Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2-33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.

Current developments and perspectives in psoriasis.

The study of psoriasis has yielded fundamental new insights into immunologic regulation and innovative therapies in a way that few other diseases have. In this review, we summarize the main features of current psoriasis research with emphasis on pathophysiological processes and the milestones in the approval of various biologics and small molecule drugs. Thus, through psoriasis research, we are gaining a better understanding of the interplay between the components of the innate and adaptive immune systems. New therapeutics interfere with crucial regulatory networks. Based on current knowledge, we outline what we believe to be some of the most important future research directions and therapeutic and clinical developments in psoriasis. These span multiple areas, ranging from the study of genetic, epigenetic, cellular, and immunological mechanisms to studies of particular clinical forms of psoriasis, individual systemic effects of the disease and its treatment, and the incorporation of large connected data sets and artificial intelligence. The goal is to understand psoriasis holistically, from the molecular to the organismic and societal levels, in order to develop individualized prevention and treatment strategies. Despite impressive progress, psoriasis research must continue to evolve at both the smallest and largest scales to comprehensively address the needs of both physicians and patients.

The gross anatomy course: SARS-CoV-2 pandemic-related effects on students' learning, interest in peer-teaching, and students' perception of its importance.

The COVID-19 pandemic required adjustments and limitations in university teaching, thereby challenging teaching concepts in anatomy requiring in-person contact, including the gross anatomy course. Therefore, the present study investigates the impact of COVID-19-associated adjustments on students' perception of the gross anatomy course's importance and quality, students' preferred learning setting and outcome, and their motivation to involve themselves in academic activities, including becoming a future peer-teacher of the course. Using paper-based questionnaires in Ulm, Germany, 397 (response rate: 82.3%) students of the winter term of 2020/2021 were surveyed using quantitative and qualitative items, which were compared with cohorts prior to the pandemic. Students reported a higher global rating on course quality during COVID-19 (pre-COVID-19: 5.3 ± 0.9, during-COVID-19: 5.6 ± 0.7, p < 0.001; 1 = very bad, 6 = very good). Students' perceived importance of the gross anatomy course showed a small but significant increase (pre-COVID-19: 4.2 ± 0.6, during-COVID-19: 4.3 ± 0.6, p < 0.001; 1 = strongly disagree, 6 = strongly agree). Students' motivation to apply as a peer-teacher remained stable, nevertheless, they reported less interest in transferring their knowledge to junior students. Finally, students reported that they spent significantly more learning time alone and their examination grades remained unchanged during the pandemic. Astonishingly, despite radical changes of the teaching environment due to COVID-19, students appreciate the offered teaching and highly valued the gross anatomy course.

[Impact of the COVID-19 crisis in Spring 2020 on trauma case numbers of an academic teaching hospital in Stuttgart : Trauma during a pandemic]. / Einfluss der COVID-19-Krise im Frühjahr 2020 auf traumatologische Fallzahlen eines akademischen Lehrkrankenhauses in Stuttgart : Trauma während einer Pandemie.

BACKGROUND: To cope with the COVID-19 outbreak in Germany, the government imposed a lockdown, which led to restrictions and lifestyle changes for the population. PURPOSE: This study aimed to evaluate the impact of the lockdown on activities causing trauma and the consultation in emergency rooms. MATERIAL AND METHODS: All consecutive trauma patients consulting the Emergency Department of the Marienhospital Stuttgart (MHS), Germany, during the 6 weeks preceding the lockdown, during and after the lockdown were included. The time and type of consultation, treatment received, Manchester triage score, type of trauma, the anatomical region of the injury as well as demographic data were reported and compared. RESULTS: The study included 551 cases during lockdown, 943 cases before and 783 cases after the lockdown. We observed a reduced caseload during the lockdown of 41.6% compared to before and of 29.7% compared to after (p < 0.001). Patients were on average older in the observation group than in both control groups (before : 51.5 years, lockdown: 56.1 years, after: 51.6 years) (p < 0.001). Injuries to the head and neck were constant (25.0%, 25.4%, 25.5%). We noticed lower limb injuries decreasing (26.1%, 22.3%, 22.7%) and upper limb injuries increasing (25.5%, 31.8%, 30.1%). A decrease in sports injuries (11.1%, 5.1%, 9.1%) and work accidents (16.1%, 10.7%, 12.8%) resulted in more domestic accidents (30.4%, 52.5%, 31.8%). Self-referral decreased (67.7%, 53.2%, 60.3%) while referral via paramedics increased (28.3%, 38.7%, 35.6). Blunt trauma was the most common cause of injury (55.6%, 61.0%, 55.3%). Indications for surgery were higher (16.8%, 21.6%, 14.0%). CONCLUSION: The lockdown and restrictions in personal life and daily routine had an impact on the frequency, etiology and management of trauma patients in Stuttgart.

The Impact of COVID-19 Pandemic on Medical Doctors' Work-Family Balance at German University Clinics.

The measures taken to cope with the COVID-19 pandemic by governments worldwide have vast consequences on all areas of life. To assess the impact of the COVID-19 pandemic on long-term career development, we evaluated the work-family balance of medical doctors at nine German university clinics. The results indicate a severely disturbed work-family balance, which was mostly due to insufficient childcare, based on restrictions in school operations and childcare. Despite the newly created emergency childcare options, aiming to ensure the functioning of the "systematically important" professional groups, medical doctors feel that they are not sufficiently supported by the measures taken by local governments. Women, in particular, see their professional development at risk. Our results underline that proper and flexible childcare is essential for the career advancement of female medical doctors and is particularly important in times of crises such as the current COVID-19 pandemic. At university medicine clinics, increased work time flexibility and optimized schooling and childcare are needed to promote the career development of female as well as male medical doctors in the early stage of their careers.

Interdependencies of cellular and humoral immune responses in heterologous and homologous SARS-CoV-2 vaccination.

BACKGROUND: Homologous and heterologous SARS-CoV-2 vaccinations yield different spike protein-directed humoral and cellular immune responses. This study aimed to explore their currently unknown interdependencies. METHODS: COV-ADAPT is a prospective, observational cohort study of 417 healthcare workers who received vaccination with homologous ChAdOx1 nCoV-19, homologous BNT162b2 or with heterologous ChAdOx1 nCoV-19/BNT162b2. We assessed humoral (anti-spike-RBD-IgG, neutralizing antibodies, and avidity) and cellular (spike-induced T-cell interferon-γ release) immune responses in blood samples up to 2 weeks before (T1) and 2-12 weeks following secondary immunization (T2). RESULTS: Initial vaccination with ChAdOx1 nCoV-19 resulted in lower anti-spike-RBD-IgG compared with BNT162b2 (70 ± 114 vs. 226 ± 279 BAU/ml, p < .01) at T1. Booster vaccination with BNT162b2 proved superior to ChAdOx1 nCoV-19 at T2 (anti-spike-RBD-IgG: ChAdOx1 nCoV-19/BNT162b2 2387 ± 1627 and homologous BNT162b2 3202 ± 2184 vs. homologous ChAdOx1 nCoV-19 413 ± 461 BAU/ml, both p < .001; spike-induced T-cell interferon-γ release: ChAdOx1 nCoV-19/BNT162b2 5069 ± 6733 and homologous BNT162b2 4880 ± 7570 vs. homologous ChAdOx1 nCoV-19 1152 ± 2243 mIU/ml, both p < .001). No significant differences were detected between BNT162b2-boostered groups at T2. For ChAdOx1 nCoV-19, no booster effect on T-cell activation could be observed. We found associations between anti-spike-RBD-IgG levels (ChAdOx1 nCoV-19/BNT162b2 and homologous BNT162b2) and T-cell responses (homologous ChAdOx1 nCoV-19 and ChAdOx1 nCoV-19/BNT162b2) from T1 to T2. Additionally, anti-spike-RBD-IgG and T-cell response were linked at both time points (all groups combined). All regimes yielded neutralizing antibodies and increased antibody avidity at T2. CONCLUSIONS: Interdependencies between humoral and cellular immune responses differ between common SARS-CoV-2 vaccination regimes. T-cell activation is unlikely to compensate for poor humoral responses.

Einfluss der COVID-19-Krise im Frühjahr 2020 auf traumatologische Fallzahlen eines akademischen Lehrkrankenhauses in Stuttgart : Trauma während einer Pandemie Impact of the COVID-19 crisis in Spring 2020 on trauma case numbers of an academic teaching hospital in StuttgartTrauma during a pandemic

Hintergrund Zur Eindämmung des COVID-19-Ausbruchs erließ die Bundesregierung einige Regeln und Einschränkungen für die Bürger. Ziel Diese Studie widmet sich dem Einfluss der Maßnahmen auf traumatologische Vorstellungen in der Notaufnahme. Material und Methoden Alle konsekutiven traumatologischen Patienten der Notaufnahme des Marienhospitals Stuttgart (MHS), die sich in den 6 Wochen jeweils vor und nach dem Lockdown sowie währenddessen vorstellten, wurden einbezogen. Die Zeit und Art der Vorstellung, die Behandlungsart, der Manchester Triage Score, die Region und Art der Verletzung sowie demografische Daten wurden ermittelt und verglichen. Ergebnisse Es wurden 551 Fälle während des Lockdowns, 943 Fälle davor und 783 Fälle danach eingeschlossen. Es konnte eine Fallzahlreduktion um 41,6 % im Vergleich zu davor und um 29,7 % verglichen mit danach (p < 0,001) beobachtet werden. Während des Lockdowns waren die Patienten im Mittel älter (vorher: 51,5 Jahre, Lockdown: 56,1 Jahre, danach: 51,6 Jahre) (p < 0,001). Kopf-Hals-Verletzungen waren konstant (25,0 %, 25,4 %, 25,5 %). Verletzungen der unteren Extremität waren seltener (26,1 %, 22,3 %, 22,7 %), der oberen Extremität häufiger (25,5 %, 31,8 %, 30,1 %). Besonders Sportverletzungen (11,1 %, 5,1 %, 9,1 %) und Arbeitsunfälle (16,1 %, 10,7 %, 12,8 %) reduzierten sich, dafür stiegen häusliche Unfälle (30,4 %, 52,5 %, 31,8 %). Selbsteinweisungen gingen zurück (67,7 %, 53,2 %, 60,3 %), Vorstellungen mittels Rettungsdienst stiegen (28,3 %, 38,7 %, 35,6 %). Stumpfes Trauma war der häufigste Grund einer Vorstellung (55,6 %, 61,0 %, 55,3 %). Es musste öfter operiert werden (16,8 %, 21,6 %, 14,0 %). Schlussfolgerung Der Lockdown und die Einschränkungen hatten einen Einfluss auf Zahl sowie Art und Behandlung von Traumapatienten in Stuttgart.

IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro.

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) can restrict viral pathogens, but pro- and anti-viral activities have been reported for coronaviruses. Here, we show that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. However, endogenous IFITM expression supports efficient infection of SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral infection. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. IFITM-derived peptides and targeting antibodies inhibit SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are cofactors for efficient SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and are potential targets for therapeutic approaches.

COVID-19 and immunological regulations - from basic and translational aspects to clinical implications.

The COVID-19 pandemic caused by SARS-CoV-2 has far-reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS-CoV-2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS-CoV-2/COVID-19 with mediators of the acute phase of inflammation (TNF, IL-1, IL-6), type 1 and type 17 immune responses (IL-12, IL-23, IL-17, IL-36), type 2 immune reactions (IL-4, IL-13, IL-5, IL-31, IgE), B-cell immunity, checkpoint regulators (PD-1, PD-L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non-specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte-mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS-CoV-2/COVID-19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID-19 pandemic; some even appear to alleviate COVID-19.

COVID-19 and implications for dermatological and allergological diseases.

COVID-19, caused by the coronavirus SARS-CoV-2, has become pandemic. A further level of complexity opens up as soon as we look at diseases whose pathogenesis and therapy involve different immunological signaling pathways, which are potentially affected by COVID-19. Medical treatments must often be reassessed and questioned in connection with this infection. This article summarizes the current knowledge of COVID-19 in the light of major dermatological and allergological diseases. It identifies medical areas lacking sufficient data and draws conclusions for the management of our patients during the pandemic. We focus on common chronic inflammatory skin diseases with complex immunological pathogenesis: psoriasis, eczema including atopic dermatitis, type I allergies, autoimmune blistering and inflammatory connective tissue diseases, vasculitis, and skin cancers. Since several other inflammatory skin diseases display related or comparable immunological reactions, clustering of the various inflammatory dermatoses into different disease patterns may help with therapeutic decisions. Thus, following these patterns of skin inflammation, our review may supply treatment recommendations and thoughtful considerations for disease management even beyond the most frequent diseases discussed here.