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عندما يبدأ الأطفال اكتشاف العالم من حولهم، يوجد دوما الكثير من اللحظات التي يحتاجون فيها للمواساة والنصيحة، أو التشجيع والمساعدة. تشكل القصص الخيالية المستقاة من حياة الأطفال اليومية مناسبة للحديث عن شعورهم، ومن خلال القراءة المشتركة تتولد مشاعر الانتماء والود. يضم الكتاب مجموعة قصص قصيرة موجهة للأطفال تتجاوب مع اهتماماتهم وفكرهم وسلوكهم داخل المنزل وخارجه وفي طريقة تعاملهم مع الآخرين. وتأتي في ثلاثة محاور : حكايات مشجعة، تجعل الأطفال أقوياء. قصص للمواساة تجعل الأطفال سعداء. قصص لطيفة تهدئ من روع الأطفال. ينصح الكتاب الأهل والمربين بوجوب المشاركة في القراءة لتحقيق التقارب بين الطفل والمحيط الاجتماعي الذي يعيش في وسطه. فالجلوس إلى جانب الطفل، والاستماع إليه وهو يقرأ ومشاهدة الصور معه والتحاور معه حول القصة بعد الانتهاء من قراءتها كل هذه الأمور تعيد إلى الطفل في الغالب الهدوء والسكينة اللذين يتطلع إليهما الأهل.

Background Tinnitus is a leading cause of disease burden globally. Several therapeutic strategies are recommended in guidelines for the reduction of tinnitus distress; however, little is known about the potentially increased effectiveness of a combination of treatments and personalized treatments for each tinnitus patient. Methods Within the Unification of Treatments and Interventions for Tinnitus Patients project, a multicenter, randomized clinical trial is conducted with the aim to compare the effectiveness of single treatments and combined treatments on tinnitus distress (UNITI-RCT). Five different tinnitus centers across Europe aim to treat chronic tinnitus patients with either cognitive behavioral therapy, sound therapy, structured counseling, or hearing aids alone, or with a combination of two of these treatments, resulting in four treatment arms with single treatment and six treatment arms with combinational treatment. This statistical analysis plan describes the statistical methods to be deployed in the UNITI-RCT. Discussion The UNITI-RCT trial will provide important evidence about whether a combination of treatments is superior to a single treatment alone in the management of chronic tinnitus patients. This pre-specified statistical analysis plan details the methodology for the analysis of the UNITI trial results. Trial registration ClinicalTrials.gov NCT04663828 . The trial is ongoing. Date of registration: December 11, 2020. All patients that finished their treatment before 19 December 2022 are included in the main RCT analysis.

DNA of human papillomaviruses has frequently been detected in nonmelanoma skin cancers, raising the question of a possible causal contribution of these tumor viruses to skin carcinogenesis. Basal cell carcinomas are the most common nonmelanoma skin cancers; however, so far they are only poorly analyzed with regard to human papillomavirus infection. We searched for human papillomavirus-DNA in 69 biopsies from 61 immunocompetent basal cell carcinoma patients from two geographic locations in Europe using six different polymerase chain reaction primer systems. We could demonstrate human papillomavirus-DNA in 43.5% of the tested tumors. Human papillomavirus positivity did not seem to correlate with the duration of disease or patients' age. The vast majority of virus types in the biopsies belonged to the group of epidermodysplasia verruciformis-associated human papillomavirus. Of 31 sample pairs tested for human papillomavirus-DNA in tumors as well as in perilesional healthy skin, seven carried viral sequences in lesional and healthy skin and three only in the basal cell carcinoma. Six of the seven human papillomavirus-positive basal cell carcinoma/healthy skin pairs contained identical human papillomavirus types in tumors and histologically normal tissue. Forty basal cell carcinoma patients were additionally analyzed for IgG antibodies against virus-like particles of three representative epidermodysplasia verruciformis–human papillomavirus types: 8, 15, and 36. No statistically significant differences could be detected between human papillomavirus antibody prevalences of basal cell carcinoma patients and of dermatologically healthy individuals. Moreover, serologic findings did not correlate with the detection of specific human papillomavirus types in tumors. Our results seem to suggest that the occurrence of human papillomavirus-DNA in basal cell carcinoma does not reflect a major etiologic role of human papillomavirus in this cancer.

BET bromodomain inhibitors are being explored as potential therapeutics in cancer; here, AML cells are shown to evade sensitivity to BET inhibition through rewiring the transcriptional regulation of BRD4 target genes such as MYC in a process that is facilitated by suppression of PRC2 and WNT signalling activation. Emergence of resistance to BET inhibitors BET inhibitors that target bromodomain chromatin readers such as BRD4 are being explored as potential therapeutics in cancer. Two papers published in this issue of Nature identify mechanisms that may be involved in resistance to BET inhibition in models of leukaemia. In an MLL–AF9 model, Mark Dawson and colleagues find that resistance emerges from leukaemic stem cells and is, in part, a consequence of increased Wnt signalling. Johannes Zuber and colleagues find that suppression of the PRC2 complex renders acute myeloid leukaemia cells resistant to BET inhibition by rewiring the transcriptional regulation of BRD4 target genes such as MYC . Wnt signalling is also implicated as a key driver of resistance. Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML) 1 , 2 , bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers 3 , 4 , 5 . While clinical trials have reported single-agent activity in advanced haematological malignancies 6 , mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL–AF9;Nras G12D -driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc . Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.

Background German surveillance data showed a sharp rise of malaria cases in 2014 and 2015 due to the increased arrival of refugees from malaria endemic countries. A time series analysis of data from 2001 to 2016 was performed in order to describe the epidemiology of imported malaria in Germany in general and of the recent increase in particular. Results In total, 11,678 malaria cases were notified between 2001 and 2016 (range 526–1063 cases/year). Newly arriving refugees averaged 10 cases/year (1.5%) in 2001–13 and 292.5 cases/year (28.3%) in 2014–15. Plasmodium ( P .)  falciparum was the most frequently reported species (range 57.2–85.8%), followed by P. vivax (range during 2001–2013: 7.6–18.1%; during 2014–2015, mean 31.3%). In 2014–15, 22.3% of all P. vivax cases were refugees from Eritrea and 3.3% from other countries of the Horn of Africa; in 2015 and 2016, 19.5% were refugees from Afghanistan and Pakistan. Five P. knowlesi malaria infections were reportedly acquired in Thailand between 2012 and 2016. Total numbers of malaria notifications among native Germans and residents with migration background showed an increasing trend since 2007. Chemoprophylaxis use was reported for 24.3% (1695/6984) of cases and showed a declining trend. Native German cases took significantly more frequently chemoprophylaxis than cases with migration background (32.6% vs. 17.9%; p < 0.001). Discussion/conclusions The steep rise in vivax malaria notifications in 2014 and 2015 was mainly due to newly arriving refugees from Eritrea but also from other countries of the Horn of Africa and South Asia. Clinicians should include malaria in their differential diagnosis in case of a febrile illness in the respective population and consider vivax malaria even if arrival to Germany dates back several months. Over the past 10 years, malaria notifications among native Germans and residents with migration background showed an increasing trend. Use of chemoprophylaxis was insufficient in both groups and deteriorating. New strategies need to be found to increase compliance to chemoprophylaxis recommendations. The surveillance provides valuable data for epidemiological assessment of imported malaria in Germany.

Gaming disorder (GD) is a disorder due to addictive behaviors (ICD-11). Cue-reactivity and craving are relevant mechanisms in the development and maintenance of addictive behaviors. When confronted with cues showing in-game content (proximal cues) individuals with higher symptom severity show increased cue-reactivity. Based on conditioning and addiction theories on incentive sensitization, cue-reactivity responses may generalize to more distal cues, e.g. when individuals at risk of developing a GD are confronted with a starting page of an online game. In cue-reactivity paradigms so far, only proximal gaming cues have been used. We investigated the effect of distal gaming cues compared to gaming-unrelated control cues on cue-reactivity and craving in 88 individuals with non-problematic use of online games (nPGU) and 69 individuals at risk for GD (rGD). The distal cues showed the use of an electronic device (e.g., desktop PC or smartphone) whose screen showed starting pages of either games (target cues), shopping- or pornography sites (control cues) from a first-person perspective. We found significantly higher urge and arousal ratings as well as longer viewing times for gaming-related compared to gaming-unrelated control cues in rGD compared to nPGU. Valence ratings did not differ between groups. The results demonstrate that already distal gaming-specific cues lead to cue-reactivity and craving in rGD. This finding indicates that based on conditioning processes, cue-reactivity and craving develop during the course of GD and generalize to cues that are only moderately related to the specific gaming activity. •distal gaming cues in contrast to proximal do not show in-game contents.•distal cues may trigger cue-reactivity in individuals at risk of gaming disorder.•risk users had higher urge and arousal ratings for gaming compared to control cues.•both groups had longer viewing times for gaming compared to control cues.

While age-related macular degeneration (AMD) poses an important personal and public health burden, comparing epidemiological studies on AMD is hampered by differing approaches to classify AMD. In our AugUR study survey, recruiting residents from in/around Regensburg, Germany, aged 70+, we analyzed the AMD status derived from color fundus images applying two different classification systems. Based on 1,040 participants with gradable fundus images for at least one eye, we show that including individuals with only one gradable eye (n = 155) underestimates AMD prevalence and we provide a correction procedure. Bias-corrected and standardized to the Bavarian population, late AMD prevalence is 7.3% (95% confidence interval = [5.4; 9.4]). We find substantially different prevalence estimates for “early/intermediate AMD” depending on the classification system: 45.3% (95%-CI = [41.8; 48.7]) applying the Clinical Classification (early/intermediate AMD) or 17.1% (95%-CI = [14.6; 19.7]) applying the Three Continent AMD Consortium Severity Scale (mild/moderate/severe early AMD). We thus provide a first effort to grade AMD in a complete study with different classification systems, a first approach for bias-correction from individuals with only one gradable eye, and the first AMD prevalence estimates from a German elderly population. Our results underscore substantial differences for early/intermediate AMD prevalence estimates between classification systems and an urgent need for harmonization.

We investigated the impact of sexual stimuli and the influence of sexual motivation on the performance in a dot-probe task and a line-orientation task in a large sample of males and females. All pictures (neutral, erotic) were rated on the dimensions of valence, arousal, disgust, and sexual arousal. Additionally, questionnaires measuring sexual interest/desire/motivation were employed. The ratings of the sexual stimuli point to a successful picture selection because sexual arousal did not differ between the sexes. The stimuli were equally arousing for men and women. Higher scores in the employed questionnaires measuring sexual interest/desire/motivation led to higher sexual arousal ratings of the sex pictures. Attentional bias towards sex pictures was observed in both experimental tasks. The attentional biases measured by the dot-probe and the line-orientation task were moderately intercorrelated suggesting attentional bias as a possible marker for a sex-attention trait. Finally, only the sexual sensation seeking score correlated with the attentional biases of the two tasks. Future research is needed to increase the predictive power of these indirect measures of sexual interest.

An epidemic of foodborne infection with Escherichia coli associated with a high rate of the hemolytic–uremic syndrome and caused by a novel E. coli strain (O104:H4) recently occurred in Germany. This final report updates epidemiologic, clinical, and microbiologic information. On May 19, 2011, the Robert Koch Institute, Germany's national-level public health authority, was informed about a cluster of three cases of the hemolytic–uremic syndrome in children admitted on the same day to the university hospital in the city of Hamburg. On May 20, a team from the Robert Koch Institute arrived in Hamburg to assist with the public health investigation. It quickly became clear that the case numbers were continuing to rise, that there were also cases in adults, and that other areas of Germany, especially northern Germany, were also affected. An investigation of the outbreak involving all levels . . .

Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate ‘enhancer hijacking’ as an efficient mechanism driving oncogene activation in a childhood cancer. Focusing on two ill-characterized subtypes of medulloblastoma (group 3 and group 4), this study identifies prevalent genomic structural variants that are restricted to these two subtypes and independently bring together coding regions of GFI1 family proto-oncogenes with active enhancer elements, leading to their mutually exclusive oncogenic activation. Oncogenesis through enhancer hijacking Medulloblastoma is a highly malignant paediatric brain tumour. Here the authors focus on two ill-characterized subtypes — group 3 and group 4 — which account for the majority of paediatric cases. They identify prevalent genomic structural variants, which are restricted to these two subtypes, and bring together coding regions of proto-oncogenes, GFI1 and GFI1B , and active enhancer elements leading to oncogene activation. This work identifies 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.