Efficacy and Treatment Satisfaction of Different Systemic Therapies in Children and Adolescents with Moderate-to-Severe Atopic Dermatitis: A Real-World Study.

For the treatment of moderate-to-severe atopic dermatitis in children and adolescents, the monoclonal antibody dupilumab and the selective JAK-1 inhibitor upadacitinib are two modern systemic therapies approved for long-term treatment. Both drugs have demonstrated high efficacy in randomized controlled trials, although evidence from real-world data in the pediatric population is limited. In a prospective analysis over 24 weeks, we investigated the efficacy, safety and treatment satisfaction of both systemic therapies in 23 patients (16 patients treated with dupilumab; 7 patients treated with upadacitinib). The median age of the patients was 16 years, with a median EASI of 18.8. A significant improvement in the EASI, VAS-itch, CDLQI, POEM and DFIQ from baseline to week 24 was demonstrated for both treatment options. No significant difference was observed between dupilumab and upadacitinib in any of the assessed scores. Less adverse events were recorded in the real-world setting compared with clinical trials. Our results confirm the efficacy and safety of dupilumab and upadacitinib as equivalent treatment options in children and adolescents in a real-world setting.

Preferences for treatment in primary care: a comparison of nondepressive, subsyndromal and major depressive patients.

OBJECTIVE: In recent years, patients' preferences concerning treatment of emotional distress in general and of depression in particular have received more emphasis in the clinical setting as well as in research. METHODS: The treatment preferences of 607 primary care patients were assessed in a cross-sectional study using a questionnaire. Besides having the opportunity to choose between psychotherapy and pharmacological treatment, the patients could also decline or choose both treatment options at one time. Moreover, the preferences of subsyndromal, major depression and nondepressive patients were compared. RESULTS: A total of 305 (51%) patients exclusively preferred psychotherapy and 110 (18%) exclusively preferred pharmacological treatment. Although 70 (12%) patients declined both forms of treatment, 113 (19%) could imagine using both treatment options. Patients with subsyndromal depression did not differ from patients with major depression in their preferences. Both groups, however, less frequently declined pharmacological treatment compared to nondepressive patients. CONCLUSIONS: Patients with subsyndromal and major depression are similar in the primary care setting with regard to their treatment preferences. The preference for combination treatment is rather low, which should be considered in routine clinical care [corrected]

A comparative study of nonspecific depressive symptoms and minor depression regarding functional impairment and associated characteristics in primary care.

BACKGROUND: Milder forms of depression are highly prevalent in the clinical setting as well as in primary care. However, it is still unclear whether there are distinguishable groups among the various subthreshold syndromes and to what extent they are associated with impairment, thus requiring treatment. Therefore, the study aimed at comparing the degree of impairment in 2 groups of subthreshold depressive patients (nonspecific and minor depressive) with nondepressive patients and with major depressive patients. Another aim of the study was to evaluate the spectrum hypothesis of depressive syndromes. SAMPLING AND METHODS: A sample of 619 primary care patients was studied using the self-administered Patient Health Questionnaire (PHQ). After defining subthreshold depressive syndromes on a criterion basis, frequencies, sociodemographic factors, and impairment of nondepressive, subthreshold depressive, and major depressive patients were compared. RESULTS: Nonspecific depressive symptoms (NDS) were diagnosed in 9.1% of the study subjects and minor depression in 6.2%. Subjects with subthreshold depressive disorders did not differ from each other or from subjects with major depression regarding sociodemographic risk factors such as age, sex, or marital status. Yet, a continually increasing impairment from NDS to minor depression to major depression could be found. Moreover, the investigated groups differed with regard to the severity index. CONCLUSIONS: The results of the study are in accordance with the spectrum hypothesis of depressive syndromes ranging from NDS to minor depression to major depression. Patients with subsyndromal depression showed significant functional impairment to the extent that at least some of these patients probably had a disorder requiring treatment.

Caffeine and human DNA metabolism: the magic and the mystery.

The ability of caffeine to reverse cell cycle checkpoint function and enhance genotoxicity after DNA damage was examined in telomerase-expressing human fibroblasts. Caffeine reversed the ATM-dependent S and G2 checkpoint responses to DNA damage induced by ionizing radiation (IR), as well as the ATR- and Chk1-dependent S checkpoint response to ultraviolet radiation (UVC). Remarkably, under conditions in which IR-induced G2 delay was reversed by caffeine, IR-induced G1 arrest was not. Incubation in caffeine did not increase the percentage of cells entering the S phase 6-8h after irradiation; ATM-dependent phosphorylation of p53 and transactivation of p21(Cip1/Waf1) post-IR were resistant to caffeine. Caffeine alone induced a concentration- and time-dependent inhibition of DNA synthesis. It inhibited the entry of human fibroblasts into S phase by 70-80% regardless of the presence or absence of wildtype ATM or p53. Caffeine also enhanced the inhibition of cell proliferation induced by UVC in XP variant fibroblasts. This effect was reversed by expression of DNA polymerase eta, indicating that translesion synthesis of UVC-induced pyrimidine dimers by DNA pol eta protects human fibroblasts against UVC genotoxic effects even when other DNA repair functions are compromised by caffeine.

An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage.

Inhibition of replicon initiation is a stereotypic DNA damage response mediated through S checkpoint mechanisms not yet fully understood. Studies were undertaken to elucidate the function of checkpoint proteins in the inhibition of replicon initiation following irradiation with 254 nm UV light (UVC) of diploid human fibroblasts immortalized by the ectopic expression of telomerase. Velocity sedimentation analysis of nascent DNA molecules revealed a 50% inhibition of replicon initiation when normal human fibroblasts were treated with a low dose of UVC (1 J/m(2)). Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and AT-like disorder fibroblasts, which lack an S checkpoint response when exposed to ionizing radiation, responded normally when exposed to UVC and inhibited replicon initiation. Pretreatment of normal and AT fibroblasts with caffeine or UCN-01, inhibitors of ATR (AT mutated and Rad3 related) and Chk1, respectively, abolished the S checkpoint response to UVC. Moreover, overexpression of kinase-inactive ATR in U2OS cells severely attenuated UVC-induced Chk1 phosphorylation and reversed the UVC-induced inhibition of replicon initiation, as did overexpression of kinase-inactive Chk1. Taken together, these data suggest that the UVC-induced S checkpoint response of inhibition of replicon initiation is mediated by ATR signaling through Chk-1 and is independent of ATM, Nbs1, and Mre11.

DNA damage responses protect xeroderma pigmentosum variant from UVC-induced clastogenesis.

Lack of DNA polymerase eta and the attendant defect in bypass replication of pyrimidine dimers induced in DNA by ultraviolet light (UV) underlie the enhanced mutagenesis and carcinogenesis observed in xeroderma pigmentosum variant (XP-V). We investigated whether diploid XP-V fibroblasts growing in culture are also more susceptible to UV-induced clastogenesis than normal human fibroblasts (NHF). This study utilized diploid fibroblasts immortalized by the ectopic expression of human telomerase. The cell lines displayed checkpoint responses to DNA damage comparable with those measured in the parental strains. Shortly after exposure to low doses of UVC (< or =4 J/m2), XP-V cells accumulated daughter strand gaps in excess of normal controls (>25-fold). Daughter strand gaps generated in UV-irradiated S phase cells are potential precursors of chromatid-type chromosomal aberrations. Nonetheless, chromatid-type chromosomal aberrations were only 1.5 to 2 times more abundant in XP-V than in NHF exposed to the same UVC dose. XP-V cells, however, displayed S phase delays at lower doses of UVC and for longer periods of time than NHF. These results support the hypothesis that aberrant DNA structures activate S phase checkpoint responses that increase the time available for postreplication repair. Alternatively, cells that cannot be properly repaired remain permanently arrested and never reach mitosis. These responses protect human cells from chromosomal aberrations, especially when other pathways, such as accurate lesion bypass, are lost.