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Association of Chemotherapy Timing in Pregnancy with Congenital Malformation
No full textImportance: Chemotherapy during the first trimester of pregnancy should be avoided owing to the risk of congenital malformations. However, the precise gestational age at which chemotherapy can be initiated safely remains unclear. Objective: To assess congenital malformation rates associated with gestational age at initiation of chemotherapy among pregnant women with cancer. Design, Setting, and Participants: This multicenter cohort study evaluated all pregnant women who received chemotherapy between 1977 and 2019 registered in the International Network on Cancer, Infertility and Pregnancy (INCIP) database. Data were analyzed from February 15 to June 2, 2020. Exposures: Cancer treatment with chemotherapy during pregnancy. Main Outcomes and Measures: Analysis was focused on major and minor structural malformations in offspring, defined by EUROCAT, detected during pregnancy or at birth. Results: A total of 755 women in the INCIP database who underwent cancer treatment with chemotherapy during pregnancy were included in analysis. The median (range) age at cancer diagnosis was 33 (14-48) years. Among offspring, the major congenital malformation rate was 3.6% (95% CI, 2.4%-5.2%), and the minor congenital malformation rate was 1.9% (95% CI, 1.0%-3.1%). Chemotherapy exposure prior to 12 weeks gestational age was associated with a high rate of major congenital malformations, at 21.7% (95% CI, 7.5%-43.7%; odds ratio, 9.24 [95% CI, 3.13-27.30]). When chemotherapy was initiated after gestational age 12 weeks, the frequency of major congenital malformations was 3.0% (95% CI, 1.9%-4.6%), which was similar to the expected rates in the general population. Minor malformations were comparable when exposure occurred before or after gestational age 12 weeks (4.3% [95% CI, 0.1%-21.9%] vs 1.8% [95% CI, 1.0-3.0]; odds ratio, 3.13 [95% CI, 0.39-25.28]). Of 29 women who received chemotherapy prior to 12 weeks gestation, 17 (58.6%) were not aware of pregnancy, and 6 (20.7%) experienced a miscarriage (3 women [10.3%]) or decided to terminate their pregnancy (3 women [10.3%]). Conclusions and Relevance: This cohort study found that chemotherapy was associated with an increased risk of major congenital malformations only in the first 12 weeks of pregnancy. The risk of congenital malformations when chemotherapy was administered during the first trimester and the high number of incidental pregnancies during cancer treatment in the INCIP registry underscore the importance of contraceptive advice and pregnancy testing at the start of chemotherapeutic treatment in young women with cancer..</p
Air pollution, residential greenness and metabolic dysfunction during early pregnancy in the infancia y medio ambiente (Inma) cohort
No full textDespite extensive study, the role of air pollution in gestational diabetes remains unclear, and there is limited evidence of the beneficial impact of residential greenness on metabolic dysfunction during pregnancy. We used data from mothers in the Spanish INfancia y Medio Ambiente (INMA) Project from 2003–2008. We obtained spatiotemporally resolved estimates of fine particulate matter (PM2.5 ) and nitrogen dioxide (NO2 ) exposures in early pregnancy and estimated residential greenness using satellite-based Normal Difference Vegetation Index (NDVI) within 100, 300 and 500 m buffers surrounding the mother’s residence. We applied logistic regression models to evaluate associations between each of the three exposures of interest and (a) glucose intolerance and (b) abnormal lipid levels. We found limited evidence of associations between increases in PM2.5 and NO2 exposures and the metabolic outcomes. Though not statistically significant, high PM2.5 exposure (≥25 µg/m3 ) was associated with increased odds of glucose intolerance (OR = 1.16, 95% CI: 0.82, 1.63) and high cholesterol (OR = 1.14, 95% CI: 0.90, 1.44). High NO2 exposure (≥39.8 µg/m3 ) was inversely associated with odds of high triglycerides (OR = 0.70, 95% CI: 0.45, 1.08). Whereas NDVI was not associated with glucose intolerance, odds of high triglycerides were increased, although the results were highly imprecise. Results were unchanged when the air pollutant variables were included in the regression models. Given the equivocal findings in our study, additional investigations are needed to assess effects of air pollution and residential greenness on metabolic dysfunction during pregnancy.</p
Early career perspectives of young Dutch cardiologists
No full textBackground: There are nationwide concerns about the unemployment rate among young Dutch cardiologists and the increase in temporary positions. Therefore, the aim of this study was to investigate the unemployment rate in this subgroup as well as the length of time between the end of their training and the acquisition of a permanent position. Methods: All cardiologists who completed their training between January 2015 and December 2018 were invited to fill in an online questionnaire about their demographic characteristics, professional profile and employment status. The unemployment rate was calculated and Kaplan-Meier curves were used to determine the time between the end of training and the first permanent contract. Results: In total, 174 participants were included (mean age 35 ± 3 years, 64% male, median follow-up 2.3 years (interquartile range 1.4–3.2 years)). The unemployment rate was 0.6% (n = 1). Only 12 participants (7%) started their career with a permanent position. The percentage of cardiologists with a temporary position was 82%, 61% and 33% at 1, 2 and 3 years, respectively. The percentage of cardiologists with a temporary position did not differ with regard to age, gender, holding a PhD degree or type of teaching institution attended (academic vs non-academic). Forty-four per cent of participants perceived the current job market to be problematic. Conclusions: The unemployment rate among young cardiologists in the Netherlands was low between 2015 and 2018. The vast majority of cardiologists start their career on a temporary contract. Three years later, 33% still hold temporary positions. Due to the resultant job insecurity, many young cardiologists describe the job market as problematic.</p
The Value of the Surprise Question to Predict One-Year Mortality in Idiopathic Pulmonary Fibrosis
No full textBackground: Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease with a heterogeneous disease course. Timely initiation of palliative care is often lacking. The surprise question "Would you be surprised if this patient died within the next year?"is increasingly used as a clinical prognostic tool in chronic diseases but has never been evaluated in IPF. Objective: We aimed to evaluate the predictive value of the surprise question for 1-year mortality in IPF. Methods: In this prospective cohort study, clinicians answered the surprise question for each included patient. Clinical parameters and mortality data were collected. The sensitivity, specificity, accuracy, negative, and positive predictive value of the surprise question with regard to 1-year mortality were calculated. Multivariable logistic regression analysis was performed to evaluate which factors were associated with mortality. In addition, discriminative performance of the surprise question was assessed using the C-statistic. Results: In total, 140 patients were included. One-year all-cause mortality was 20% (n = 28). Clinicians identified patients with a survival of <1 year with a sensitivity of 68%, a specificity of 82%, an accuracy of 79%, a positive predictive value of 49%, and a negative predictive value of 91%. The surprise question significantly predicted 1-year mortality in a multivariable model (OR 3.69; 95% CI 1.24-11.02; p = 0.019). The C-statistic of the surprise question to predict mortality was 0.75 (95% CI 0.66-0.85). Conclusions: The answer on the surprise question can accurately predict 1-year mortality in IPF. Hence, this simple tool may enable timely focus on palliative care for patients with IPF.</p
Second-Order Disjoint Factor Analysis
No full textHierarchical models are often considered to measure latent concepts defining nested sets of manifest variables. Therefore, by supposing a hierarchical relationship among manifest variables, the general latent concept can be represented by a tree structure where each internal node represents a specific order of abstraction for the latent concept measured. In this paper, we propose a new latent factor model called second-order disjoint factor analysis in order to model an unknown hierarchical structure of the manifest variables with two orders. This is a second-order factor analysis, which—respect to the second-order confirmatory factor analysis—is exploratory, nested and estimated simultaneously by maximum likelihood method. Each subset of manifest variables is modeled to be internally consistent and reliable, that is, manifest variables related to a factor measure “consistently” a unique theoretical construct. This feature implies that manifest variables are positively correlated with the related factor and, therefore, the associated factor loadings are constrained to be nonnegative. A cyclic block coordinate descent algorithm is proposed to maximize the likelihood. We present a simulation study that investigates the ability to get reliable factors. Furthermore, the new model is applied to identify the underlying factors of well-being showing the characteristics of the new methodology. A final discussion completes the paper.</p
Association of phthalate exposure with thyroid function during pregnancy
No full textBackground: The extent of thyroid disruptive effects of phthalates during pregnancy remains unclear. Aim: To investigate the association of maternal urinary phthalates with markers of the thyroid system during early pregnancy. Methods: Urinary concentrations of phthalate metabolites and serum concentrations of thyroid stimulating hormone (TSH), free and total thyroxine (FT4 and TT4) and free and total triiodothyronine (FT3 and TT3) were measured in pregnant women in early pregnancy in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study (2007-ongoing), a population-based prospective cohort. Results: In the 1,996 included women, higher di-ethyl-hexyl phthalate (DEHP) metabolites were associated with a lower FT4 (β [SE] for the molar sum: −0.13 [0.06], P = 0.03) and a higher TSH/FT4 ratio (0.003 [0.001], P = 0.03). Higher concentrations of di-iso-nonyl phthalate (DINP) metabolites were associated with a lower TT4 (β [SE] for the molar sum: 0.93 [0.44], P = 0.03) as well as with lower TT4/FT4 and TT4/TT3 ratios. Higher metabolites of both dibutyl and butyl-benzyl phthalate (DBP and BBzP) were associated with lower T4/T3 ratio (free and total) and higher FT4/TT4 and FT3/TT3 ratios. A higher diisononyl cyclohexane dicarboxylate (DINCH) metabolite concentration was associated with a higher TT3. Conclusions: These results translate results from experimental studies suggesting that exposure to phthalates may interfere with the thyroid system during pregnancy. This is also true for compounds that have been introduced to replace known disruptive phthalates. Further experimental studies should take into account the human evidence to better investigate the potential underlying mechanisms of thyroid disruption by phthalates.</p
Clinical Implementation of Biologics and Small Molecules in the Treatment of Hidradenitis Suppurativa
No full textHidradenitis suppurativa (HS) is a chronic, recurrent, auto-inflammatory skin disease originating from the hair follicles. The typical inflammatory nodules, abscesses, and draining sinus tracts (tunnels) are characterized by a massive influx of neutrophils, macrophages, B-cells, plasma cells, T helper (Th)1, Th17 cells and upregulation of pro-inflammatory cytokines such as IL-1, IL-17, IL-12/23, and TNF-α. Over the last decades, several clinical trials evaluated the clinical efficacy of different biologics targeting these pro-inflammatory cytokines, in particular TNF-α and IL-1. However, adalimumab is still the only registered drug for HS. This review discusses biologics and small molecules with high level of evidence for their clinical application, provides guidance on when and how to use these biologics and small molecules in clinical practice, and elaborates on the combination with medical and surgical treatment options beyond the current guidelines. Furthermore this review provides an overview of potential biologics and small molecules currently under investigation for novel targets in HS such as IL-36, C5a, Janus kinase family members, CD-40, LTA4 and CXCR1/2.</p
Are pain coping strategies and neuropathic pain associated with a worse outcome after conservative treatment for Achilles tendinopathy?
No full textObjectivesTo analyse whether (1) passive or active pain coping strategies and (2) presence of neuropathic pain component influences the change of Achilles tendinopathy (AT) symptoms over a course of 24 weeks in conservatively-treated patients.DesignProspective cohort study.MethodsPatients with clinically-diagnosed chronic midportion AT were conservatively treated. At baseline, the Pain Coping Inventory (PCI) was used to determine scores of coping, which consisted of two domains, active and passive (score ranging from 0 to 1; the higher, the more active or passive). Presence of neuropathic pain (PainDETECT questionnaire, −1 to 38 points) was categorized as (a) unlikely (≤12 points), (b) unclear (13–18 points) and (c) likely (≥19 points). The symptom severity was determined with the validated Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire (0–100) at baseline, 6, 12 and 24 weeks. We analysed the correlation between (1) PCI and (2) PainDETECT baseline scores with change in VISA-A score using an adjusted Generalized Estimating Equations model.ResultsOf 80 included patients, 76 (95%) completed the 24-weeks follow-up. The mean VISA-A score (standard deviation) increased from 43 (16) points at baseline to 63 (23) points at 24 weeks. Patients had a mean (standard deviation) active coping score of 0.53 (0.13) and a passive score of 0.43 (0.10). Twelve patients (15%) had a likely neuropathic pain component. Active and passive coping mechanisms and presence of neuropathic pain did not influence the change in AT symptoms (p = 0.459, p = 0.478 and p = 0.420, respectively).ConclusionsContrary to widespread belief, coping strategy and presence of neuropathic pain are not associated with a worse clinical outcome in this homogeneous group of patients with clinically diagnosed AT
The nature of the self
No full textHow neural correlates of self-concept are influenced by environmental versus genetic factors is currently not fully understood. We investigated heritability estimates of behavioral and neural correlates of self-concept in middle childhood since this phase is an important time window for taking on new social roles in academic and social contexts. To do so, a validated self-concept fMRI task was applied in a twin sample of 345 participants aged between 7 and 9 years. In the self-concept condition, participants were asked to indicate whether academic and social traits applied to them whereas the control condition required trait categorization. The self-processing activation analyses (n = 234) revealed stronger medial prefrontal cortex (mPFC) activation for self than for control conditions. This effect was more pronounced for social-self than academic self-traits, whereas stronger dorsolateral prefrontal cortex (DLPFC) activation was observed for academic versus social self-evaluations. Behavioral genetic modeling (166 complete twin pairs) revealed that 25–52% of the variation in academic self-evaluations was explained by genetic factors, whereas 16–49% of the variation in social self-evaluations was explained by shared environmental factors. Neural genetic modeling (91 complete twin pairs) for variation in mPFC and anterior prefrontal cortex (PFC) activation for academic self-evaluations confirmed genetic and unique environmental influences, whereas anterior PFC activation for social self-evaluations was additionally influenced by shared environmental influences. This indicates that environmental context possibly has a larger impact on the behavioral and neural correlates of social self-concept at a young age. This is the first study demonstrating in a young twin sample that self-concept depends on both genetic and environmental factors, depending on the specific domain.</p