Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

Pseudoxanthoma elasticum (PXE) primarily affects organs that are abundant in elastic fibers, such as the skin, eye and blood vessels, and may eventually cause loss of vision or cardiovascular disease (CVD). Because CVD is a potentially life-threatening complication, its early detection is important for improving the quality of life of PXE patients. To determine the relationship between the distribution of skin and mucous membrane lesions and the prevalence of CVD in patients with PXE, we examined 14 PXE cases who presented between 2004 and 2007. All patients had angioid streaks (AS) and positive pathological findings. The skin lesions in PXE patients are distributed discontinuously and thus the degrees of skin involvement were assessed by determining the presence or absence of PXE skin and mucous membrane lesions in six sites (oral mucosa, neck, periumbilical region, cubital fossa, axillae and inguinal regions). Each site was given a binary score (i.e. present = 1, absent = 0) irrespective of severity and the scores were summed to yield a total distribution score (potential range of 0-6). Four cases had PXE-associated CVD. Their mean distribution score was 5.7, which was significantly higher than the score of the cases without CVD (1.8) (P = 0.0049). There was also significant correlation between the high distribution score (P = 0.0053) as well as CVD (P = 0.029) with the maximum width of AS. A higher distribution score and the presence of oral mucosal lesions were associated with CVD. This scoring method may be useful for predicting the presence of CVD in PXE patients.

Background We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. Methods We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. Results Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. Conclusions We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

No abstract

We report a case of malignant melanoma (MM) derived from cerebriform intradermal naevus (CIN) in a 66-year-old Japanese man. The patient had cutis verticis gyrata (CVG) on the posterior area of the scalp at birth. He noticed a dome-shaped nodule at the centre of the CVG at 66 years of age. Histopathological examination found a nodule of MM arising within an extensive area of intradermal naevus. There was no metastasis to lymph nodes or other organs. To our knowledge, only two cases of CIN in which MM had later developed have been reported. We estimated that the incidence of melanoma from CIN including our case is 4.5% (3 of 67 reported cases), which seems to be comparable to the frequency of malignant alteration of giant pigmented naevi. This suggests that pathological examination is recommended for CVG, and once pathological diagnosis of CIN is confirmed, long clinical follow-ups are necessary for detecting development of MM.