Enthesitis in a European registry-based cohort of patients with psoriatic arthritis treated with tumour necrosis factor inhibitors: clinical burden, patient-reported outcomes, and treatment response.

OBJECTIVE: To explore the registration of enthesitis among biologic-naïve patients with psoriatic arthritis (PsA) initiating tumour necrosis factor inhibitor (TNFi) treatment across 12 European registries, compare the disease burden and patient-reported outcomes (PROs) between patients with and without enthesitis, and assess the enthesitis treatment response. METHOD: Demographics, clinical characteristics, and PROs at first TNFi (TNFi-1) initiation (baseline) were assessed in patients with PsA, diagnosed by a rheumatologist, with versus without assessment of entheses and between those with versus without enthesitis. Enthesitis scores and resolution frequency were identified at follow-up. RESULTS: Of 10 547 patients in the European Spondyloarthritis (EuroSpA) Research Collaboration Network initiating TNFi, 1357 underwent evaluation for enthesitis. Eight registries included a validated scoring system for enthesitis. At baseline, 874 patients underwent entheses assessment [Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) 485 patients, Spondyloarthritis Research Consortium of Canada (SPARCC) 389 patients]. Enthesitis was detected by MASES in 170/485 (35%, mean score ± sd 3.1 ± 2.4) and by SPARCC in 236/389 (61%, 4 ± 3.4). Achilles enthesitis was most frequent, by both MASES (unilateral/bilateral 28%/9%) and SPARCC (48%/18%). MASES/SPARCC baseline and follow-up scores for TNFi-1 were available for 100/105 patients. Of these, 63 patients (63%) (MASES) and 46 (43.8%) (SPARCC) achieved resolution of enthesitis. The site-specific enthesitis resolution was overall lower at SPARCC sites (peripheral; 63-80%) than at MASES sites (mainly axial; 82-100%) following TNFi-1. Disease activity and PROs were worse in patients with versus without enthesitis. CONCLUSION: Entheseal assessments are only registered in a minority of patients with PsA in routine care. When assessed, enthesitis was common, and a substantial proportion demonstrated resolution following treatment with TNFi-1.

Antibody response in patients with autoimmune inflammatory rheumatic disease after pneumococcal polysaccharide prime vaccination or revaccination.

OBJECTIVE: The aim of the study was to assess the pneumococcal antibody response in autoimmune inflammatory rheumatic disease (AIIRD) patients receiving 23-valent pneumococcal polysaccharide vaccine (PPV23) as a prime vaccination or revaccination. METHOD: Antibodies to 12 serotypes occurring in the commonly applied pneumococcal vaccines in Denmark were measured in AIIRD patients receiving biological disease-modifying anti-rheumatic drug (bDMARD) treatment for rheumatoid arthritis, spondyloarthritis, or psoriatic arthritis. Patients with a non-protective level of pneumococcal antibodies (geometric mean pneumococcal antibody level < 1 µg/mL) were invited to receive vaccination with PPV23 followed by control of antibody titre 3 months later. RESULTS: In total, 224 (74%) of 301 patients were included in the analyses, of whom 126 patients had previously received PPV23 vaccination. Post-vaccination antibody measurement revealed that only 80 patients (36%) achieved a protective level of antibodies. In a multivariable logistic regression analysis, significantly more patients without a previous PPV23 vaccination history achieved a protective antibody level compared with patients with a history of PPV23 vaccination less than 5 years ago (p = 0.005). This difference was not seen when comparing the former group with patients vaccinated 5 years ago or more. Methotrexate (MTX) treatment at the time of vaccination was associated with a non-protective antibody level (p < 0.001). CONCLUSION: Only 36% of patients with a non-protective antibody level achieved a protective level in response to pneumococcal vaccination. Pneumococcal vaccination within the last 5 years and MTX treatment at the time of vaccination were independently associated with a poor antibody response.

Association of placental and umbilical cord characteristics with cerebral palsy: national cohort study.

OBJECTIVES: Cerebral palsy (CP) is a group of movement disorders usually diagnosed in childhood. A substantial proportion are thought to be caused by antenatal events. Abnormalities of the umbilical cord and placenta are associated with an increased risk of adverse neonatal outcomes, but it is unclear whether these conditions also carry an increased risk of CP. We aimed to determine whether abnormalities of the umbilical cord or placenta are associated with CP and assess if these associations differ by sex of the child or gestational age at birth. METHODS: We performed a national cohort study by linking data from The Medical Birth Registry of Norway with other national registries. All liveborn singletons born between 1999 and 2017 (n = 1 087 486) were included and followed up until the end of 2019. Diagnoses of CP were provided by the Norwegian National Insurance Scheme and the Norwegian Patient Register. We used generalized estimating equations and multilevel log binomial regression to calculate relative risks (RR), adjusted for year of birth, and stratified analyses were carried out based on sex and gestational age at birth. Exposures were abnormal umbilical cord (velamentous or marginal insertion, single umbilical artery (SUA), knots and entanglement), and placental abnormalities (retained placenta, placental abruption and previa). RESULTS: A total of 2443 cases with CP (59.8% males) were identified. Velamentous cord insertion (adjusted RR (aRR), 2.11 (95% CI, 1.65-2.60)), cord knots (aRR, 1.53 (95% CI, 1.15-2.04)) and placental abnormalities (placenta previa (aRR, 3.03 (95% CI, 2.00-4.61)), placental abruption (aRR, 10.63 (95% CI, 8.57-13.18)) and retained placenta (aRR, 1.71 (95% CI, 1.32-2.22))) carried an increased risk of CP. Velamentous cord insertion was associated with CP regardless of gestational age or sex. A retained placenta was associated with a 2-fold increased risk for CP in males, while the associations of SUA and cord knot with CP were significant only among females. CONCLUSIONS: The detection of placental and umbilical cord abnormalities may help identify children at increased risk of CP. The associations between placental or umbilical cord abnormalities and the risk of CP do not vary substantially with gestational age at birth or sex of the child. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study.

Objective: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease. Studies suggest that pro-inflammatory cytokines may be attenuated by the vagus nerve through the cholinergic anti-inflammatory pathway. We aimed to evaluate the anti-inflammatory effects of short-term transcutaneous non-invasive vagus nerve stimulation (n-VNS) applied to the cervical vagus nerve in patients with RA. Method: We conducted a single-centre, open-label, preliminary proof-of-concept study of n-VNS in two cohorts of participants with RA: one with high disease activity (n = 16) and one with low disease activity (n = 20). Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines were measured at baseline and after 1 and 4 days of n-VNS. Results: In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02). In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone (p = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02). Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs 4.9 ± 3 linear vagal scale, p = 0.03). Cardiac vagal tone was negatively associated with DAS28-CRP (r = -0.37, p = 0.03). Overall, n-VNS was well tolerated. Conclusion: This study provides preliminary support for an anti-inflammatory effect of n-VNS in patients with RA. These findings warrant further investigation in larger placebo-controlled trials.

Prediction of preterm pre-eclampsia according to NICE and ACOG criteria: descriptive study of 597 492 Danish births from 2008 to 2017.

OBJECTIVE: The aim of this national study was to examine the incidence of preterm pre-eclampsia (PE) and the proportion of women with risk factors for PE, according to the criteria suggested by the National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG), during a 10-year period in Denmark. METHODS: Data from The Danish National Patient Registry and the Danish Medical Birth Registry were used to obtain the incidence of preterm PE with delivery < 37 weeks' gestation and risk factors for PE for all deliveries in Denmark from 1 January 2008 to 31 December 2017. The proportion of women with at least one high-risk factor and/or at least two moderate-risk factors for PE, according to the NICE and ACOG criteria, and the detection rate for preterm PE were examined. Race, socioeconomic status and the woman's weight at birth were not available from the registries used, and information on Type-2 diabetes was found to be invalid. RESULTS: Of the 597 492 deliveries during the study period, any PE was registered in 3.2%, preterm PE < 37 weeks in 0.7% and early-onset PE < 34 weeks' gestation in 0.3%. These proportions remained largely unchanged from 2008 to 2017. Overall, the NICE criteria were fulfilled in 7.5% of deliveries and the ACOG criteria in 17.3%. In the total population, the NICE criteria identified 47.6% of those with preterm PE and the ACOG criteria identified 60.5%. The current criteria for offering aspirin treatment in Denmark largely correspond to having at least one NICE high-risk factor. In 2017, a total of 3.5% of deliveries had at least one NICE high-risk factor, which identified 28.4% of cases that later developed preterm PE. CONCLUSIONS: The incidence of preterm PE remained largely unchanged in Denmark from 2008 to 2017. Prediction of PE according to high-risk maternal factors could be improved by addition of moderate-risk factors. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Vagal Nerve Stimulation-Modulation of the Anti-Inflammatory Response and Clinical Outcome in Psoriatic Arthritis or Ankylosing Spondylitis.

OBJECTIVES: The vagal nerve exerts an essential pathway in controlling the cholinergic anti-inflammatory reflex. Thus, the study is aimed at investigating the acute effect of a noninvasive transcutaneous vagus nerve stimulation on clinical disease activity and systemic levels of inflammation in patients with psoriatic arthritis or ankylosing spondylitis. METHODS: Twenty patients with psoriatic arthritis (PsA) and 20 patients with ankylosing spondylitis (AS) were included and stimulated bilaterally with a handheld vagal nerve stimulator for 120 seconds 3 times a day for 5 consecutive days. All patients were in remission. Cardiac vagal tone, clinical scores, CRP, and cytokine levels were assessed. RESULTS: In PsA and AS, decreased heart rate was observed, confirming compliance. Furthermore, in PsA, a clear reduction of clinical disease activity associated with a 20% reduction in CRP was shown. In AS, a reduction in interferon-γ, interleukin- (IL-) 8, and 10 was shown. No side effects were described. CONCLUSION: This open-label study provides support for an anti-inflammatory effect of transcutaneous vagus nerve stimulation in patients with psoriatic arthritis and ankylosing spondylitis. The modulated immune response and reduced disease activity and CRP-levels raise the fascinating possibility of using neuromodulation as an add-on to existing pharmacological treatments.

Cost-effectiveness of 12 weeks of supervised treatment compared to written advice in patients with knee osteoarthritis: a secondary analysis of the 2-year outcome from a randomized trial.

OBJECTIVE: To assess the 24-month cost-effectiveness of supervised treatment compared to written advice in knee osteoarthritis (OA). DESIGN: 100 adults with moderate-severe OA not eligible for total knee replacement (TKR) randomized to a 12-week individualized, supervised treatment (exercise, education, diet, insoles and pain medication) or written advice. Effectiveness was measured as change in quality-adjusted life years (QALYs) from baseline to 24 months, including data from baseline, 3, 6, 12 and 24 months, while healthcare costs and transfer payments were derived from national registries after final follow-up. Incremental costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. A sensitivity analysis resampling existing data was conducted and the probability of cost-effectiveness was estimated using a 22,665 Euros/QALY threshold. In a sensitivity analysis, cost-effectiveness was calculated for different costs of the supervised treatment (actual cost in study; cost in private practice; and in-between cost). RESULTS: Average costs were similar between groups (6,758 Euros vs 6,880 Euros), while the supervised treatment were close to being more effective (incremental effect (95% CI) of 0.075 (-0.005 to 0.156). In the primary analysis excluding deaths, this led the supervised treatment to be cost-effective, compared to written advice. The sensitivity analysis demonstrated that the results were sensitive to changes in the cost of treatment, but in all scenarios the supervised treatment was cost-effective (ICERs of 6,229 to 20,688 Euros/QALY). CONCLUSIONS: From a 24-month perspective, a 12-week individualized, supervised treatment program is cost-effective compared to written advice in patients with moderate-severe knee OA not eligible for TKR. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01535001.

Imprinting disorders in children born after ART: a Nordic study from the CoNARTaS group.

STUDY QUESTION: Is the risk of imprinting disorders increased in children conceived after ART? SUMMARY ANSWER: We found an adjusted odds ratio (AOR) of 2.84 [95% CI: 1.34-6.01] for Beckwith-Wiedemann syndrome in ART children, while the risk of Prader-Willi syndrome, Silver-Russell syndrome or Angelman syndrome was not increased in children conceived after ART. WHAT IS KNOWN ALREADY: Earlier studies, most of them small, have suggested an association between ART and imprinting disorders. STUDY DESIGN, SIZE, DURATION: This was a binational register-based cohort study. All children conceived by ART in Denmark (n = 45 393, born between 1994 and 2014) and in Finland (n = 29 244, born between 1990 and 2014) were identified. The full background populations born during the same time periods in the two countries were included as controls. Odds ratios of imprinting disorders in ART children compared with naturally conceived (NC) children were calculated. The median follow-up time was 8 years and 9 months for ART children and 11 years and 9 months for NC children. PARTICIPANTS/MATERIALS, SETTING, METHODS: From the national health registries in Denmark and Finland, we identified all children diagnosed with Prader-Willi syndrome (n = 143), Silver-Russell syndrome (n = 69), Beckwith-Wiedemann syndrome (n = 105) and Angelman syndrome (n = 72) born between 1994/1990 and 2014, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a total of 388 children diagnosed with imprinting disorders; 16 of these were conceived after ART. The overall AOR for the four imprinting disorders in ART children compared with NC children was 1.35 [95% CI: 0.80-2.29], but since eight ART children were diagnosed with Beckwith-Wiedemann syndrome, the AOR for this specific imprinting disorder was 2.84 [95% CI: 1.34-6.01]. The absolute risk of Beckwith-Wiedemann syndrome in children conceived after ART was still low: 10.7 out of 100 000 newborns. The risks of Prader-Willi syndrome, Silver-Russell syndrome and Angelman syndrome were not increased in children conceived after ART. LIMITATIONS, REASONS FOR CAUTION: Imprinting disorders are rare events and our results are based on few ART children with imprinting disorders. The aetiology is complex and only partly clarified, and the clinical diagnoses are challenged by a broad phenotypic spectrum. WIDER IMPLICATIONS OF THE FINDINGS: In the existing studies, results on the risk of imprinting disorders in children conceived after ART are ambiguous. This study adds that the risk of imprinting disorders in ART children is very small and perhaps restricted to Beckwith-Wiedemann syndrome. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (grant number: 71450), the Nordic Federation of Obstetrics and Gynecology (grant numbers: NF13041, NF15058, NF16026 and NF17043) and the Interreg Öresund-Kattegat-Skagerak European Regional Development Fund (ReproUnion project). The authors have no conflicts of interest related to this work. TRIAL REGISTRATION NUMBER: N/A.

Pneumococcal antibody protection in patients with autoimmune inflammatory rheumatic diseases with varying vaccination status.

Objectives: The aims of this cross-sectional study were to assess the pneumococcal antibody coverage in patients with autoimmune inflammatory rheumatic disease (AIRD) and to identify predictors associated with inadequate protective antibody levels. Method: Antibodies to 12 serotypes occurring in the commonly applied pneumococcal vaccines in Denmark were measured in AIRD patients with a diagnosis of rheumatoid arthritis, spondyloarthritis, or psoriatic arthritis attending the Department of Rheumatology at the North Denmark Regional Hospital. Immunization against pneumococcal infection was defined as a geometric mean level ≥ 1 µg antibodies/mL. Clinical information about vaccination status and disease/treatment history was retrieved from the medical file system. Results: Results of antibody measurement and vaccination status were available from 346 AIRD patients, of whom 200 (58%) were registered as receiving pneumococcal vaccination, whereas the remaining 146 patients (42%) were not. Of all 346 patients, only 61 (18%) were measured with an adequate level of protective antibodies (30% vs 1%, respectively). Methotrexate treatment at the time of vaccination and increasing age were identified as predictors of poor vaccination outcome in multiple logistic regression analysis. Conclusions: This post-vaccination study showed that less than one-fifth of the AIRD patients are adequately protected against pneumococcal infection, although the immunization programme had been implemented in more than half of the study population. Development of improved vaccination strategies is required to achieve a higher immunization coverage rate and more efficient lasting antibody response.

Complications after benign hysterectomy, according to procedure: a population-based prospective cohort study from the Danish hysterectomy database, 2004-2015.

OBJECTIVE: To compare the risk of complications associated with benign hysterectomy according to surgical procedure. DESIGN: Register-based prospective cohort study. SETTING: Danish Hysterectomy Database, 2004-2015. POPULATION: All Danish women with benign elective hysterectomy (n = 51 141). METHODS: Multivariate log-binomial regression to compute relative risks (RRs) stratified by calendar period, and adjusted for age, height, weight, smoking habits, use of alcohol, comorbidity, indications, uterine weight and adhesions. Multiple imputation and 'intention to treat' analyses were performed. MAIN OUTCOME MEASURES: Major (grades III-V) and minor (grades I-II) Clavien-Dindo modified complications within 30 days. RESULTS: Overall, major complications occurred in 3577 (7.0%) hysterectomies and minor complications occurred in 4788 (9.4%). The proportions of major and minor complications according to type of hysterectomy were: 10.3 and 9.6% for abdominal hysterectomy (AH); 4.1 and 12.1% for laparoscopic hysterectomy (LH); and 4.9 and 8.0% for vaginal hysterectomy (VH) for non-prolapse, and 2.3 and 6.4% for prolapse. In multivariate analyses, compared with VH for non-prolapse, the risk of major complications was higher for AH (RR 1.82, 95% CI 1.63-2.03) but lower for both LH (RR 0.78, 95% CI 0.68-0.90) and VH for prolapse (RR 0.55; 95% CI 0.41-0.75). For LH, the risk of major complications reduced from a RR of 0.96 (95% CI 0.75-1.22) in the time period 2004-2009 to an RR of 0.72 (95% CI 0.60-0.87) between 2010 and 2015. CONCLUSION: Laparoscopic hysterectomy and VH for uterine prolapse are associated with fewer major complications, and AH is associated with more major complications, compared with VH performed in the absence of uterine prolapse. TWEETABLE ABSTRACT: Laparoscopic hysterectomy has fewer major complications compared with vaginal hysterectomy, in the absence of uterine prolapse.

Single umbilical artery and risk of congenital malformation: population-based study in Norway.

OBJECTIVES: Single umbilical artery (SUA) is associated with congenital malformations in most organ systems, but reported findings have not been consistent. While it has been suggested that genetic and persisting environmental factors influence the development of SUA, it is not known whether there is an increased risk of recurrence in a subsequent pregnancy of the same woman. The aims of this study were to investigate the occurrence of, and risk factors for, SUA in Norway, to assess its association with congenital malformations and trisomies 13, 18 and 21 and to study the risk of recurrence of SUA in subsequent pregnancies. METHODS: This was a population-based study of all (n = 918 933) singleton pregnancies of > 16 weeks' gestation recorded in the Medical Birth Registry of Norway from 1999 to 2014. To identify risk factors and congenital malformations associated with SUA, generalized estimating equations and logistic regression were used to calculate odds ratios (OR) with 95% CIs. ORs were also calculated for the recurrence of SUA in subsequent pregnancy. RESULTS: The occurrence of SUA in our population was 0.46% (4241/918 933). Parity ≥ 4, smoking, maternal pregestational diabetes, epilepsy, chronic hypertension, previous Cesarean delivery and conception by assisted reproductive technology increased the odds of having SUA. There was a particularly strong association between SUA and gastrointestinal atresia or stenosis in the neonate, with ORs of 25.8 (95% CI, 17.0-39.1) and 20.3 (95% CI, 13.4-30.9) for esophageal and anorectal atresia or stenosis, respectively, followed by an OR of 5.9 (95% CI, 1.9-18.5) for renal agenesis. SUA was associated with an up to 7-8 times increased risk of congenital heart defects. There was an association with microcephaly, congenital hydrocephalus and other congenital malformations of the brain and spinal cord. Diaphragmatic hernia, limb reductions and cleft lip or palate had a weaker association with SUA, with ORs ranging from 4.8 to 2.8. The associations with trisomy 18 and 13 were equally strong (OR 14.4 (95% CI, 9.3-22.4) and OR 13.6 (95% CI, 6.7-27.8), respectively), and the risk of trisomy 21 was doubled (OR 2.1 (95% CI, 1.2-3.6)). Pregnancies with SUA, with or without an associated malformation, had a 2-fold increased risk for SUA in a subsequent pregnancy. CONCLUSIONS: SUA is associated strongly with gastrointestinal atresia or stenosis, suggesting common developmental mechanisms. The increased risk of recurrence of SUA suggests that genetic and/or persisting environmental factors influence the risk. We found that SUA had equally strong associations with trisomies 13 and 18. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Sex-specific reference ranges of cerebroplacental and umbilicocerebral ratios: longitudinal study.

OBJECTIVES: Observational studies have shown that low cerebroplacental ratio (CPR) values predict an increased risk of adverse perinatal outcome. The inverse ratio, i.e. the umbilicocerebral ratio (UCR), has been suggested to be a better predictor as it rises with increasing degree of fetal compromise. However, longitudinal reference ranges for UCR have not been established, and whether gestational-age-dependent changes in CPR or UCR differ between male and female fetuses has not been studied. Thus, the aims of this study were to investigate sex-specific, gestational-age-associated serial changes in CPR and UCR during the second half of pregnancy and to establish longitudinal reference ranges. METHODS: This was a secondary analysis of prospectively collected data from a dual-center longitudinal observational cohort study of low-risk singleton pregnancies. Doppler blood-flow velocity waveforms were obtained serially from the umbilical artery (UA) and fetal middle cerebral artery (MCA) from 19-41 weeks' gestation, and pulsatility indices (PIs) were determined. CPR and UCR were calculated as the ratios MCA-PI/UA-PI and UA-PI/MCA-PI, respectively. The course and outcome of pregnancies were recorded, and the sex of the fetus was determined after delivery. Reference intervals for CPR and UCR were constructed using multilevel modeling, and gestational-age-specific Z-scores in male and female fetuses were compared. RESULTS: Of a total of 299 pregnancies enrolled, 284 (148 male and 136 female fetuses) were included in the final analysis, and 979 paired measurements of UA-PI and MCA-PI were used to construct sex-specific longitudinal reference intervals. The relationship of both CPR and UCR with gestational age was U-shaped, but in opposite directions. There was a small but significant difference in Z-scores of CPR and UCR between male and female fetuses throughout the second half of pregnancy (P = 0.007). CONCLUSIONS: We have established longitudinal reference ranges for CPR and UCR suitable for serial monitoring, with the possibility of refining assessment by using fetal sex-specific ranges and conditioning by a previous measurement. The clinical significance of such refinements needs further evaluation. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Academic performance in adolescents aged 15-16 years born after frozen embryo transfer compared with fresh embryo transfer: a nationwide registry-based cohort study.

OBJECTIVE: To assess academic performance in singletons aged 15-16 years conceived after frozen embryo transfer (FET) compared with singletons born after fresh embryo transfer (ET) in Danish cohorts born from 1995 to 2001. DESIGN: Danish national registry-based cohort study. SETTING: Danish national registries. POPULATION: All 6495 singletons conceived after assisted reproductive technology (ART) treatment in Denmark from 1995 to 2001 [FET (n) = 423; fresh ET (n) = 6072]. METHODS: Mean test scores on a national standardised and international comparable grading-scale. Comparisons of test score were first made in univariate analysis (Model 1) and secondly in a multivariate linear model (Model 2) adjusting for relevant reproductive and socio-demographic covariates such as the occupational and educational level of the parents. Sensitivity analyses on FET-IVF (in vitro fertilisation) versus fresh ET-IVF and FET-ICSI (intracytoplasmic sperm injection) versus fresh ET-ICSI were made. Linear mixed models were used to account for the correlation in test scores of siblings for continuous outcome. MAIN OUTCOME MEASURES: Mean overall test score and test score in Danish, mathematics, English, and physics/chemistry. RESULTS: Crude and adjusted mean test scores were similar for adolescents conceived after FET compared with fresh ET. The crude mean difference was +0.11 (95% CI -0.11; 0.34), and the adjusted mean difference was +0.12 (95% CI -0.09; 0.34). CONCLUSIONS: Adolescents conceived after FET had similar academic performance at 15-16 of years of age compared with children conceived after fresh ET. TWEETABLE ABSTRACT: Using frozen embryos in fertility treatment does not affect school performance in Danish adolescents aged 15-16 years.

Total knee replacement and non-surgical treatment of knee osteoarthritis: 2-year outcome from two parallel randomized controlled trials.

OBJECTIVES: To compare 2-year outcomes of total knee replacement (TKR) followed by non-surgical treatment to that of non-surgical treatment alone and outcomes of the same non-surgical treatment to that of written advice. DESIGN: In two randomized trials, 200 (mean age 66) adults with moderate to severe knee osteoarthritis (OA), 100 eligible for TKR and 100 not eligible for TKR, were randomized to TKR followed by non-surgical treatment, non-surgical treatment alone, or written advice. Non-surgical treatment consisted of 12 weeks of supervised exercise, education, dietary advice, use of insoles, and pain medication. The primary outcome was the mean score of the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales, covering pain, symptoms, activities of daily living (ADL), and quality of life (QOL). RESULTS: Patients randomized to TKR had greater improvements than patients randomized to non-surgical treatment alone (difference of 18.3 points (95% CI; 11.3 to 25.3)), who in turn improved more than patients randomized to written advice (difference of 7.0 points (95% CI; 0.4 to 13.5)). Among patients eligible for TKR, 16 (32%) from the non-surgical group underwent TKR during 2 years and among those initially ineligible, seven patients (14%) from the non-surgical group and ten (20%) from the written advice group underwent TKR. CONCLUSIONS: TKR followed by non-surgical treatment is more effective on pain and function than non-surgical treatment alone, which in turn is more effective than written advice. Two out of three patients with moderate to severe knee OA eligible for TKR delayed surgery for at least 2 years following non-surgical treatment. TRIAL REGISTRATION: ClinicalTrials.gov numbers NCT01410409 and NCT01535001.

Vagal influences in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease with a prevalence of 0.5-1% in Western populations. Conventionally, it is treated with therapeutic interventions that include corticosteroids, disease-modifying anti-rheumatic drugs, and biological agents. RA exerts a significant socio-economic burden and despite the use of existing treatments some patients end up with disabling symptoms. The autonomic nervous system (ANS) is a brain-body interface that serves to regulate homeostasis by integrating the external environment with the internal milieu. The main neural substrate of the parasympathetic branch of the ANS is the vagus nerve (VN). The discovery of the role of the ANS and the VN in mediating and dampening the inflammatory response has led to the proposal that modulation of neural circuits may serve as a valuable therapeutic tool. Recent studies have explored the role of the VN in this inflammatory reflex and have provided evidence that stimulation may represent a novel new therapeutic intervention. Accumulating evidence suggests that modulation of the parasympathetic tone results in a broad physiological multi-level response, including decreased pro-inflammatory cytokine response in terms of tumour necrosis factor-α, interleukin-1 (IL-1), and IL-6, and may result in an enhanced macrophage switch from M1 to M2 cells and potentially an increased level of the anti-inflammatory cytokine IL-10. Therefore, therapeutic electrical modulation of the VN may serve as an alternative, non-pharmacological, neuroimmunomodulatory intervention in RA in the future. This review gives a focused introduction to the mechanistic link between the ANS and the immune system.

Placental abruption in parents who were born small: registry-based cohort study.

OBJECTIVE: To assess whether parents who were born small for gestational age (below the 10th birthweight centile, SGA) have increased risk of severe or mild placental abruption. To assess whether a history of SGA in other family members modifies this intergenerational effect. DESIGN: Prospective population-based observational study. SETTING: The Medical Birth Registry of Norway. POPULATION: From 1967 to 2013, 785 333 mother-offspring pairs, 643 066 father-offspring pairs, 272 941 maternal tetrads (i.e. her offspring, sibling, and niece/nephew), and 265 505 paternal tetrads were identified. METHODS: Cohort study based on linked data from the Medical Birth Registry of Norway. MAIN OUTCOME MEASURES: Relative risk (RR) of severe placental abruption (preterm birth, birthweight below the 10th centile, or perinatal death) and mild placental abruption (other cases) in families with SGA. RESULTS: Mothers who were born SGA had increased risk of severe placental abruption (RR 1.5; 95% confidence interval, 95% CI 1.3-1.8), but not mild abruption. The paternal effects were weaker. The combined effect of SGA in the mother and her sibling on severe abruption was twofold (RR 2.4; 95% CI 1.7-3.3) compared with birthweight centiles ≥10 for both. Similarly, the effect of adding an SGA niece/nephew was twofold (RR 2.3; 95% CI 1.3-3.9), whereas the combined effect of SGA in the mother, her sibling and her niece/nephew was fourfold (RR 3.6; 95% CI 1.9-6.8). CONCLUSIONS: Women who were born SGA have an increased risk of severe placental abruption. The corresponding paternal effect was modest. A history of SGA in other family members increases the generational effect. TWEETABLE ABSTRACT: Women born small for gestational age have excess risk of placental abruption.

Skills among young and elderly laypersons during simulated dispatcher assisted CPR and after CPR training.

BACKGROUND: Dispatcher assisted cardiopulmonary resuscitation (DA-CPR) increase the rate of bystander CPR. The aim of the study was to compare the performance of DA-CPR and attainable skills following CPR training between young and elderly laypersons. METHODS: Volunteer laypersons (young: 18-40 years; elderly: > 65 years) participated. Single rescuer CPR was performed in a simulated DA-CPR cardiac arrest scenario and after CPR training. Data were obtained from a manikin and from video recordings. The primary endpoint was chest compression depth. RESULTS: Overall, 56 young (median age: 26, years since last CPR training: 6) and 58 elderly (median age: 72, years since last CPR training: 26.5) participated. Young laypersons performed deeper (mean (SD): 56 (14) mm vs. 39 (19) mm, P < 0.001) and faster (median (25th-75th percentile): 107 (97-112) per min vs. 84 (74-107) per min, P < 0.001) chest compressions compared to elderly. Young laypersons had shorter time to first compression (mean (SD): 71 (11) seconds vs. 104 (38) seconds, P < 0.001) and less hands-off time (median (25th-75th percentile): 0 (0-1) seconds vs. 5 (2-10) seconds, P < 0.001) than elderly. After CPR training chest compressions were performed with a depth (mean (SD): 64 (8) mm vs. 50 (14) mm, P < 0.001) and rate (mean (SD): 111 (11) per min vs. 93 (18) per min, P < 0.001) for young and elderly laypersons respectively. CONCLUSION: Despite long CPR retention time for both groups, elderly laypersons had longer retention time, and performed inadequate DA-CPR compared to young laypersons. Following CPR training the attainable CPR level was of acceptable quality for both young and elderly laypersons.

The association between eccentric hip abduction strength and hip and knee angular movements in recreational male runners: An explorative study.

Weak hip abductors may be related with increased hip adduction and knee abduction angular movement, which may be risk factors of lower extremity injuries. As the role of eccentric hip abduction strength (EHAS) on hip adduction angular movement and knee abduction angular movement (KABD) remains unclear, the purpose of this study was to explore the association between EHAS and hip and knee angular movement. In 100 healthy male recreational runners, EHAS was quantified using an isokinetic dynamometer, while hip and knee angular movements were collected using pressure-sensitive treadmill and Codamotion active marker system. Using multiple linear regression models (n=186 legs), no relationships between EHAS and hip and knee kinematics were found. A possible reason for the lack of relationship between EHAS and hip and knee kinematics may be owing to differences in the running kinematics. Some runners with weak EHAS may compensate the weakness by leaning toward the stance limb and thereby reduces the demand on the hip abductors with the consequence of increased knee abduction moment, which may lead to an increased knee abduction angular excursion. Possible, others mechanism as the quadriceps strength and activity in the hip and thigh muscles may also be able to explain the lack of relationship that may or may not exist. Despite the inconclusive results of this study, the findings may suggest that weak hip abductor muscles may be a relevant factor to focus on in future studies.

Considering Tangible Benefit for Interdependent Donors: Extending a Risk-Benefit Framework in Donor Selection.

From its infancy, live donor transplantation has operated within a framework of acceptable risk to donors. Such a framework presumes that risks of living donation are experienced by the donor while all benefits are realized by the recipient, creating an inequitable distribution that demands minimization of donor risk. We suggest that this risk-tolerance framework ignores tangible benefits to the donor. A previously proposed framework more fully considers potential benefits to the donor and argues that risks and benefits must be balanced. We expand on this approach, and posit that donors sharing a household with and/or caring for a potential transplant patient may realize tangible benefits that are absent in a more distantly related donation (e.g. cousin, nondirected). We term these donors, whose well-being is closely tied to their recipient, "interdependent donors." A flexible risk-benefit model that combines risk assessment with benefits to interdependent donors will contribute to donor evaluation and selection that more accurately reflects what is at stake for donors. In so doing, a risk-benefit framework may allow some donors to accept greater risk in donation decisions.

The long-term prognosis for live birth in couples initiating fertility treatments.

STUDY QUESTION: What are the long-term chances of having a child for couples starting fertility treatments and how many conceive with ART, IUI and without treatment? SUMMARY ANSWER: Total 5-year live birthrates were strongly influenced by female age and ranged from 80% in women under 35-26% in women ≥40 years, overall, 14% of couples conceived naturally and one-third of couples starting treatments with intrauterine insemination delivered from that treatment. WHAT IS KNOWN ALREADY: Few studies report success rates in fertility treatments across a couple's complete fertility treatment history, across clinics, evaluating live births after insemination, ART and natural conceptions. STUDY DESIGN, SIZE, DURATION: This register-based national cohort study from Denmark includes all women initiating fertility treatments in public and private clinics with homologous gametes in 2007-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were identified in the Danish ART Registry and were cross-linked with the Medical Birth Registry to identify live births. Subfertile couples were followed 2 years (N = 19 884), 3 years (N = 14 445) and 5 years (N = 5165), or until their first live birth. Cumulative live birthrates were estimated 2, 3 and 5 years from the first treatment cycle, in all women, including drop-outs. Birthrates were stratified by type of first treatment (ART/IUI), mode of conception (ART/IUI/natural conception) and female age. MAIN RESULTS AND THE ROLE OF CHANCE: Within 5 years, in women aged <35 years (N = 3553), 35-39 years (N = 1156) and ≥40 years (N = 451), a total of 64%, 49% and 16% had a live birth due to treatment, respectively. Additionally, in women aged < 35 years, 35-39 years and ≥40 years, 16%, 11% and 10% delivered after natural conception, yielding total 5-year birthrates of 80%, 60% and 26%. In women starting treatments with IUI (N = 3028), 35% delivered after IUI within 5 years, 24% delivered after shift to ART treatments and 17% delivered after natural conception. Within 5 years from starting treatments with ART (N = 2137), 53% delivered after ART, 11% delivered after natural conception and 0.6% delivered after IUI. LIMITATIONS, REASONS FOR CAUTION: Birthrates are most likely higher compared to countries without national coverage of treatments and results are influenced by laws and regulations. Information on duration of infertility prior to treatment was not available. Future prospective intervention studies should focus on the role of expectant management. WIDER IMPLICATIONS OF THE FINDINGS: Our results can provide couples with a comprehensible age-stratified prognosis at start of treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was unconditionally funded by Ferring Pharmaceuticals and the Augustinus foundation. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: S.S.M. received an unconditional grant from Ferring Pharmaceuticals; A.A.H. has received personal fees from Ferring Pharmaceuticals not related to this work; A.N.A. reports grants and personal fees from Ferring Pharmaceuticals, personal fees from Merck Serono, grants and personal fees from MSD, outside the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: The study was approved by the Danish Data Protection Agency (J.nr. 2012-41-1330).