Children’s psychological well-being and problem behavior during the COVID-19 pandemic: An online study during the lockdown period in Germany

As COVID-19 dramatically changes human social life, restrictive lockdown periods to slow the spread of the virus have been suggested to particularly affect the psychological well-being of children and their families. To capture lockdown-related effects on a large scale, the present study used an online questionnaire completed by parents of 3-10-year-olds during the most restrictive lockdown period in Germany thus far (N = 2,672). Parents reported their stress level, their child’s well-being, and their child’s problem behaviors among others. Results showed that most parents and children experienced lockdown-related stress. Concerning children, not being able to meet with friends and family members outside the household emerged as the primary challenge. Older children (7–10 years) evidenced more emotional symptoms as well as less conduct problems and hyperactivity than younger children (3–6 years). Children’s own and their parents’ stress level, the degree to which children missed other children, and children’s age all showed to be negatively related to children’s general life satisfaction. Single parenthood and being an only child were associated with higher levels of child problems. Taken together, these findings shed light on the psychological well-being of children and their families during governmental lockdown measures, as well as on relations between children’s coping and demographic background. They have implications for possible avenues for interventions, inter alia by encouraging policies that facilitate the maintenance of social relationships and focus particularly on children from single parent families, on only children as well as on families in challenging housing situations

Prognostic factors in non small cell lung cancer

peer reviewedRésumé : Le cancer pulmonaire non à petites cellules est le plus fréquent des cancers du poumon et son pronostic reste très réservé. Les rechutes sont fréquentes et peuvent même s’observer dans des stades précoces de la maladie, en dépit d’une prise en charge chirurgicale à visée curative. Cette revue de la littérature donne un aperçu des facteurs pronostiques principaux dont les deux plus importants, conditionnant la stratégie thérapeutique, demeurent la stadification («staging») et l’histologie de la tumeur. D’autres facteurs péjoratifs pourraient également s’avérer utiles pour les cliniciens, notamment en orientant le patient vers des thérapies adjuvantes.Summary : Non small cell lung cancer is the most frequent type of lung cancer and its prognosis is still very poor. Relapse is frequent and can be observed even in early stages of the disease, in spite of a surgical management with curative intent. This paper gives an overview of the main prognostic factors, the two most important of which remain the staging and tumor histology. These also determine the therapeutic strategy. Other factors of poor prognosis might also be useful for clinicians, particularly in their decision to refer patients for adjuvant therapies. Keywords : Non-small cell lung cancer – Prognostic factors – Pulmonary oncology – Surger

Bridging the gap

Social and Emotional Learning (SEL) is significant for providing children with adequate skills so that they can shape a supportive society. Even though children’s moral self-concept (MSC) and their prosocial behavior are critical components of SEL, research on their association and development is comparatively novel. In a longitudinal study, we investigated the associations between children’s MSC, their normative stances, and their sharing behavior. Data of N = 500 preschoolers with an average age of 61 months at t1 (SD = 4.61) were analyzed in a mixed-method design across the period of one year (t1–t3) with structural equation models. Findings revealed sharing behavior as a stable predictor for subsequent MSC across time. As children got older, their normative stances predicted sharing behavior. This connection was further moderated by their MSC. Our findings are the first to depict stable longitudinal predictive effects of prior sharing behavior on subsequent MSC, highlighting preschool age as a critical stage in the formation of MSC. Overall, they demonstrate how in the course of the preschool years, the MSC and normative stances developmentally interact in their relation to prosocial behavior

Skeletal muscle alterations in tachycardia-induced heart failure are linked to deficient natriuretic peptide signalling and are attenuated by RAS-/NEP-inhibition

Background Heart failure induced cachexia is highly prevalent. Insights into disease progression are lacking. Methods Early state of left ventricular dysfunction (ELVD) and symptomatic systolic heart failure (HF) were both induced in rabbits by tachypacing. Tissue of limb muscle (LM) was subjected to histologic assessment. For unbiased characterisation of early and late myopathy, a proteomic approach followed by computational pathway-analyses was performed and combined with pathway-focused gene expression analyses. Specimen of thoracic diaphragm (TD) served as control for inactivity-induced skeletal muscle alterations. In a subsequent study, inhibition of the renin-angiotensin-system and neprilysin (RAS-/NEP) was compared to placebo. Results HF was accompanied by loss of protein content (8.7±0.4% vs. 7.0±0.5%, mean±SEM, control vs. HF, p<0.01) and a slow-to-fast fibre type switch, establishing hallmarks of cachexia. In ELVD, the enzymatic set-up of LM and TD shifted to a catabolic state. A disturbed malate-aspartate shuttle went well with increased enzymes of glycolysis, forming the enzymatic basis for enforced anoxic energy regeneration. The histological findings and the pathway analysis of metabolic results drew the picture of suppressed PGC-1α signalling, linked to the natriuretic peptide system. In HF, natriuretic peptide signalling was desensitised, as confirmed by an increase in the ratio of serum BNP to tissue cGMP (57.0±18.6pg/ml/nM/ml vs. 165.8±16.76pg/ml/nM/ml, p<0.05) and a reduced expression of natriuretic peptide receptor-A. In HF, combined RAS-/NEP-inhibition prevented from loss in protein content (8.7±0.3% vs. 6.0±0.6% vs. 8.3±0.9%, Baseline vs. HF-Placebo vs. HF-RAS/NEP, p<0.05 Baseline vs. HF-Placebo, p = 0.7 Baseline vs. HF-RAS/NEP). Conclusions Tachypacing-induced heart failure entails a generalised myopathy, preceding systolic dysfunction. The characterisation of “pre-cachectic” state and its progression is feasible. Early enzymatic alterations of LM depict a catabolic state, rendering LM prone to futile substrate metabolism. A combined RAS-/NEP-inhibition ameliorates cardiac-induced myopathy independent of systolic function, which could be linked to stabilised natriuretic peptide/cGMP/PGC-1α signalling

465 Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety and pharmacokinetic results of the INTR@PID LUNG 024 study

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1. Here we report cumulative safety and pharmacokinetic (PK) results from the global, phase 1b/2 INTR@PID LUNG 024 study (NCT03840915), which evaluated bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC.MethodsAdult patients with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 were included. Cohorts A, B, and C included patients with no prior systemic therapy; patients in cohort D had disease that progressed with previous anti–PD-(L)1 therapy. Cohorts received bintrafusp alfa 2400 mg every 3 weeks intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or in combination with pemetrexed in cohort A) for up to 31 cycles. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Dose-limiting toxicities (DLTs) were assessed during a 3-week observation period. Serial samples were drawn to assess serum concentration and calculate PK parameters by noncompartmental analysis.ResultsAs of the May 5, 2021, data cutoff, 70 patients received bintrafusp alfa in combination with CT. Of 35 patients included in the DLT analysis, 4 experienced 1 DLT according to a safety monitoring committee (data cutoff May 5, 2021; A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). Cumulative safety data are reported in table 1. PK data were available for 67 patients (A: n=38; B: n=9; C: n=8; D: n=12). PK profiles were similar across cohorts and between patients who did and did not experience a DLT. Observed bintrafusp alfa first-cycle exposures (Cmax, AUC, and Ctrough) were consistent with the published population PK (popPK) model.1Abstract 465 Table 1Safety results from the INTR@PID LUNG 024 studyConclusionsThe safety profile of bintrafusp alfa in combination with CT was manageable and similar to that reported for ICIs in combination with CT, with the exception of TGF-β–related skin lesions known to occur with TGF-β inhibition. No new safety signals were identified and there were no treatment-related deaths. The PK profile was consistent with the predicted monotherapy popPK model, suggesting no victim DDI potential for bintrafusp alfa with CT.AcknowledgementsThe authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, at the healthcare business of Merck KGaA, Darmstadt, Germany, and at EMD Serono, Billerica, Massachusetts, USA.Trial RegistrationNCT03840915ReferenceWilkins JJ, Vugmeyster Y, Dussault I. Population pharmacokinetic analysis of bintrafusp alfa in different cancer types. Adv Ther 2019;36:2414–2433.Ethics ApprovalThe trial was approved by each site's independent ethics committee

Mediterranean Diet Score and Its Association with Age-Related Macular Degeneration: The European Eye Study

To examine associations between adherence to a Mediterranean diet and prevalence of age-related macular degeneration (AMD) in countries ranging from Southern to Northern Europe. Cross-sectional, population-based epidemiologic study. Of 5060 randomly sampled people aged 65 years or older from 7 study centers across Europe (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain), full dietary data were available in 4753. The mean age of participants was 73.2 years (standard deviation, 5.6), and 55% were women. Participants underwent an eye examination and digital retinal color photography. The images were graded at a single center. Dietary intake during the previous 12 months was assessed by using a semiquantitative food-frequency questionnaire (FFQ). A previously published Mediterranean Diet Score (MDS) was used to classify participants according to their responses on the FFQ. Multivariable logistic regression was used to investigate the association of the MDS score and AMD, taking account of potential confounders and the multicenter study design. Images were graded according to the International Classification System for age-related maculopathy and stratified using the Rotterdam staging system into 5 exclusive stages (AMD 0-4) and a separate category of large drusen (≥125 μm). Age-related macular degeneration 4 included neovascular AMD (nvAMD) and geographic atrophy (GA). Increasing MDS was associated with reduced odds of nvAMD in unadjusted and confounder-adjusted analysis. Compared with the lowest MDS adherence (≤4 score), those in the highest category MDS adherence (&gt;6 score) showed lower odds of nvAMD (odds ratio, 0.53; 0.27-1.04; P trend = 0.01). The association with MDS did not differ by Y204H risk allele (P = 0.89). For all early AMD (grade 1-3), there was no relationship with MDS (P trend = 0.9). There was a weak trend (P = 0.1) between MDS and large drusen; those in the highest category of MDS had 20% reduced odds compared with those in the lowest (P = 0.05). This study adds to the limited evidence of the protective effect of adherence to a Mediterranean dietary pattern in those with late AMD, although it does not support previous reports of a relationship with genetic susceptibility. Interventions to encourage the adoption of the Mediterranean diet should be developed, and methods by which such behavior change can be achieved and maintained investigated

Associations between Serum Vitamin D and Genetic Variants in Vitamin D Pathways and Age-Related Macular Degeneration in the European Eye Study.

PURPOSE: To study associations between early and late age-related macular degeneration (AMD) and neovascular AMD (nvAMD) with serum 25-hydroxy vitamin D (25(OH)D) and genetic variants in vitamin D pathway genes. DESIGN: Population-based, cross-sectional study in a random sample aged 65 years or older from 7 European countries. PARTICIPANTS: Of 4753 participants, 4496 (2028 men and 2468 women), with a mean age of 73 years, provided a blood sample; 2137 had no signs of AMD, 2209 had early AMD, and 150 had late AMD, of whom 104 had nvAMD. METHODS: Participants were interviewed to determine smoking and alcohol use, sunlight exposure, and diet; underwent fundus photography. Fundus images were graded using the International Classification System for Age-Related Maculopathy. The 25(OH)D was measured by liquid chromatography-tandem mass spectrometry and categorized as deficient (<30 nmol/l), insufficient (30-50 nmol/l), or adequate (≥50 nmol/l). Genotyping was performed on a subsample of 1284 AMD cases and controls for 93 single nucleotide polymorphisms (SNPs) from 7 genes. Associations were investigated by linear or logistic regression adjusted for potential confounders. MAIN OUTCOME MEASURES: Adjusted odds ratio (OR) for 3 outcomes (early AMD, late AMD, nvAMD). RESULTS: No linear association was found with 25(OH)D and early or late AMD or nvAMD. There was no association between insufficient or deficient status with early or late AMD. Deficient status was associated with nvAMD (adjusted OR, 1.27; 95% confidence interval, 1.1-1.45; P < 0.0001). Significant (P < 0.05) associations with 25(OH)D were found for SNPs in genes GC, VDR, CYP2R1, and CYP27B1. Two SNPs (VDR) were associated with early AMD, 4 SNPs (RXRA) and 1 SNP (VDR) were associated with nvAMD, and 1 SNP (RXRA), 2 SNPs (VDR), and 1 SNP (CYP2R1) were associated with late AMD. After Bonferroni correction, no SNPs were associated with early AMD, late AMD, or nvAMD. CONCLUSIONS: Deficiency in 25(OH)D was associated with nvAMD, but the adjusted OR was small, and we cannot exclude residual confounding. The hypothesis of a causal association of vitamin D with AMD is not supported by clear evidence for an association of vitamin D SNPs with early AMD, late AMD, or nvAMD

ATRT–SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT–TYR, ATRT–MYC and ATRT–SHH. ATRT–SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT–SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT–SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT–SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT–SHH has prognostic relevance and might aid to stratify patients within future clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02424-5

Anticoagulation with edoxaban in patients with long Atrial High-Rate Episodes ≥24 hours

BACKGROUND AND AIMS: Patients with long atrial high-rate episodes (AHRE) ≥ 24 hours and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared to no anticoagulation in these patients.METHODS: This secondary prespecified analysis of NOAH-AFNET 6 examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared to placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and ECG-diagnosed atrial fibrillation.RESULTS: AHRE ≥24 hours were present at baseline in 259/2389 patients enrolled in NOAH-AFNET 6 (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc score 4). Clinical characteristics were not different from patients with shorter AHRE. During a median follow-up of 1.8 years, the primary outcome occurred in 9/132 patients with AHRE ≥24 hours (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). AHRE duration did not interact with the efficacy (p-interaction = 0.65) or safety (p-interaction = 0.98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 hours developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; p &lt; 0.001).CONCLUSIONS: This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.</p

Oncological patients' reactions to COVID-19 pandemic: A single institution prospective study.

peer reviewedBACKGROUND: The spread of the COVID-19 pandemic has led to a rapid reorganization in all human and hospital activities, with impact on cancer patients. AIM: An analysis of cancer patients fears, and awareness of COVID-19 has been done in this study. METHODS AND RESULTS: We analyzed cancer patients' reactions to the pandemic and their perception of oncological care reorganization, through a 12-item survey, proposed at the peak of pandemic and 3 months later. Overall, 237 patients were included in the study. During the peak of pandemic 34.6% of patients were more worried about COVID-19 than cancer versus 26.4% in the post-acute phase (p = .013). Although 49.8% of patients in the acute phase and 42.3% in the post-acute phase considered their risk of death if infected ≥50%, and more than 70% of patients thought to be at higher risk of complications, the majority of them did not consider the possibility to stop or delay their treatment. Patients were more interested in following news about COVID-19 than cancer and they complied with all preventive measures in more than 90% of the cases. CONCLUSIONS: Although cancer patients worried about COVID-19 and evaluated the risk of complication or death due to COVID-19 as extremely high, they were still asking for the best oncological treatment