Re-attendance in supplemental breast MRI screening rounds of the DENSE trial for women with extremely dense breasts.

OBJECTIVES: Supplemental MRI screening improves early breast cancer detection and reduces interval cancers in women with extremely dense breasts in a cost-effective way. Recently, the European Society of Breast Imaging recommended offering MRI screening to women with extremely dense breasts, but the debate on whether to implement it in breast cancer screening programs is ongoing. Insight into the participant experience and willingness to re-attend is important for this discussion. METHODS: We calculated the re-attendance rates of the second and third MRI screening rounds of the DENSE trial. Moreover, we calculated age-adjusted odds ratios (ORs) to study the association between characteristics and re-attendance. Women who discontinued MRI screening were asked to provide one or more reasons for this. RESULTS: The re-attendance rates were 81.3% (3458/4252) and 85.2% (2693/3160) in the second and third MRI screening round, respectively. A high age (> 65 years), a very low BMI, lower education, not being employed, smoking, and no alcohol consumption were correlated with lower re-attendance rates. Moderate or high levels of pain, discomfort, or anxiety experienced during the previous MRI screening round were correlated with lower re-attendance rates. Finally, a plurality of women mentioned an examination-related inconvenience as a reason to discontinue screening (39.1% and 34.8% in the second and third screening round, respectively). CONCLUSIONS: The willingness of women with dense breasts to re-attend an ongoing MRI screening study is high. However, emphasis should be placed on improving the MRI experience to increase the re-attendance rate if widespread supplemental MRI screening is implemented. CLINICAL RELEVANCE STATEMENT: For many women, MRI is an acceptable screening method, as re-attendance rates were high - even for screening in a clinical trial setting. To further enhance the (re-)attendance rate, one possible approach could be improving the overall MRI experience. KEY POINTS: • The willingness to re-attend in an ongoing MRI screening study is high. • Pain, discomfort, and anxiety in the previous MRI screening round were related to lower re-attendance rates. • Emphasis should be placed on improving MRI experience to increase the re-attendance rate in supplemental MRI screening.

Widening epidemiological data on the prevalence of child maltreatment: Validation of the German ICAST-R in a student sample and national household survey.

BACKGROUND: A number of instruments for measuring child maltreatment (CM) prevalence have repeatedly been used across different countries. Although they hold the potential for providing benchmarks to tackle the gap of lacking comparability of CM prevalence across countries, contextual information about the adverse experiences such as perpetrator, chronicity, frequency, or severity are rarely covered. The ISPCAN Child Abuse Screening Tool - Retrospective (ICAST-R) covers these important dimensions. The German version increases the number of available versions to 21 different languages. Spoken by about 120 million people, German is one of the 20 most prevalent languages around the world. Moreover, the ICAST-R is intended to be used with young adults. This study further aims at adding towards the gap of psychometrics in older age groups. METHODS: Analyses are based on both a sample of German students (n = 333) and a nationally representative household survey (n = 2515). The validation process covered six steps: (1) Analyses of missing data on single items, (2) calculation of descriptive statistics to estimate the prevalence CM as well as subjective severity and main perpetrators. (3) Structural validity of the four conceptualized subtypes of CM (neglect, physical abuse, emotional abuse and sexual abuse) was tested using confirmatory factor analyses (CFA). Next (4), equivalence testing by multigroup confirmatory factor analyses (MGCFA) on age groups was conducted within the representative sample; (5) reliability was tested by determining internal consistencies for each subscale via the McDonald's Omega, Kuder-Richardson 20 (KR-20), and Cronbach's alpha. Lastly (6), criterion validity was tested in regression models comparing depressive/anxious symptomatology for single victimization and polyvictimization. RESULTS: The German ICAST-R yielded low missing values items in both samples. 16 % of the participants in the national household survey reported neglect, 20.3 % physical abuse, 22.2 % emotional abuse, and 8.6 % sexual abuse. Polyvictimization was prevalent with 20.6 % of subjects reporting >2 types of CM. Students in the pilot-survey reported much higher prevalence estimates than participants in the nationally representative sample. The types of CM subjectively rated as most harmful were emotional abuse and sexual abuse. In both samples, structural validity was similarly confirmed as CFA was reproducing the four conceptualized subtypes of CM with adequate fit (household survey: CFI 0.919, TLI 0.907, RMSEA 0.017, SRMR 0.046). Internal consistency achieved acceptable and comparable values for all three types of coefficients; criterion validity was established with a significant dose-response effect of CM experiences on both anxiety and depressive symptoms/diagnoses. Age dependent analyses on structural validity (MGCFA) and reliability in the household survey revealed potential weaknesses of items. CONCLUSION: The German version of the ICAST-R both widens the possibility of international CM prevalence comparison and provides novel epidemiological data for Germany on subjective severity of CM and CM perpetrators. Even in the presence of a marked selection bias, the ICAST-R had similarly good psychometric properties in the student and nationally representative household sample. Except for issues with two items, equivalence testing was comparable across age groups.

Condemn or Treat? The Influence of Adults' Stigmatizing Attitudes on Mental Health Service Use for Children.

Stigmatizing attitudes towards mental disorders influence parents' help-seeking behavior for their child's mental health problems. As untreated mental disorders can cause morbidity and mortality, such parental attitudes are a serious barrier for public health promotion. Therefore, the help-seeking readiness in a distressed child's broad social environment is essential. However, the role of stigma was unexplored in this context. This study empirically investigated the influence of adults' stigmatizing attitudes towards mentally disabled people on their readiness to seek professional help for children's mental health issues. Data from a representative German sample (N = 1906; 52% female) were collected between July and October 2021. A heteroscedastic ordered probit model was used for estimation. An empirical analysis provides evidence for a significant negative relationship between adults' stigmatizing attitudes and their readiness to initiate mental health support for children (ß = −0.01; p < 0.001). Support acceptance seems to be independent of having children. To tackle stigmatizing attitudes and to promote public health, mental health literacy should be fostered through broad-based approaches. Awareness should be raised that children are also entitled to mental health care, just as they are in other health areas. Policy makers need to promote comprehensive information about mental illnesses and create incentives for acute and preventive service use.

Can You Sleep? - Effect of Retrospective Recall of Child Maltreatment on Sleep Parameters and the Mediating Role of Psychological Distress Among Students of Two German Universities.

Purpose: Child maltreatment may be linked with long-term sleeping disorders and limited coping with stress. Yet, the potential relationships are only marginally studied. Patients and Methods: Based on a sample of young adults (n = 312) this study aims at exploring the effects of child maltreatment and the experience of threat to personal safety and life in childhood on sleep disturbances in early adulthood. Data were collected at the two study sites, Ulm University and Bielefeld University, by an online survey. For both risk factors, child maltreatment and the experience of threat to personal safety and life in childhood, a direct impact on sleep disturbances and an indirect path via psychological distress were tested using Structural Equation Modelling (SEM). Results: In these models, the direct path to sleep disturbances turned out to be significant for the experience of threat to personal safety and life (Path C: b = 0.18, p = 0.013), but not for child maltreatment (Path C: b = 0.05, p = 0.491). However, the current level of psychological distress was found to have a mediating effect on sleep disturbances for both risk factors, thereby confirming indirect significant effects. Conclusion: Considering that the etiological pathway of child maltreatment on sleeping disturbances is mediated via psychological distress, this provides a venue to test in future research whether stress reduction interventions can reduce the negative consequences of child maltreatment on sleep disorders.

COVID-19-What Price Do Children Pay? An Analysis of Economic and Social Policy Factors.

Numerous studies have addressed the indirect consequences of the COVID-19 pandemic for children such as social isolation or increases in reported child maltreatment. Research on the economic and sociopolitical consequences is scarce as they can only be evaluated with a time lag. To improve our understanding of future, long-term developments in the context of the COVID-19 pandemic, we gathered findings from the still unexploited empirical literature on the aftermath of earlier pandemics, epidemics, and other infectious disease outbreaks. On top of this, we scrutinized research on past economic crises to interpret the link between changes in the economy and the health of children. Many of the side effects of battling the spread of the current pandemic, such as school closures, the stigma of infection, or conflicts about vaccines, are not novel and have already been documented in connection with previous infectious disease outbreaks. Results highlight that changes in the financial situation of families and socio-political challenges affect the situation and daily routine of children and youth in the long term. In consequence, the already pronounced socioeconomic inequalities will likely further increase. On top of this, due to reduced revenues, child protective services are likely to face challenges in the availability of human and financial resources.

Cost-Effectiveness of Magnetic Resonance Imaging Screening for Women With Extremely Dense Breast Tissue.

BACKGROUND: Extremely dense breast tissue is associated with increased breast cancer risk and limited sensitivity of mammography. The DENSE trial showed that additional magnetic resonance imaging (MRI) screening in women with extremely dense breasts resulted in a substantial reduction in interval cancers. The cost-effectiveness of MRI screening for these women is unknown. METHODS: We used the MISCAN-breast microsimulation model to simulate several screening protocols containing mammography and/or MRI to estimate long-term effects and costs. The model was calibrated using results of the DENSE trial and adjusted to incorporate decreases in breast density with increasing age. Screening strategies varied in the number of MRIs and mammograms offered to women ages 50-75 years. Outcomes were numbers of breast cancers, life-years, quality-adjusted life-years (QALYs), breast cancer deaths, and overdiagnosis. Incremental cost-effectiveness ratios (ICERs) were calculated (3% discounting), with a willingness-to-pay threshold of €22 000. RESULTS: Calibration resulted in a conservative fit of the model regarding MRI detection. Both strategies of the DENSE trial were dominated (biennial mammography; biennial mammography plus MRI). MRI alone every 4 years was cost-effective with €15 620 per QALY. Screening every 3 years with MRI alone resulted in an incremental cost-effectiveness ratio of €37 181 per QALY. All strategies with mammography and/or a 2-year interval were dominated because other strategies resulted in more additional QALYs per additional euro. Alternating mammography and MRI every 2 years was close to the efficiency frontier. CONCLUSIONS: MRI screening is cost-effective for women with extremely dense breasts, when applied at a 4-year interval. For a willingness to pay more than €22 000 per QALY gained, MRI at a 3-year interval is cost-effective as well.

Reducing False-Positive Screening MRI Rate in Women with Extremely Dense Breasts Using Prediction Models Based on Data from the DENSE Trial.

Background High breast density increases breast cancer risk and lowers mammographic sensitivity. Supplemental MRI screening improves cancer detection but increases the number of false-positive screenings. Thus, methods to distinguish true-positive MRI screening results from false-positive ones are needed. Purpose To build prediction models based on clinical characteristics and MRI findings to reduce the rate of false-positive screening MRI findings in women with extremely dense breasts. Materials and Methods Clinical characteristics and MRI findings in Dutch breast cancer screening participants (age range, 50-75 years) with positive first-round MRI screening results (Breast Imaging Reporting and Data System 3, 4, or 5) after a normal screening mammography with extremely dense breasts (Volpara density category 4) were prospectively collected within the randomized controlled Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial from December 2011 through November 2015. In this secondary analysis, prediction models were built using multivariable logistic regression analysis to distinguish true-positive MRI screening findings from false-positive ones. Results Among 454 women (median age, 52 years; interquartile range, 50-57 years) with a positive MRI result in a first supplemental MRI screening round, 79 were diagnosed with breast cancer (true-positive findings), and 375 had false-positive MRI results. The full prediction model (area under the receiver operating characteristics curve [AUC], 0.88; 95% CI: 0.84, 0.92), based on all collected clinical characteristics and MRI findings, could have prevented 45.5% (95% CI: 39.6, 51.5) of false-positive recalls and 21.3% (95% CI: 15.7, 28.3) of benign biopsies without missing any cancers. The model solely based on readily available MRI findings and age had a comparable performance (AUC, 0.84; 95% CI: 0.79, 0.88; P = .15) and could have prevented 35.5% (95% CI: 30.4, 41.1) of false-positive MRI screening results and 13.0% (95% CI: 8.8, 18.6) of benign biopsies. Conclusion Prediction models based on clinical characteristics and MRI findings may be useful to reduce the false-positive first-round screening MRI rate and benign biopsy rate in women with extremely dense breasts. Clinical trial registration no. NCT01315015 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Imbriaco in this issue.

Mothers' daily perceived stress influences their children's mental health during SARS-CoV-2-pandemic-an online survey.

BACKGROUND: The current situation caused by the SARS-CoV-2-pandemic is associated with serious losses for everyone and has been affecting social life, politics, the economy and the media worldwide. Preventive isolation and social distancing strategies have confronted families with a large number of different challenges. The current epidemic and quarantine restrictions have a verifiable influence on the emotional and social development of children and adolescents. During this ongoing situation children of parents, who already were mentally stressed, seem particularly at risk. OBJECTIVE: We aimed to assess the role of maternal daily perceived stress on children's mental health during the SARS-CoV-2-pandemic. METHODS: An online "SARS-CoV-2-pandemic survey" was developed to assess children's mental health since the beginning of the SARS-CoV-2 pandemic. To describe maternal perceived everyday stress, data from a longitudinal survey was utilized. Our survey includes elements and versions of the Childhood Trauma Questionnaire, the Strengths and Difficulties Questionnaire and the Perceived Stress Scale. We furthermore collected socio-demographic data. Due to our limited dependent variables we applied Tobit models for estimation. RESULTS: We found a positive and significant effect of the maternal perceived everyday stress on children's emotional problems during the pandemic. Furthermore, results provide empirical evidence for an increase of the children's hyperactivity level dependent on the mother's perceived stress before the SARS-COV-2 crisis. We could not find significant effects for the relationship between mother's perceived everyday stress and the children's behavioral problems. CONCLUSIONS: Analyses illustrate the effects on children's mental distress during everyday life in the SARS-CoV-2 pandemic. Future research needs to identify influencing factors with regard to political, economic and social restrictions, in order to prevent children's mental health problems.

Supplemental Breast MRI for Women with Extremely Dense Breasts: Results of the Second Screening Round of the DENSE Trial.

Background In the first (prevalent) supplemental MRI screening round of the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial, a considerable number of breast cancers were found at the cost of an increased false-positive rate (FPR). In incident screening rounds, a lower cancer detection rate (CDR) is expected due to a smaller pool of prevalent cancers, and a reduced FPR, due to the availability of prior MRI examinations. Purpose To investigate screening performance indicators of the second round (incidence round) of the DENSE trial. Materials and Methods The DENSE trial (ClinicalTrials.gov: NCT01315015) is embedded within the Dutch population-based biennial mammography screening program for women aged 50-75 years. MRI examinations were performed between December 2011 and January 2016. Women were eligible for the second round when they again had a negative screening mammogram 2 years after their first MRI. The recall rate, biopsy rate, CDR, FPR, positive predictive values, and distributions of tumor characteristics were calculated and compared with results of the first round using 95% CIs and χ2 tests. Results A total of 3436 women (median age, 56 years; interquartile range, 48-64 years) underwent a second MRI screening. The CDR was 5.8 per 1000 screening examinations (95% CI: 3.8, 9.0) compared with 16.5 per 1000 screening examinations (95% CI: 13.3, 20.5) in the first round. The FPR was 26.3 per 1000 screening examinations (95% CI: 21.5, 32.3) in the second round versus 79.8 per 1000 screening examinations (95% CI: 72.4, 87.9) in the first round. The positive predictive value for recall was 18% (20 of 110 participants recalled; 95% CI: 12.1, 26.4), and the positive predictive value for biopsy was 24% (20 of 84 participants who underwent biopsy; 95% CI: 16.0, 33.9), both comparable to that of the first round. All tumors in the second round were stage 0-I and node negative. Conclusion The incremental cancer detection rate in the second round was 5.8 per 1000 screening examinations-compared with 16.5 per 1000 screening examinations in the first round. This was accompanied by a strong reduction in the number of false-positive results. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Moy and Gao in this issue.

Supplemental MRI Screening for Women with Extremely Dense Breast Tissue.

BACKGROUND: Extremely dense breast tissue is a risk factor for breast cancer and limits the detection of cancer with mammography. Data are needed on the use of supplemental magnetic resonance imaging (MRI) to improve early detection and reduce interval breast cancers in such patients. METHODS: In this multicenter, randomized, controlled trial in the Netherlands, we assigned 40,373 women between the ages of 50 and 75 years with extremely dense breast tissue and normal results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The groups were assigned in a 1:4 ratio, with 8061 in the MRI-invitation group and 32,312 in the mammography-only group. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period. RESULTS: The interval-cancer rate was 2.5 per 1000 screenings in the MRI-invitation group and 5.0 per 1000 screenings in the mammography-only group, for a difference of 2.5 per 1000 screenings (95% confidence interval [CI], 1.0 to 3.7; P<0.001). Of the women who were invited to undergo MRI, 59% accepted the invitation. Of the 20 interval cancers that were diagnosed in the MRI-invitation group, 4 were diagnosed in the women who actually underwent MRI (0.8 per 1000 screenings) and 16 in those who did not accept the invitation (4.9 per 1000 screenings). The MRI cancer-detection rate among the women who actually underwent MRI screening was 16.5 per 1000 screenings (95% CI, 13.3 to 20.5). The positive predictive value was 17.4% (95% CI, 14.2 to 21.2) for recall for additional testing and 26.3% (95% CI, 21.7 to 31.6) for biopsy. The false positive rate was 79.8 per 1000 screenings. Among the women who underwent MRI, 0.1% had either an adverse event or a serious adverse event during or immediately after the screening. CONCLUSIONS: The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography resulted in the diagnosis of significantly fewer interval cancers than mammography alone during a 2-year screening period. (Funded by the University Medical Center Utrecht and others; DENSE ClinicalTrials.gov number, NCT01315015.).

Tremors in white rhinoceroses (Ceratotherium simum) during etorphine-azaperone immobilisation.

Little is known about the mechanisms causing tremors during immobilisation of rhinoceros and whether cardiorespiratory supportive interventions alter their intensity. Therefore, we set out to determine the possible mechanisms that lead to muscle tremors and ascertain whether cardiorespiratory supportive interventions affect tremor intensity. We studied tremors and physiological responses during etorphine-azaperone immobilisation in eight boma-held and 14 free-living white rhinoceroses. Repeated measures analysis of variance and a Friedman test were used to determine differences in variables over time and between interventions. Spearman and Pearson correlations were used to test for associations between variables. Tremor intensity measured objectively by activity loggers correlated well (p < 0.0001; r2 = 0.9) with visual observations. Tremor intensity was greatest when animals were severely hypoxaemic and acidaemic. Tremor intensity correlated strongly and negatively with partial pressure of oxygen (PaO2 ) (p = 0.0003; r2 = 0.9995) and potential of hydrogen (pH) (p = 0.02, r2 = 0.97). It correlated strongly and positively with adrenaline concentrations (p = 0.003; r2 = 0.96), and adrenaline correlated strongly and negatively with PaO2 (p = 0.03; r2 = 0.95) and pH (p = 0.03; r2 = 0.94). Therefore, hypoxaemia and acidaemia were likely associated with the intensity of tremors through their activation of the release of tremorgenic levels of adrenaline. Tremors can be reduced if circulating adrenaline is reduced, and this can be achieved by the administration of butorphanol plus oxygen insufflation. Furthermore, to assist with reducing the risks associated with rhinoceros immobilisation, tremor intensity could be used as a clinical indicator of respiratory and metabolic compromise.

Comparative Metabolomic Profiling Reveals That Dysregulated Glycolysis Stemming from Lack of Salvage NAD+ Biosynthesis Impairs Reproductive Development in Caenorhabditis elegans.

Temporal developmental progression is highly coordinated in Caenorhabditis elegans. However, loss of nicotinamidase PNC-1 activity slows reproductive development, uncoupling it from its typical progression relative to the soma. Using LC/MS we demonstrate that pnc-1 mutants do not salvage the nicotinamide released by NAD(+) consumers to resynthesize NAD(+), resulting in a reduction in global NAD(+) bioavailability. We manipulate NAD(+) levels to demonstrate that a minor deficit in NAD(+) availability is incompatible with a normal pace of gonad development. The NAD(+) deficit compromises NAD(+) consumer activity, but we surprisingly found no functional link between consumer activity and reproductive development. As a result we turned to a comparative metabolomics approach to identify the cause of the developmental phenotype. We reveal widespread metabolic perturbations, and using complementary pharmacological and genetic approaches, we demonstrate that a glycolytic block accounts for the slow pace of reproductive development. Interestingly, mitochondria are protected from both the deficiency in NAD(+) biosynthesis and the effects of reduced glycolytic output. We suggest that compensatory metabolic processes that maintain mitochondrial activity in the absence of efficient glycolysis are incompatible with the requirements for reproductive development, which requires high levels of cell division. In addition to demonstrating metabolic requirements for reproductive development, this work also has implications for understanding the mechanisms behind therapeutic interventions that target NAD(+) salvage biosynthesis for the purposes of inhibiting tumor growth.

Nicotinamidase modulation of NAD+ biosynthesis and nicotinamide levels separately affect reproductive development and cell survival in C. elegans.

Nicotinamide adenine dinucleotide (NAD(+)) is a central molecule in cellular metabolism and an obligate co-substrate for NAD(+)-consuming enzymes, which regulate key biological processes such as longevity and stress responses. Although NAD(+) biosynthesis has been intensely studied, little analysis has been done in developmental models. We have uncovered novel developmental roles for a nicotinamidase (PNC), the first enzyme in the NAD(+) salvage pathway of invertebrates. Mutations in the Caenorhabditis elegans nicotinamidase PNC-1 cause developmental and functional defects in the reproductive system; the development of the gonad is delayed, four uterine cells die by necrosis and the mutant animals are egg-laying defective. The temporal delay in gonad development results from depletion of the salvage pathway product NAD(+), whereas the uv1 cell necrosis and egg-laying defects result from accumulation of the substrate nicotinamide. Thus, regulation of both substrate and product level is key to the biological activity of PNC-1. We also find that diet probably affects the levels of these metabolites, as it affects phenotypes. Finally, we identified a secreted isoform of PNC-1 and confirmed its extracellular localization and functional activity in vivo. We demonstrate that nicotinamide phosphoribosyltransferase (Nampt), the equivalent enzyme in nicotinamide recycling to NAD(+) in vertebrates, can functionally substitute for PNC-1. As Nampt is also secreted, we postulate an evolutionarily conserved extracellular role for NAD(+) biosynthetic enzymes during development and physiology.

Toward understanding the mechanism of the complex cyclization reaction catalyzed by imidazole glycerolphosphate synthase: crystal structures of a ternary complex and the free enzyme.

Imidazole glycerol phosphate synthase catalyzes formation of the imidazole ring in histidine biosynthesis. The enzyme is also a glutamine amidotransferase, which produces ammonia in a glutaminase active site and channels it through a 30-A internal tunnel to a cyclase active site. Glutaminase activity is impaired in the resting enzyme, and stimulated by substrate binding in the cyclase active site. The signaling mechanism was investigated in the crystal structure of a ternary complex in which the glutaminase active site was inactivated by a glutamine analogue and the unstable cyclase substrate was cryo-trapped in the active site. The orientation of N(1)-(5'-phosphoribulosyl)-formimino-5-aminoimidazole-4-carboxamide ribonucleotide in the cyclase active site implicates one side of the cyclase domain in signaling to the glutaminase domain. This side of the cyclase domain contains the interdomain hinge. Two interdomain hydrogen bonds, which do not exist in more open forms of the enzyme, are proposed as molecular signals. One hydrogen bond connects the cyclase domain to the substrate analogue in the glutaminase active site. The second hydrogen bond connects to a peptide that forms an oxyanion hole for stabilization of transient negative charge during glutamine hydrolysis. Peptide rearrangement induced by a fully closed domain interface is proposed to activate the glutaminase by unblocking the oxyanion hole. This interpretation is consistent with biochemical results [Myers, R. S., et al., (2003) Biochemistry 42, 7013-7022, the accompanying paper in this issue] and with structures of the free enzyme and a binary complex with a second glutamine analogue.