RILEVANZA DEL SESSO NELLA MALATTIA DA COVID-19: QUANDO UN CROMOSOMA IN PIÙ FA LA DIFFERENZA!

Meta-analysis of epidemiological world-wide reports of SARS-CoV-2 patients requiring mechanical ventilation in intensive care units highlighted the male sex as a risk factor for severe, often fatal evolution of COVID-19 disease, as signaled by previous coronavirus infections. X chromosome inactivation (XCI), an epigenetic mechanism used by female somatic cells to equalize the dosage of X-linked genes between the sexes and the female advantage with mosaicism of the numerous immune-related genes and the increased expression of those escaping XCI determined a growing recognition of the unique biology of the X chromosome to account for females more robust immune response. In the wake of studies aimed at establishing the contribution of immune-regulatory X-linked genes to sex-specific differences of COVID-19 disease, the expression of TLR7, a gene of innate immune response encoding a member of Toll-like family receptors sensing the SARS-CoV-2 endosomal RNA, has been quantified in human female plasmacytoid dendritic cells which are high producers of interferons, acting as powerful viral inhibitors. The study confirmed that TLR7 escapes XCI promoting higher TLR7 mRNA and higher interferon mRNA at the single-cell level. The relevance of TLR7 signaling has been highlighted by a Dutch study exploring the presence of genetic variants among young men with severe COVID-19 which identified pathogenic TLR7 variants in two pairs of brothers (mean age 26 years) without medical history admitted to intensive care units due to SARS-CoV-2 acute respiratory syndrome, one of whom deceased due to septic shock. Whole exome sequencing of the patients identified “loss of function variants” of the X-chromosomal TLR7 and functional studies on their peripheral blood mononucleate cells after in vitro stimulation with a TLR7 agonist showed significant reduction of TLR7-specific mRNA and decreased mRNA expression of various interferon type I genes as compared to family members and controls. While rare mutations in TLR7 are unlikely to be a major drive of severe COVID-19 disease, their identification begins to unravel the molecular underpinning of COVID-19 infection highlighting TLR7 receptor as a critical node in recognizing SARS-CoV-2 and initiating an early immune response to clear the virus and prevent the development of COVID-19.

P-P53 Textbook outcomes in pancreatoduodenectomy are improved in high volume specialist pancreas-only centres

Background Traditional single surgical quality indicators are commonly used however they are poor for assessing global outcomes for patients. Composite outcomes such as the ‘Textbook Outcome’ (TO) is a composite outcome to determine the success of the quality of the surgical process, and compare outcomes between institutions and patient groups, described by the Dutch Pancreatic Cancer Audit Group for Pancreatoduodenectomy (PD). They reported national TOs for PD of 58.3%, we compared this to TOs in a UK high volume specialist pancreas-only centre, Royal Stoke. Methods Patients who underwent PD from January 2017 to December 2020 were identified from our database. TO was defined as absence the following: post-operative pancreatic fistula (POPF) (grade B/C), post-pancreatectomy haemorrhage (PPH), bile leak, severe complications (Clavien Dindo grade III or more), 30-day readmission and 30-day mortality. Results 153 patients underwent PD during the 4-year study period. The median age was 71years (range 37-85 years), and there was a slight male preponderance (54.9%, 84/153). 47% had pancreatic ductal adenocarcinoma (72/153), 17% ampullary carcinoma (26/153), 9% cholangiocarcinoma (14/153), 9% duodenal carcinoma (14/153), and benign pathology included cases with IPMN and duodenal polyps with high grade dysplasia. There was a statistically significant difference in textbook outcome in our cohort compared to the Dutch Study (70.3%, 108/153 vs 58.3%, 895/1536; p=0.003086), with components of TO shown in Figure 1. Conclusions TO represent composite outcome for identifying good practice, areas for shared learning and areas for improvement. PD performed in high-volume pancreas-only specialist centers appear to have better outcomes following PD than lower-volume centres. Further investigation is required to assess why outcomes are different between centres, and identify how best practice can be shared.

Screening for anticoagulation undertreatment in more than 100,000 patients with atrial fibrillation in general practices in the Netherlands

Background and aim Atrial fibrillation (AF) is associated with a significant morbidity and increased mortality risk, predominantly due to risk of stroke and thromboembolism. Despite availability of highly effective and practical oral anticoagulation (OAC) guidelines recommended therapy is often underutilized. Therefore, we investigated the underuse of OAC in individual AF patients through on-demand screening of general practices (GPs) across the Netherlands. Methods We performed a multi-center, cross-sectional study in 39 GPs. Using electronic patient files, we were able to screen the entire GP population for AF, CHA2DS2-VASc scores, and the use of guidelines recommended OAC. In case of OAC undertreatment we checked for any documented reason. Additionally, six weeks following the screening we asked all GPs to provide information on actions taken for the undertreated patients. Results In total 101,207 patients records were screened identifying 2,375 non-valvular AF patients with a mean CHA2DS2-VASc score of 3.2. OAC use consisted of direct oral anticoagulants in 1,342/1,984 (68%) and vitamin K antagonists in the remainder of patients. OAC undertreatment was present in 92/1001 (9,2%) males and 102/1374 (7,4%) in females, respectively. Figure 1 shows the GP patient population with AF, divided into groups by CHA2DS2-VASc score and their corresponding antithrombotic therapies. Reasons to withhold OAC were patient refusal (n=10), cardiologist advice (n=7), high risk of bleeding (n=7), and terminal illness (n=4). In 159/194 (82%) patients no reason was reported. Data regarding actions following the identification of OAC undertreatment was available in 29 practices representing 92/194 (47%) of the OAC undertreatment cases. After consultation OAC was initiated in 9/92 (10%) only. Conclusions In this large Dutch study among GPs we observe 8.2% undertreatment of OAC in AF patients. More males than females were undertreated as were those with the highest CHA2DS2-VASc scores. Only in a small minority of cases detection of OAC undertreatment lead to OAC initiation. This highlights the need to improve awareness and communication of OAC treatment aimed at preventing strokes. FUNDunding Acknowledgement Type of funding sources: None. Figure 1

Pregnancy-associated breast cancer: nationwide Dutch study confirms a discriminatory aggressive histopathologic profile

Purpose Breast cancer is the most common type of malignancy in pregnant women, occurring approximately once in every 3000 pregnancies. Pregnancy-associated breast cancer (PABC) is commonly defined as breast cancer diagnosed during or within one year after pregnancy, and it accounts for up to 6.9% of all breast cancers in women younger than 45 years old. Whether these cancers arise before or during pregnancy, and whether they are stimulated by the high hormonal environment of pregnancy, is currently unknown. This study assesses the histopathological profile of PABC in a large Dutch population-based cohort. Methods We identified 744 patients with PABC (in this cohort defined as breast cancer diagnosed during or within 6 months after pregnancy) diagnosed between 1988 and 2019, in the nationwide Dutch Pathology Registry (PALGA). An age-matched PALGA cohort of unselected breast cancer patients (≤ 45 years), diagnosed between 2013 and 2016, was used as a control. Histopathologic features of both cohorts were compared. Results The median age of PABC patients was 34.3 years old (range 19–45 years) and most breast cancers were diagnosed during pregnancy (74.2%). As compared to age-matched controls, PABC patients had tumors of higher Bloom–Richardson grade (grade I: 1.5% vs. 12.4%, grade II: 16.9% vs. 31.3%, grade III: 80.3% vs. 39.5%, p < 0.0001). Furthermore, estrogen (ER)- and progesterone (PR)-receptor expression was less frequently reported positive (ER: 38.9% vs. 68.2% and PR: 33.9% vs. 59.0%, p < 0.0001), while a higher percentage of PABC tumors overexpressed HER2 (20.0% vs. 10.0%, p < 0.0001). The most observed intrinsic subtype in PABC was triple-negative breast cancer (38.3% vs. 22.0%, p < 0.0001), whereas hormone-driven cancers were significantly less diagnosed (37.9% vs. 67.3%, p < 0.0001). Conclusion This study, based on a large population-based cohort of 744 PABC Dutch patients, underlines the more aggressive histopathologic profile compared to age-matched breast cancer patients ≤ 45 years. Further in-depth genetic analysis will be performed to unravel the origin of this discriminating phenotype. It definitely calls for timely detection and optimal treatment of this small but delicate subgroup of breast cancer patients.

The Perception of Patient Safety Strategies by Primary Health Professionals

Almost all European citizens rank patient safety as very or fairly important in their country. However, few patient safety initiatives have been undertaken or implemented in Poland. The aim was to identify patient safety strategies perceived as important in Poland and compare them with those identified in an earlier Dutch study. A web-based survey was conducted among primary healthcare providers in Poland. The findings were compared with those obtained from eight other countries. The strategies regarded as most important in Poland included the use of integrated medical records for communication with specialists and others, patient-held medical records, acceptable workload in general practice, and availability of information technology. However, despite being seen as important, these strategies have not been widely implemented in Poland. This is the first study to identify strategies considered by primary care physicians in Poland to be important for improving patient safety. These strategies differed significantly from those indicated in other countries.

How Specific is Alcohol-Specific Self-Control? A Longitudinal Study of the Mediating Role of Alcohol-Specific Self-Control in the Relation between General Self-Control and Adolescent Alcohol Use

Background: Although accumulating studies indicate that alcohol-specific self-control can be useful in predicting adolescent alcohol use, little is known about its specificity. This longitudinal study aimed to advance our understanding of domain-specific self-control by examining whether alcohol-specific self-control mediates the effect of general self-control on adolescent alcohol use or has generalizing effects by also mediating the effect of general self-control on other behavior requiring self-control (adolescent digital media use and smoking).Methods: Data from 906 adolescents aged 11-14 years who were enrolled in the Dutch study Prevention of Alcohol Use in Students were used. Data were collected using online questionnaires at four annual measurements. Results: Structural equation modelling revealed that higher alcohol-specific self-control fully mediated the effect of higher general self-control on alcohol use. Alcohol-specific self-control did not mediate the effect of higher general self-control on digital media use, but did partially mediate the effect of higher general self-control on smoking. Conclusions: These results suggest that alcohol-specific self-control is domain-specific, but not necessarily substance-specific. The domain-specificity of alcohol-specific self-control provides evidence for its theoretical relevance for the explanation of adolescent alcohol use. It also suggests leverage points for intervention programs focusing on improving alcohol-specific self-control to reduce adolescent alcohol use. Trial registration. The trial protocol (NTR649) was approved by the Medical Ethical Committee.

De verwerving van de groene en rode woordvolgorde in Vlaanderen* : Een descriptieve, methodologische en theoretische aanvulling bij Meyer & Weerman (2016)

The acquisition of [PART+AUX] and [AUX+PART] word order in Flanders. A descriptive, methodological and theoretical addition to <italic/><italic/>Meyer & Weerman (2016)This paper presents new data on the acquisition of verb clusters in Flemish children. The data were collected by means of a sentence repetition task and the results are in line with the development path for verb clusters in Dutch children as proposed by Meyer & Weerman (2016). While Flemish children also show a development from more 2-1 orders in the youngest group to more 1-2 orders in the older group, this development seems to happen more slowly in Flemish children than in Dutch children. In spite of the fact that the results of both the Flemish and the Dutch study refute an analysis that takes the input adult language as the main factor in verb cluster formation in children, the Flemish data suggest that the higher frequency of 2-1 orders in the Flemish context could help to explain why 1-2 orders are acquired more slowly in Flemish children than Dutch children. In addition, this paper also discusses the results of a production test in Flanders that shows a high preference for 2-1 orders until the age of 7, thus questioning the type of linguistic skills that are assessed in a sentence repetition task.

Longitudinal Linkages Between Father and Mother Autonomy Support and Adolescent Problem Behaviors: Between-Family Differences and Within-Family Effects

Despite existing evidence on negative associations between parental autonomy support and children’s internalizing and externalizing problem behavior, it is difficult to draw conclusions on the effect that parents’ autonomy support has on children’s problem behavior. This study contributed to the existing literature by unraveling the temporal ordering of parental autonomy support and adolescent problem behavior. In addition, this study examined whether these linkages differed by parent’s sex, child sex, and reporter of autonomy support. Data of 497 adolescents (mean age at T1 = 13.03 years, percentage male = 56.9) and their parents from six annual waves of the Dutch study Research on Adolescent Development And Relationships (RADAR) were used. The results showed that stable differences between families explained most linkages between autonomy support and problem behavior. Adolescents with fewer problem behaviors have fathers (both child- and parent-reported) and mothers (only child-reported) who are more autonomy supportive. The results did not differ between boys and girls. The findings suggest that prior studies may have overstated the existence of a causal effect of parental autonomy support on adolescent problem behavior.