it leads to better clinical outcome. Although self-reported and objectively measured medication adherence in HF patients have been compared in previous studies, none of these studies have used an evidence-based cutpoint to differentiate between adherence and non-adherence. METHODS: In 37 HF patients (mean age 68 ± 10 years, 27 % female, 40 % NYHA functional class III-IV), medication (ACEi/ARB) adherence was objectively measured using the Medication Event Monitoring System (MEMS). Adherence to and importance of taking medication was also assessed by self-report using the Revised HF Compliance Questionnaire. RESULTS: All patients reported that adherence was (highly) important to them and that they 'always' took their medication as prescribed (i.e. 100 % adherence). However, when measured by the MEMS, only 76 % of all patients were adherent. Non-adherent patients more often had a complex medication regimen (78 % vs. 21 %, P < .01), more often depressive symptoms (75 % vs. 29 %, P = .04) and a shorter history of HF (8 vs. 41 months, P = .04), compared with adherent patients. CONCLUSIONS: Medication adherence measured by the MEMS was remarkably lower than self-reported adherence. Given the evidence of its importance, further efforts are needed to improve adherence to the pharmacological regimen in HF patients.

A clinimetric overview of scar assessment scales.

Standardized validated evaluation instruments are mandatory to increase the level of evidence in scar management. Scar assessment scales are potentially suitable for this purpose, but the most appropriate scale still needs to be determined. This review will elaborate on several clinically relevant scar features and critically discuss the currently available scar scales in terms of basic clinimetric requirements. Many current scales can produce reliable measurements but seem to require multiple observers to obtain these results reliably, which limits their feasibility in clinical practice. The validation process of scar scales is hindered by the lack of a "gold standard" in subjective scar assessment or other reliable objective instruments which are necessary for a good comparison. The authors conclude that there are scar scales available that can reliably measure scar quality. However, further research may lead to improvement of their clinimetric properties and enhance the level of evidence in scar research worldwide.

Contribution of overweight and obesity to the occurrence of adverse pregnancy outcomes in a multi-ethnic cohort: population attributive fractions for Amsterdam.

OBJECTIVE: To estimate the contribution of pre-pregnancy excessive weight to the occurrence of adverse pregnancy outcomes and to detect the differences in these contributions between different ethnic groups. DESIGN: Prospective multi-ethnic community-based cohort study. SETTING: The prevalence of excessive weight is increasing and in general higher in immigrant groups in many industrialised countries. Maternal excessive weight, like smoking during pregnancy, is an important risk factor for adverse pregnancy outcomes. POPULATION: A total of 8266 pregnant women, living in the Netherlands, were included in the ABCD study between January 2003 and March 2004. METHODS: After applying the exclusion criteria, the analysis included 7871 pregnancies. Binomial log-linear regression analyses were performed to estimate relative risks (RRs) expressing the association between overweight/obesity and small-for-gestational-age (SGA), large-for-gestational-age (LGA), preterm birth (PTB; <37 weeks of gestation) and extreme PTB (<32 weeks of gestation), controlling for parity, maternal age, education level and smoking. Next, the RRs were used to estimate population attributive fractions (PAF) for Amsterdam and separately for several ethnic groups. MAIN OUTCOME MEASURES: The RRs and PAFs. RESULTS: The PAFs for overweight/obesity were: SGA -4.9%, LGA 15.3%, PTB 6.6% and extreme PTB 22.0%. In absolute terms, this corresponds to -47 SGA infants, 126 LGA infants, 35 PTB and 20 extreme PTB per year in Amsterdam. Except for SGA, these PAFs were higher than those for smoking (6.2%, -3.9%, 5.5% and 10.6%, respectively). The contribution of overweight/obesity to LGA and PTB was higher in non-Western immigrant groups. CONCLUSIONS: Overweight/obesity has become an important contributor to the occurrence of adverse pregnancy outcomes in Amsterdam. For most outcomes, these contributions are larger than those for smoking. Development of special obesity prevention programmes for young women is required, especially focused on immigrant groups.

Surgical strategy in patients with secondary and tertiary hyperparathyroidism. A bi-institutional series.

BACKGROUND: Although total parathyroidectomy with forearm autotransplantation is a widely accepted treatment for patients with secondary/tertiary hyperparathyroidism (HPT) some debate persists about the optimal surgical strategy. In particular, the question what to do when less than four parathyroid glands can be found during surgery has yet to be resolved. The aim of this retrospective study was to review the outcome of total parathyroidectomy with autotransplantation and to assess the proper procedure (to autotransplant or not) when finding less than 4 glands after extensive surgical exploration. METHODS: Between 1995 and 2005, parathyroidectomy was performed in 74 patients in two affiliated centers. In this case-control study both clinical and biochemical outcomes of a total or subtotal parathyroidectomy were compared. The parathyroid hormone (PTH), serum calcium concentration, phosphate and alkaline phosphatase levels were monitored preoperatively, 1 and 12 months postoperatively. RESULTS: Sixty five patients underwent a total parathyroidectomy and nine patients underwent a subtotal parathyroidectomy. Persistent HPT was seen in nine patients (12%). Recurrent HPT was seen in eight patients (11%). There were no significant differences between the group with > or = 4 glands excised and the group with three glands excised regarding serum PTH levels after 12 months and the number of patients with a hypo- or hyperparathyroidism (persistent or recurrent). Procedure related morbidity was minimal. CONCLUSIONS: Total parathyroidectomy with forearm autotransplantation is safe and effective for patients with secondary/tertiary hyperparathyroidism. In case of not finding a fourth gland after extensive surgical exploration, our general advice is to proceed as planned with the autotransplantation.