Clock monitoring is associated with age-related decline in time-based prospective memory

In laboratory time-based prospective memory tasks, older adults typically perform worse than younger adults do. It has been suggested that less frequent clock checking due to problems with executive functions may be responsible. We aimed to investigate the role of clock checking in older adults’ time-based prospective memory and to clarify whether executive functions would be associated with clock checking and consequently, with time-based prospective memory. We included 62 healthy older adults (62-85 years of age) and applied tasks of time-based prospective memory as well as of executive functions (i.e., inhibition, fluency, and working memory). We used mediation analysis to test whether time-based prospective memory declined with advancing age due to less frequent clock checking. In addition, we tested whether there would be an association between executive functions and clock checking or time-based prospective memory. Time-based prospective memory declined with advancing age due to less frequent clock checking within 30s prior to intention completion. We only found a link between executive functions and clock checking (or time-based prospective memory) when not controlling for age. Our results support the importance of clock checking for time-based prospective memory and add to the current literature that older adults’ prospective memory declines because they are less able to adapt their clock checking. Yet, the reason why older adults are less able to adapt their clock checking still remains open. Our results do not indicate that executive function deficits play a central role

The effect of loss incentives on prospective memory in healthy older adults: study protocol of a randomized controlled trial using ultra-high field fMRI.

BACKGROUND Prospective memory is important for our health and independence but declines with age. Hence, interventions to enhance prospective memory, for example by providing an incentive, may promote healthy ageing. The neuroanatomical correlates of prospective memory and the processing of incentive-related prospective memory changes in older adults are not fully understood. In an fMRI study, we will therefore test whether incentives improve prospective memory in older adults and how prospective memory is processed in the brain in general, and when incentives are provided. Since goals and interests change across adulthood, avoiding losses is becoming more important for older adults than achieving gains. We therefore posit that loss-related incentives will enhance prospective memory, which will be subserved by increased prefrontal and midbrain activity. METHODS We will include n = 60 healthy older adults (60-75 years of age) in a randomized, single-blind, and parallel-group study. We will acquire 7T fMRI data in an incentive group and a control group (n = 30 each, stratified by education, age, and sex). Before and after fMRI, all participants will complete questionnaires and cognitive tests to assess possible confounders (e.g., income, personality traits, sensitivity to reward or punishment). DISCUSSION The results of this study will clarify whether loss-related incentives can enhance prospective memory and how any enhancement is processed in the brain. In addition, we will determine how prospective memory is processed in the brain in general. The results of our study will be an important step towards a better understanding of how prospective memory changes when we get older and for developing interventions to counteract cognitive decline

Modulating prospective memory and attentional control with high-definition transcranial current stimulation: Study protocol of a randomized, double-blind, and sham-controlled trial in healthy older adults.

The ability to remember future intentions (i.e., prospective memory) is influenced by attentional control. At the neuronal level, frontal and parietal brain regions have been related to attentional control and prospective memory. It is debated, however, whether more or less activity in these regions is beneficial for older adults' performance. We will test that by systematically enhancing or inhibiting activity in these regions with anodal or cathodal high-definition transcranial direct current stimulation in older adults. We will include n = 105 healthy older volunteers (60-75 years of age) in a randomized, double-blind, sham-controlled, and parallel-group design. The participants will receive either cathodal, anodal, or sham high-definition transcranial direct current stimulation of the left or right inferior frontal gyrus, or the right superior parietal gyrus (1mA for 20 min). During and after stimulation, the participants will complete tasks of attentional control and prospective memory. The results of this study will clarify how frontal and parietal brain regions contribute to attentional control and prospective memory in older healthy adults. In addition, we will elucidate the relationship between attentional control and prospective memory in that age group. The study has been registered with ClinicalTrials.gov on the 12th of May 2021 (trial identifier: NCT04882527)

dolls/puppets like mensch – dolls/puppets as artificial beings. Part 1.2

Die dritte Ausgabe der Zeitschrift denkste: puppe / just a bit of: doll (de:do), ein multi-disziplinäres Online-Journal für Mensch-Puppen-Diskurse, erscheint als Doppelheft, dessen gemeinsamer Themenschwerpunkt lautet: puppen/dolls like mensch – puppen als künstliche meschen. Mit diesem Fokus wird ein Thema aufgegriffen, das Menschen seit der Antike berührt und bis heute ihren Verstand und ihre Imagination, ihre Bedürfnisse und ihre Gefühle in Unruhe versetzt. In Mythologien, literarischen Fiktionen und Narrativen für Erwachsene und Kinder, in Werken der bildenden Künste, im Film, in mechanisch-technischen Anwendungen und Utopien, in den performativen Künsten, in der (Spiel-)Pädagogik und in den verschiedenen Bereichen der Popkultur wirft das Motiv der Puppe mit seinen unterschiedlichsten Ausdrucksformen immer auch existenzielle Fragen auf: Wer und was ist der Mensch? Die Puppe als künstlicher Mensch ist in gewisser Weise wie mensch, ohne Mensch zu sein. Als von Menschen geschaffene Abbilder, Vorbilder, Nachahmungen und Entwürfe des Menschen spiegeln und bestätigen Puppen vorhandene Lebenswelten und loten gleichzeitig Potenziale und Abgründe des Mensch-Seins zwischen Utopie und Dystopie, zwischen Neugier und Hingabe, zwischen Horror und Glückseligkeit, zwischen Macht und Ohnmacht aus. Puppen/dolls like mensch – der doppelte Wortsinn betont die gegebene Ambiguität der Puppen und die spannenden, ihnen innewohnenden Ambivalenzen. Im ersten Teilband (1.1) wird den Spuren und Erscheinungsformen des Puppenmotivs und der Puppe(n) – als literarisches Narrativ, als künstlerisches Motiv, als materialisiertes Objekt – vor allem im Kontext von bildender Kunst, Literatur, Fotografie, Theater und Androidentechnologien nachgegangen. Im zweiten Teilband (1.2) werden zum einen kinderliterarische und (spiel-)didaktische Texte akzentuiert, zum anderen sind hier verschiedene mediale und popkulturelle Formate aus den Bereichen Computerspiel, Comic-Film-Adaptation, Film (unterschiedlicher Genres) und dem Figurentheater versammelt sowie Thematisierungen der Verknüpfung von materiellen Artefakten und literarischen Narrativen. Rezensionen in Form von Essays über literarische Puppen-Narrative, eine Foto-Ausstellung und ein Ballett runden beide Ausgaben ab. Die zeitliche Spanne reicht vom Mittelalter bis in die Gegenwart und Zukunft und zeigt einmal mehr, wie über das Narrativ der Puppe uralte Menschheitsfragen in Traditionslinien eingebunden werden und sie auf faszinierende Weisen fortschreiben.The third edition of the journal denkste: puppe / just a bit of: doll (de: do), a multidisciplinary online journal for human-doll discourses, is a double issue whose shared thematic focus is: puppen/dolls like mensch – dolls/puppets as artificial beings. With this focus, we take up a topic that has concerned mankind since ancient times and has always upset their 'minds' and 'hearts’, their needs and feelings. In mythologies, literary fictions and narratives for adults as well as for children, in works of the visual arts, in film, in mechanical-technical applications and utopias, in the performative arts, in (play-)pedagogy and in the various fields of pop culture, the motif of the doll with its various forms of expression always raises existential questions: Who is man, what is human? The doll as an artificial human being is in a certain way like mensch without being human. As man-made images, as models, imitations and designs of humans, dolls/puppets reflect and confirm existing worlds and at the same time sound out the potentials and abysses of being human between utopia and dystopia, between curiosity and devotion, between horror and bliss, between power and powerlessness. Dolls/puppets like mensch – the double meaning of these words emphasizes the given ambiguity of the dolls/puppets and the intriguing ambivalences inherent in them. In the first part of volume (1.1) the traces and manifestations of the doll motif and of doll(s) – as literary narrative, as artistic motif, as materialized object – will be explored primarily in the context of the fine arts, of literature, photography, theater and android technologies. In the second part of the volume (1.2), on the one hand, children's literature and (play)didactic texts are accentuated; on the other hand, various media and pop-cultural formats from the fields of computer games, comic-film adaptations, films (of different genres) and puppet theater performances are gathered here, as well as issues that link material artifacts and literary narratives. Reviews in the form of essays on literary doll narratives, a photo exhibition and a ballet round off both editions. The time span extends from the Middle Ages to the present and future and shows once again how age-old questions regarding mankind and humanity are integrated into traditional lines and are carried on continuously in fascinating ways

Protease- and cell type–specific activation of protease-activated receptor 2 in cutaneous inflammation

Background: Protease-activated receptor 2 (PAR2) signaling controls skin barrier function and inflammation, but the roles of immune cells and PAR2-activating pro teases in cutaneous diseases are poorly understood. Objective: To dissect PAR2 signaling contributions to skin inflammation with new ge netic and pharmacological tools. Methods/Results: We found markedly increased numbers of PAR2+ infiltrating my eloid cells in skin lesions of allergic contact dermatitis (ACD) patients and in the skin of contact hypersensitivity (CHS) in mice, a murine ACD model for T cell–mediated allergic skin inflammation. Cell type–specific deletion of PAR2 in myeloid immune cells as well as mutation-induced complete PAR2 cleavage insensitivity significantly re duced skin inflammation and hapten-specific Tc1/Th1 cell response. Pharmacological approaches identified individual proteases involved in PAR2 cleavage and demon strated a pivotal role of tissue factor (TF) and coagulation factor Xa (FXa) as upstream activators of PAR2 in both the induction and effector phase of CHS. PAR2 mutant mouse strains with differential cleavage sensitivity for FXa versus skin epithelial cell–expressed proteases furthermore uncovered a time-dependent regulation of CHS development with an important function of FXa-induced PAR2 activation during the late phase of skin inflammation. Conclusions: Myeloid cells and the TF–FXa–PAR2 axis are key mediators and poten tial therapeutic targets in inflammatory skin disease

Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.)

The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection