Fetal myocardial deformation measured with two-dimensional speckle-tracking echocardiography: longitudinal prospective cohort study of 124 healthy fetuses.

OBJECTIVES: Two-dimensional speckle-tracking echocardiography (2D-STE) is a promising technique which allows assessment of fetal cardiac function, and can be used in the evaluation of cardiac and non-cardiac diseases in pregnancy. However, reliable fetal reference values for deformation parameters measured using 2D-STE are needed before it can be introduced into clinical practice. This study aimed to obtain reference values for fetal global longitudinal strain (GLS) and GLS rate (GLSR) measured using 2D-STE and compare right and left ventricular values. METHODS: This was a prospective longitudinal cohort study of uncomplicated pregnancies that underwent echocardiography every 4 weeks from inclusion at 18-21 weeks until delivery to obtain four-chamber loops of the fetal heart. Left and right ventricular GLS and GLSR were measured using 2D-STE at each examination. Using Bayesian mixed-effects models, reference values with lower and upper 5% prediction limits were calculated according to gestational age. Right and left ventricular GLS values according to gestational age were compared using the Wilcoxon signed-rank test. RESULTS: A total of 592 left ventricular and 566 right ventricular GLS and GLSR measurements were obtained from 124 women with uncomplicated pregnancy and non-anomalous, appropriately grown fetuses. Reference values were obtained for both fetal ventricles according to gestational week. GLS and GLSR values of both ventricles increased (i.e. became less negative) significantly during pregnancy. Right ventricular GLS values were significantly higher (i.e. less negative) than the respective left ventricular values at every gestational week. CONCLUSIONS: Reference values were obtained for fetal GLS and GLSR measured using 2D-STE. GLS and GLSR values increased significantly for both ventricles from the second trimester until delivery. GLS values were significantly higher for the right ventricle compared with the left ventricle. Future studies are needed to assess whether the obtained reference values are helpful in clinical practice in the assessment of pregnancy complications, such as fetal growth restriction or cardiac anomaly. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Diagnostic accuracy of saline contrast sonohysterography in detecting endometrial polyps in women with postmenopausal bleeding: systematic review and meta-analysis.

OBJECTIVE: In women with postmenopausal bleeding, endometrial polyps are a frequent finding and the risk of a focal (pre)malignancy in a polyp is up to 6%. Because of this reported risk, the detection of polyps in these women, preferably by a minimally invasive method, is important. The aim of this systematic review was to assess the accuracy of saline contrast sonohysterography (SCSH) for diagnosis of endometrial polyps in women with postmenopausal bleeding. METHODS: In August 2018, an electronic search was performed of MEDLINE, EMBASE and Web of Science databases to identify all diagnostic studies in which SCSH was used to detect endometrial polyps in postmenopausal women. Studies were included if SCSH was performed to detect endometrial polyps in women with postmenopausal bleeding and if detection of a polyp on hysteroscopy or diagnosis on histopathology was used as a reference standard. Two reviewers assessed methodological quality using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. Two separate analyses were performed for each reference standard. Pooled sensitivity and specificity were calculated using the hierarchical summary receiver-operating characteristics (HSROC) model and HSROC curves were plotted. RESULTS: After selection and quality assessment, five studies were included. Using 'polyps diagnosed with histopathology' as the reference standard, the pooled sensitivity of SCSH was 86.5% (95% CI, 63.6-100%) and the pooled specificity was 91.1% (95% CI, 63.2-100%). Using 'polyps seen on hysteroscopy' as the reference standard, the pooled sensitivity of SCSH was 85.1% (95% CI, 66.9-100%) and the pooled specificity was 84.5% (95% CI, 68.1-100%). Excluding the one study that included women in whom the SCSH examination was reported to be suboptimal, the pooled sensitivity increased to 90.7% (95% CI, 72.8-100%) using hysteroscopy as the reference standard. The sensitivity of hysteroscopy to detect polyps, as reported in two studies, was 81-98%. CONCLUSIONS: Provided that the SCSH examination is of optimal quality, it can be considered as a method to stratify women with postmenopausal bleeding for further diagnostic workup and treatment with hysteroscopy. In women without suspicion of a polypoid lesion on SCSH, and with a benign endometrial sample, expectant management should be considered. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Precisión del diagnóstico de la sonohisterografía con contraste salino en la detección de pólipos endometriales en mujeres con hemorragia postmenopáusica: revisión sistemática y metaanálisis OBJETIVO: En las mujeres con hemorragia postmenopáusica, los pólipos endometriales son frecuentes y el riesgo de una (pre)malignidad focal en un pólipo es de hasta el 6%. Debido a este riesgo reportado, es importante la detección de pólipos en estas mujeres, preferiblemente por un método mínimamente invasivo. El objetivo de esta revisión sistemática fue evaluar la precisión de la sonohisterografía con contraste salino (SCSH, por sus siglas en inglés) para el diagnóstico de pólipos endometriales en mujeres con hemorragia postmenopáusica. MÉTODOS: En agosto de 2018 se realizó una búsqueda electrónica en las bases de datos MEDLINE, EMBASE y Web of Science para identificar todos los estudios diagnósticos en los que se utilizó la SCSH para detectar pólipos endometriales en mujeres postmenopáusicas. Los estudios se incluyeron cuando la SCSH se realizó para detectar pólipos endometriales en mujeres con hemorragia postmenopáusica o cuando la detección de un pólipo en la histeroscopia o el diagnóstico sobre la histopatología se utilizó como estándar de referencia. Dos revisores evaluaron la calidad metodológica mediante la evaluación de calidad de la herramienta de estudios de precisión diagnóstica (QUADAS-2). Se realizaron dos análisis separados para cada estándar de referencia. La sensibilidad y especificidad combinadas se calcularon utilizando el modelo jerárquico de resumen de las características operativas del receptor (HSROC, por sus siglas en inglés) y se trazaron las curvas HSROC. RESULTADOS: Después de la selección y la evaluación de calidad, se incluyeron cinco estudios. Utilizando los 'pólipos diagnosticados con histopatología' como estándar de referencia, la sensibilidad combinada de la SCSH fue del 86,5% (IC 95%, 63,6-100%) y la especificidad combinada fue del 91,1% (IC 95%, 63,2-100%). Utilizando como estándar de referencia los 'pólipos observados en la histeroscopia', la sensibilidad combinada de la SCSH fue del 85,1% (IC 95%: 66,9-100%) y la especificidad combinada fue del 84,5% (IC 95%: 68,1-100%). Excluyendo el único estudio que incluyó mujeres en las que se reportó que el examen por SCSH no fue adecuado, la sensibilidad combinada aumentó al 90,7% (IC 95%: 72,8-100%), usando la histeroscopia como estándar de referencia. La sensibilidad de la histeroscopia para detectar pólipos, tal y como se informó en dos estudios, fue del 81-98%. CONCLUSIONES: Siempre que el examen por SCSH sea de calidad óptima, puede considerarse como un método para estratificar a las mujeres con hemorragia postmenopáusica para su posterior diagnóstico y tratamiento con histeroscopia. En mujeres sin sospecha de una lesión polipoide mediante SCSH y con una muestra endometrial benigna, se debe considerar el tratamiento expectante. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Determinants of perceived sleep quality in normal sleepers.

Objective: This study aimed to establish the determinants of perceived sleep quality over a longer period of time, taking into account the separate contributions of actigraphy-based sleep measures and self-reported sleep indices. Methods: Fifty participants (52 ± 6.6 years; 27 females) completed two consecutive weeks of home monitoring, during which they kept a sleep-wake diary while their sleep was monitored using a wrist-worn actigraph. The diary included questions on perceived sleep quality, sleep-wake information, and additional factors such as well-being and stress. The data were analyzed using multilevel models to compare a model that included only actigraphy-based sleep measures (model Acti) to a model that included only self-reported sleep measures to explain perceived sleep quality (model Self). In addition, a model based on the self-reported sleep measures and extended with nonsleep-related factors was analyzed to find the most significant determinants of perceived sleep quality (model Extended). Results: Self-reported sleep measures (model Self) explained 61% of the total variance, while actigraphy-based sleep measures (model Acti) only accounted for 41% of the perceived sleep quality. The main predictors in the self-reported model were number of awakenings during the night, sleep onset latency, and wake time after sleep onset. In the extended model, the number of awakenings during the night and total sleep time of the previous night were the strongest determinants of perceived sleep quality, with 64% of the variance explained. Conclusion: In our cohort, perceived sleep quality was mainly determined by self-reported sleep measures and less by actigraphy-based sleep indices. These data further stress the importance of taking multiple nights into account when trying to understand perceived sleep quality.

Long-term cognitive trajectories and heterogeneity in patients with schizophrenia and their unaffected siblings.

OBJECTIVE: This study aimed to assess the heterogeneity and stability of cognition in patients with a non-affective psychotic disorder and their unaffected siblings. In addition, we aimed to predict the cognitive subtypes of siblings by their probands. METHOD: Assessments were conducted at baseline, 3 and 6 years in 1119 patients, 1059 siblings and 586 controls from the Genetic Risk and Outcome of Psychosis (GROUP) study. Group-based trajectory modeling was applied to identify trajectories and clustered multinomial logistic regression analysis was used for prediction modeling. A composite score of eight neurocognitive tests was used to measure cognitive performance. RESULTS: Five stable cognitive trajectories ranging from severely altered to high cognitive performance were identified in patients. Likewise, four stable trajectories ranging from moderately altered to high performance were found in siblings. Siblings had a higher risk of cognitive alteration when patients' alteration was mild (OR = 2.21), moderate (OR = 5.70), and severe (OR = 10.07) compared with patients with intact cognitive function. The familial correlation coefficient between pairs of index patients and their siblings was 0.27 (P = 0.003). CONCLUSIONS: The cognitive profiles identified in the current study might be suitable as endophenotypes and could be used in future genetic studies and predicting functional and clinical outcomes.

Adult periodontitis treated with a new device for subgingival lavage-a randomized controlled clinical trial using a split-mouth design.

OBJECTIVES: To evaluate in patients with untreated adult periodontitis, the effect of treatment with a novel pocket irrigator/evacuator device (IED) compared to conventional subgingival debridement (CPT), both provided during the initial phase of active periodontal therapy. METHODS: This study was an examiner-blind, randomized controlled clinical trial using a split-mouth design. Systemically healthy patients with adult periodontitis were selected. Full-mouth probing pocket depth (PPD), gingival bleeding on pocket probing scores (BOPP), gingival recession (REC) and dental plaque (PI) were assessed at baseline. All participants received oral hygiene instructions and supragingival prophylaxis including polishing. In 2 randomly assigned contra-lateral quadrants, approximal sites were irrigated with the IED, whereas in the other quadrants, CPT was provided. The CPT consisted of subgingival debridement using ultrasonic devices followed by the use of hand instruments. At 3 months post-treatment, the clinical parameters were re-assessed. RESULTS: Twenty-five patients met the inclusion criteria and were willing to participate. At 3 months post-treatment, the PPD and BOPP had significantly improved for both treatment modalities. Pockets of ≥5 mm reduced by 0.64 mm in the IED group (P < .001), compared to a reduction of 0.82 mm for the CPT group (P < .001). With respect to the primary outcome parameter (PPD) and BI, the results with the IED were less pronounced. Between the test and control groups, no significant differences were observed for REC and PI. CONCLUSIONS: Oral hygiene instructions, supragingival prophylaxis and subgingival lavage with the IED resulted in a significant reduction in PPD and BOPP. However, the effect does not reach the results of CPT which included the subgingival use of ultrasonic and hand instruments.

Survival analysis of the CEAwatch multicentre clustered randomized trial.

BACKGROUND: The CEAwatch randomized trial showed that follow-up with intensive carcinoembryonic antigen (CEA) monitoring (CEAwatch protocol) was better than care as usual (CAU) for early postoperative detection of colorectal cancer recurrence. The aim of this study was to calculate overall survival (OS) and disease-specific survival (DSS). METHODS: For all patients with recurrence, OS and DSS were compared between patients detected by the CEAwatch protocol versus CAU, and by the method of detection of recurrence, using Cox regression models. RESULTS: Some 238 patients with recurrence were analysed (7·5 per cent); a total of 108 recurrences were detected by CEA blood test, 64 (55·2 per cent) within the CEAwatch protocol and 44 (41·9 per cent) in the CAU group (P = 0·007). Only 16 recurrences (13·8 per cent) were detected by patient self-report in the CEAwatch group, compared with 33 (31·4 per cent) in the CAU group. There was no significant improvement in either OS or DSS with the CEAwatch protocol compared with CAU: hazard ratio 0·73 (95 per cent 0·46 to 1·17) and 0·78 (0·48 to 1·28) respectively. There were no differences in survival when recurrence was detected by CT versus CEA measurement, but both of these methods yielded better survival outcomes than detection by patient self-report. CONCLUSION: There was no direct survival benefit in favour of the intensive programme, but the CEAwatch protocol led to a higher proportion of recurrences being detected by CEA-based blood test and reduced the number detected by patient self-report. This is important because detection of recurrence by blood test was associated with significantly better survival than patient self-report, indirectly supporting use of the CEAwatch protocol.

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations.

Voriconazole (VCZ) exhibits great inter- and intrapatient variability. The latter variation cannot exclusively be explained by concomitant medications, liver disease or dysfunction, and genetic polymorphisms in cytochrome P450 2C19 (CYP2C19). We hypothesized that inflammatory response in patients under VCZ medication might also influence this fluctuation in concentrations. In this study, we explored the association between inflammation, reflected by the C-reactive protein (CRP) concentration, and VCZ trough concentrations over time. A retrospective analysis of data was performed for patients with more than one steady-state VCZ trough concentration and a CRP concentration measured on the same day. A longitudinal analysis was used for series of observations obtained from many study participants over time. The approach involved inclusion of random effects and autocorrelation in linear models to reflect within-person cross-time correlation. A total of 50 patients were eligible for the study, resulting in 139 observations (paired VCZ and CRP concentrations) for the analysis, ranging from 2 to 6 observations per study participant. Inflammation, marked by the CRP concentration, had a significant association with VCZ trough concentrations (P < 0.001). Covariates such as age and interacting comedication ([es]omeprazole), also showed a significant correlation between VCZ and CRP concentrations (P < 0.05). The intrapatient variation of trough concentrations of VCZ was 1.401 (confidence interval [CI], 0.881 to 2.567), and the interpatient variation was 1.756 (CI, 0.934 to 4.440). The autocorrelation between VCZ trough concentrations at two sequential time points was calculated at 0.71 (CI, 0.51 to 0.92). The inflammatory response appears to play a significant role in the largely unpredictable pharmacokinetics of VCZ, especially in patients with high inflammatory response, as reflected by high CRP concentrations.

Age of onset of recurrent respiratory papillomatosis: a distribution analysis.

OBJECTIVE: Distribution of age of onset of recurrent respiratory papillomatosis (RRP) is generally described to be bimodal, with peaks at approximately 5 years and 30 years. This assumption has never been scientifically confirmed, and authors tend to refer to an article that does not describe distribution. Knowledge of the distribution of age of onset is important for virological and epidemiological comprehension. The objective of this study was to determine the distribution of age of onset of RRP in a large international sample. DESIGN: Cross-sectional distribution analysis. PARTICIPANTS: Laryngologists from 12 European hospitals provided information on date of birth and date of onset of all their RRP patients treated between 1998 and 2012. Centers that exclusively treated either patients with juvenile onset RRP or patients with adult onset RRP, or were less accessible for one of these groups, were excluded to prevent skewness. MAIN OUTCOME MEASURES: A mixture model was implemented to describe distribution of age of onset. The best fitting model was selected using the Bayesian information criterion. RESULTS: Six hundred and thirty-nine patients were included in the analysis. Age of onset was described by a three component mixture distribution with lognormally distributed components. Recurrent respiratory papillomatosis starts at three median ages 7, 35 and 64 years. CONCLUSIONS: Distribution of age of onset of RRP shows three peaks. In addition to the already adopted idea of age peaks at paediatric and adult age, there is an additional peak around the age of 64.

The impact of age on changes in quality of life among breast cancer survivors treated with breast-conserving surgery and radiotherapy.

BACKGROUND: The purpose of the study was to determine the impact of young age on health-related quality of life (HRQoL) by comparing HRQoL of younger and older breast cancer patients, corrected for confounding, and of young patients and a general Dutch population. METHODS: The population consisted of breast cancer survivors (stage 0-III) after breast-conserving surgery and radiotherapy. Health-related quality of life was prospectively assessed using the EORTC QLQ-C30 and QLQ-BR23 questionnaires. The association between age (⩽50; 51-70; ⩾70 years) and HRQoL over time was analysed with mixed modelling. The clinical relevance of differences between/within age groups was estimated with Cohen's D and consensus-based guidelines. The HRQoL data from the young patient cohort were compared with Dutch reference data at 3 years after radiotherapy. RESULTS: A total of 1420 patients completed 3200 questionnaires. Median follow-up was 34 (range 6-70) months. Median age was 59 (range 28-85) years. Compared with older subjects, young women reported worse HRQoL in the first year after radiotherapy, but clinical relevance was limited. Three years after radiotherapy, HRQoL values in the younger group were equal to those in the reference population. Pain and fatigue after radiotherapy improved, with medium clinical relevance. CONCLUSIONS: Three years after radiotherapy for breast cancer, young age was not a risk factor for decreased HRQoL.

Influence of inflammation on voriconazole metabolism.

Voriconazole pharmacokinetics shows a large inter- and intrapatient variability. Inflammation is associated with changes in the expression of CYP isoenzymes. Here, we evaluated the influence of inflammation, marked by C-reactive protein (CRP) levels in blood, on the metabolism of voriconazole. Observational data showed an association between CRP level and the ratio of voriconazole N-oxide to voriconazole.

Efficacy of bilateral repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: results of a multicenter double-blind randomized controlled trial.

BACKGROUND: Few studies have investigated the efficacy of repetitive transcranial magnetic stimulation (rTMS) treatment for negative symptoms of schizophrenia, reporting inconsistent results. We aimed to investigate whether 10 Hz stimulation of the bilateral dorsolateral prefrontal cortex during 3 weeks enhances treatment effects. METHOD: A multicenter double-blind randomized controlled trial was performed in 32 patients with schizophrenia or schizo-affective disorder, and moderate to severe negative symptoms [Positive and Negative Syndrome Scale (PANSS) negative subscale ⩾15]. Patients were randomized to a 3-week course of active or sham rTMS. Primary outcome was severity of negative symptoms as measured with the Scale for the Assessment of Negative Symptoms (SANS) and the PANSS negative symptom score. Secondary outcome measures included cognition, insight, quality of life and mood. Subjects were followed up at 4 weeks and at 3 months. For analysis of the data a mixed-effects linear model was used. RESULTS: A significant improvement of the SANS in the active group compared with sham up to 3 months follow-up (p = 0.03) was found. The PANSS negative symptom scores did not show a significant change (p = 0.19). Of the cognitive tests, only one showed a significant improvement after rTMS as compared with sham. Finally, a significant change of insight was found with better scores in the treatment group. CONCLUSIONS: Bilateral 10 Hz prefrontal rTMS reduced negative symptoms, as measured with the SANS. More studies are needed to investigate optimal parameters for rTMS, the cognitive effects and the neural basis.

An activity stimulation programme during a child's first year reduces some indicators of adiposity at the age of two-and-a-half.

AIM: Obesity tracks from childhood into adulthood. We evaluated the effect of early stimulation of physical activity on growth, body composition, motor activity and motor development in toddlers. METHODS: We performed a cluster randomised controlled single-blinded trial in Dutch Well Baby Clinics, with seven nurses and 96 children (40% girls) randomised to the intervention group and six nurses and 65 children (57% girls) to the control group. Intervention nurses advised parents on stimulating motor development and physical activity during regular visits at 2 weeks and two, four, eight and 11 months. Baseline characteristics such as birthweight and mode of feeding were comparable. Outcomes at two-and-a-half years included anthropometry, skinfold thicknesses, bioelectrical impedance analyses, motor development and daily physical activity. We used linear mixed models with nurses as cluster. RESULTS: We evaluated 143 children (89 intervention, 54 control) as 18 dropped out. Skinfolds were significantly lower in intervention children (29.6 ± 4.7 mm) than controls (32.4 ± 6.0 mm), without differences in motor development or daily physical activity. Female interventions showed lower weight, skinfolds, waist and hip circumference. CONCLUSION: An activity stimulating programme during the child's first year improved indicators of adiposity when they were toddlers, especially in girls. Further research should determine whether these effects persist.

Surgery under general anaesthesia in severe hidradenitis suppurativa: a study of 363 primary operations in 113 patients.

BACKGROUND: Treatment of hidradenitis suppurativa (HS) is a difficult undertaking, especially as there is no consensus on what surgical technique is preferred. At our centre severe HS (Hurley II/III) is operated under general anaesthesia, mostly with the STEEP procedure. OBJECTIVES: To investigate characteristics, surgical outcomes and patient satisfaction of HS patients who underwent deroofing or STEEP under general anaesthesia. METHODS: A clinical records-based retrospective analysis was conducted of all patients who had surgery under general anaesthesia between 1999 and 2013. Patient satisfaction was retrospectively investigated with questionnaires. RESULTS: A total of 482 operations (363 primary operations and 119 re-operations) were performed during the study period. The proportion of women in the included population was 68%. The median diagnostic delay (patient's and doctor's delay) was 6.5 years. Relapses occurred after 29.2% of primary operations. Women had higher relapse rates than men [odds ratio 2.85 (1.07;7.61)]. Hypergranulation of the wound was the most common complication and occurred in 7% of all operations. The median score patients attributed to the medical effect of surgery was eight of 10 (zero corresponding to very dissatisfied and 10 to very satisfied). CONCLUSION: The diagnostic delay in HS is long due to a lack of knowledge in both patients and health care professionals, indicating that there is a need for education. Deroofing and the STEEP are effective surgical procedures in severe cases of HS and lead to a relatively high patient satisfaction. The postoperative relapse risk is higher in women. Prospective studies are required for the development of clear guidelines on the appropriate choice of surgery.

Increased time to pregnancy is associated with less optimal neurological condition in 4-year-old singletons, in vitro fertilization itself is not.

STUDY QUESTION: Does ovarian hyperstimulation, the in vitro procedures required for in vitro fertilization (IVF)/ intracytoplasmic sperm injection or the combination of both, affect the neurological outcome of 4-year-old singletons? SUMMARY ANSWER: Ovarian hyperstimulation, the in vitro procedure and the combination of both, were not associated with the worse neurological outcome in 4-year-old singletons. WHAT IS KNOWN ALREADY: Assisted reproduction techniques (ARTs) are not associated with neurological dysfunction during the first post-natal years; however, effects on the long-term neurological outcome are still inconclusive. An increased time to pregnancy (TTP, a proxy for the severity of subfertility) has been associated with a less optimal neurological condition at age 2. The present study focuses on the neurodevelopmental outcome of 4-year-old ART-offspring. STUDY DESIGN, SIZE, DURATION: Longitudinal, prospective follow-up study. PARTICIPANTS, SETTING, METHODS: Four-year-old singletons born to subfertile parents (subfertile group, n = 195), including singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 63), modified natural cycle IVF (MNC-IVF, n = 53) and natural conception (Sub-NC, n = 79). Data on underlying cause of subfertility and TTP were present. In addition, we assessed newly recruited 4-year-old singletons born to fertile parents after natural conception (reference group, n = 98). Neurological development was evaluated with the neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the occurrence of the clinically relevant form of minor neurological dysfunction (complex MND). The primary outcome was the fluency score, as fluency of movements is easily reduced by subtle brain dysfunction. Data were analysed with univariable and multivariable regression analyses, in which special attention was paid to sex differences in the neurological outcome. MAIN RESULTS AND THE ROLE OF CHANCE: The fluency score, NOS and the prevalence of complex MND were similar in COH-IVF, MNC-IVF and Sub-NC children. The neurological condition of children born to subfertile parents was similar to that of children of fertile parents and was independent of the underlying cause of subfertility. No statistically significant associations were found between TTP and the fluency score and NOS. However, a positive correlation was found between TTP and the prevalence of complex MND (TTP in years, adjusted odds ratio [OR] [95% confidence interval, CI]: 1.207 [1.038 to 1.404], P = 0.014); a correlation which could be attributed to girls, in whom an evident positive correlation was present (adjusted OR [95% CI]: 1.542 [1.161 to 2.047], P = 0.003). A similar association was absent in boys. LIMITATIONS, REASONS FOR CAUTION: The prospective design of our study and small post-natal attrition rate (9.3%) reduced potential selection bias based on the child's development or health. The assessors were blind to the mode of conception, except for the group of children born to fertile parents, which was newly recruited. The study lacks sufficient power to conclude firmly that increased TTP is associated with a higher prevalence of complex MND. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that the severity of subfertility, rather than its simple presence or components of IVF treatment, affects the neurological outcome. Moreover, girls may be neurologically more vulnerable for the effect of severity of subfertility. The finding that the severity of subfertility may be the decisive factor rather than the presence of a history of subfertility per se corroborates previous reports. Our results cannot be generalized to multiples, as we studied singletons only. STUDY FUNDING/COMPETING INTERESTS: The study was financially supported by the University Medical Center Groningen, grant number: 754510, the Junior Scientific Masterclass, the Postgraduate School Behavioural and Cognitive Neurosciences and the Cornelia Foundation, Groningen, The Netherlands. The authors have no conflicts of interest to declare.

Cognitive subtypes in non-affected siblings of schizophrenia patients: characteristics and profile congruency with affected family members.

BACKGROUND: Although cognitive subtypes have been suggested in schizophrenia patients, similar analyses have not been carried out in their non-affected siblings. Subtype classification may provide more insight into genetically driven variation in cognitive function. We investigated cognitive subtypes in siblings. METHOD: Cluster analyses were performed in 654 non-affected siblings, on a cognitive battery that included tests of attention, intellectual function and episodic memory. Resulting subtypes in the siblings were analyzed for cognitive, demographic and clinical characteristics and compared with those of their probands. RESULTS: Three sibling subtypes of cognitive function were distinguished: 'normal', 'mixed' and 'impaired'. Normal profile siblings (n = 192) were unimpaired on cognitive tests, in contrast to their proband (n = 184). Mixed profile siblings (n = 228) and their probands (n = 222) had a more similar performance pattern. Impaired profile siblings had poorer functional outcomes (n = 234) and their profile was almost identical to that of their proband (n = 223). Probands with cognitively impaired siblings could be distinguished from other schizophrenia patients by their own cognitive performance. They also had poorer clinical characteristics, including achievement of symptomatic remission. CONCLUSIONS: Unaffected siblings of patients with schizophrenia are heterogeneous with respect to cognitive function. The poorer the cognitive profile of the sibling, the higher the level of correspondence with the proband. The sibling's cognitive subtype was predictive for disease course in the proband. Distinguishing cognitive subtypes of unaffected siblings may be of relevance for genetic studies.

Impact of primary local treatment on the development of distant metastases or death through locoregional recurrence in young breast cancer patients.

In this study, we tested the hypothesis whether breast conserving therapy (BCT) compared with mastectomy is associated with a negative outcome in terms of distant metastases or death (DMD) and investigated the relation between locoregional recurrence (LRR) and DMD in young breast cancer (BC) patients. This study included a consecutive series of 536 patients ≤40 years of age at diagnosis with pathological T1N0-3M0 BC, treated between 1989 and 2005. A multistate survival model was used to evaluate the influences of local treatment and LRR on DMD, adjusted for potential prognostic factors. Patients were treated with mastectomy (N = 213) or BCT (N = 323). Median age at diagnosis was 36.3 years, with a median follow-up of 9.0 years. The 10-year actuarial cumulative incidence of DMD was 30.6 % after mastectomy and 26.3 % after BCT (P = 0.04). In total, 81 (15 %) LRRs were observed. After BCT, patients had a threefold higher risk of LRR than after mastectomy (HR 2.9; 95 % CI 1.6-5.3). Patients with LRR had a higher risk of DMD compared with patients without LRR (HR 5.5; 95 % CI 2.1-14.5). However, BCT was not negatively associated with DMD-after-LRR (HR 0.47; 95 % CI 0.2-1.1, BCT vs mastectomy). In conclusion, although LRR significantly affected DMD, the increased risk of LRR after BCT compared with mastectomy did not lead to a worse DMD outcome in BC patients ≤40 years of age.

The effect of preimplantation genetic screening on neurological, cognitive and behavioural development in 4-year-old children: follow-up of a RCT.

STUDY QUESTION: Does embryo biopsy inherent to preimplantation genetic screening (PGS) affect neurological, cognitive and behavioural development of 4-year-old children? SUMMARY ANSWER: PGS does not seem to affect neurological, cognitive and behavioural development of 4-year-old singletons; however, our data suggest that it may be associated with altered neurodevelopment in twins. WHAT IS KNOWN ALREADY: Evidence concerning the safety of PGS on neurodevelopmental outcome in offspring is scarce. The present study provides information on neurodevelopmental, cognitive and behavioural outcome of 4-year-old PGS offspring. STUDY DESIGN, SIZE, DURATION: A prospective, assessor-blinded follow-up study of children born to women who participated in a multi-centre RCT on the effect of IVF with or without PGS. PARTICIPANTS/MATERIALS, SETTING, METHODS: At 4 years, 49 children (31 singletons, 9 sets of twins) born following IVF with PGS and 64 children (42 singletons, 11 sets of twins) born following IVF without PGS (controls) were assessed (post-natal attrition 18%). Neurological development was evaluated with the standardized, age-specific and sensitive neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the rate of adverse neurological outcome. Primary outcome was the fluency score, as fluency of movements is easily reduced by subtle dysfunction of the brain. Cognitive development was evaluated with the Kaufman Assessment Battery for Children; behavioural development was evaluated with the Child Behavior Checklist. The effect of PGS was analysed with a mixed effects model. MAIN RESULTS AND THE ROLE OF CHANCE: Based on the intention to treat analysis, neurodevelopmental outcome of PGS children was similar to that of controls. However, additional analyses indicated that PGS affected neurodevelopmental outcome of twins in a different way than that of singletons. The fluency score of singletons born following PGS was similar to that of control singletons [mean values, 95% confidence intervals (CIs): 12.2 (11.5;12.8) and 12.2 (11.6;12.8)], respectively, P = 0.977) that was also true for the other neurodevelopmental parameters. The fluency score of PGS twins was significantly lower than that of control twins [mean values, 95% CIs: 10.6 (9.8;11.3) and 12.3 (11.5;13.1)], respectively, P = 0.001); the same was true for the NOS. In addition, PGS in twins was associated with a higher sequential intelligence quotient score. On the other hand, other neurodevelopmental parameters were similar for PGS twins and control twins. Post hoc sample size calculation for the primary outcome parameter, the fluency score, indicated that the study groups, including the subgroups of singletons and twins, were adequately powered. LIMITATIONS, REASONS FOR CAUTION: We assessed singletons and twins who contributed to the generalizability of the study. A limitation of our study is the relative small size of our study groups and the selective dropout in both groups (dropouts PGS group: higher gestational age; control group: less well-educated parents). These preclude the conclusion that PGS per se is not associated with neurodevelopmental, cognitive and behavioural problems in singletons and the conclusion that PGS is associated with altered neurodevelopmental outcome in twins. WIDER IMPLICATIONS OF THE FINDINGS: The need for careful long-term monitoring of children born following embryo biopsy remains, as it is still applied in the form of PGD and it is still unknown whether embryo biopsy affects long-term neurodevelopmental outcome.

Safety of intralesional cidofovir in patients with recurrent respiratory papillomatosis: an international retrospective study on 635 RRP patients.

Intralesional use of cidofovir (Vistide(®)) has been one of the mainstays of adjuvant therapy in patients with recurrent respiratory papillomatosis (RRP) since 1998. In 2011, a communication provided by the producer of cidofovir addressed very serious side effects concerning its off-label use. As this was a general warning, it was inconclusive whether this would account for its use in RRP. The aim of this study is to determine whether nephrotoxic, neutropenic, or oncogenic side effects have occurred after intralesional use of cidofovir in patients with RRP. Update of recent developments in RRP, a multicentre questionnaire and a multicentre retrospective chart review. Sixteen hospitals from eleven countries worldwide submitted records of 635 RRP patients, of whom 275 were treated with cidofovir. RRP patients received a median of three intralesional injections (interquartile range 2-6). There were no statistical differences in occurrence of neutropenia or renal dysfunction before and after cidofovir. There was no statistical difference in occurrence of upper airway and tracheal malignancies between the cidofovir and the non-cidofovir group. In this retrospective patient chart review, no clinical evidence was found for more long-term nephrotoxicity, neutropenia or laryngeal malignancies after the administration of intralesional cidofovir in RRP patients.

The electrical heart axis in fetuses with congenital heart disease, measured with non-invasive fetal electrocardiography.

OBJECTIVES: To determine if the electrical heart axis in different types of congenital heart defects (CHD) differs from that of a healthy cohort at mid-gestation. METHODS: Non-invasive fetal electrocardiography (NI-fECG) was performed in singleton pregnancies with suspected CHD between 16 and 30 weeks of gestation. The mean electrical heart axis (MEHA) was determined from the fetal vectorcardiogram after correction for fetal orientation. Descriptive statistics were used to determine the MEHA with corresponding 95% confidence intervals (CI) in the frontal plane of all fetuses with CHD and the following subgroups: conotruncal anomalies (CTA), atrioventricular septal defects (AVSD) and hypoplastic right heart syndrome (HRHS). The MEHA of the CHD fetuses as well as the subgroups was compared to the healthy control group using a spherically projected multivariate linear regression analysis. Discriminant analysis was applied to calculate the sensitivity and specificity of the electrical heart axis for CHD detection. RESULTS: The MEHA was determined in 127 fetuses. The MEHA was 83.0° (95% CI: 6.7°; 159.3°) in the total CHD group, and not significantly different from the control group (122.7° (95% CI: 101.7°; 143.6°). The MEHA was 105.6° (95% CI: 46.8°; 164.4°) in the CTA group (n = 54), -27.4° (95% CI: -118.6°; 63.9°) in the AVSD group (n = 9) and 26.0° (95% CI: -34.1°; 86.1°) in the HRHS group (n = 5). The MEHA of the AVSD and the HRHS subgroups were significantly different from the control group (resp. p = 0.04 and p = 0.02). The sensitivity and specificity of the MEHA for the diagnosis of CHD was 50.6% (95% CI 47.5% - 53.7%) and 60.1% (95% CI 57.1% - 63.1%) respectively. CONCLUSION: The MEHA alone does not discriminate between healthy fetuses and fetuses with CHD. However, the left-oriented electrical heart axis in fetuses with AVSD and HRHS was significantly different from the control group suggesting altered cardiac conduction along with the structural defect. TRIAL REGISTRATION: Clinical trial registration number: NL48535.015.14.

A randomized controlled trial studying the effect of maternal hyperoxygenation on fetal heart rate in suspected fetal distress.

OBJECTIVE: To investigate the effect of maternal hyperoxygenation on fetal heart rate (FHR) when applied for suspected fetal distress during the second stage of term labor. APPROACH: A single-center randomized controlled trial was conducted in a tertiary care hospital in The Netherlands. Participants were included during the second stage of labor in case of an intermediary or abnormal FHR pattern. Patients were randomized to receive either 100% oxygen at 10 l/min until delivery, or conventional care without additional oxygen. The primary outcome was the change in FHR pattern before and after the onset of the study, measured as the change in depth and duration of FHR decelerations. Secondary outcome measures were features based on phase-rectified signal averaging (PRSA), baseline assignability, and deceleration characteristics of the FHR pattern. MAIN RESULTS: Between March 2016 and April 2018, 117 women were included. The FHR pattern could be analyzed for 71 participants, the other 46 women delivered before the end of the post time-frame. A 2.3% reduction in depth and duration of FHR decelerations was found after maternal hyperoxygenation, compared to a 10% increase in the control group (p = 0.24). Maternal hyperoxygenation had a significantly positive effect on PRSA metrics, with a decrease in PRSA-acceleration capacity (p = 0.03) and PRSA-deceleration capacity (p = 0.02) in the intervention group compared to the control group. SIGNIFICANCE: The difference in depth and duration of decelerations after the start of the study was not significantly different between both study groups. A statistically significant positive effect on PRSA-deceleration capacity and PRSA-acceleration capacity was found after maternal hyperoxygenation, which might be associated with a positive effect on neonatal outcome.