Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_297

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Ichthyoplankton assemblages associated with pink snapper (Pagrus auratus) spawning aggregations in coastal embayments of southwestern Australia

Pink snapper (Pagrus auratus) form spawning aggregations during the austral spring/summer in three adjacent, sheltered, coastal embayments in southwestern Australia (Cockburn Sound, Warnbro Sound and Owen Anchorage). Larval fishes were sampled in these embayments, as well as in the more exposed adjacent waters of Five Fathom Bank, to ascertain which teleost species utilised these areas for spawning concurrently with P. auratus. Obliquely towed bongo nets (500 μm mesh) were used to collect icthyoplankton in November 2007 over three days during the new moon period when spawning of P. auratus is known to peak. A total of 13 270 larvae from 30 teleost families was collected with an overall mean larval fish concentration of 1.91 m -3 (± s.e. 0.28). Larval fish assemblages were significantly different in each of the three embayments and Five Fathom Bank, reflecting the degree of shelter, water-circulation patterns and associated benthic habitats. The highest larval fish concentrations were recorded in Cockburn Sound (3.69 m -3 ± s.e. 0.05) and the lowest along Five Fathom Bank (0.16 m -3 ± s.e. 0.02). P. auratus larvae were only present in samples from the three embayments. The most abundant larvae were those of the Australian anchovy (Engraulis australis), which occurred predominantly in Cockburn Sound and, to a lesser extent, Owen Anchorage. The most ubiquitous larvae included the longspine dragonet (Callionymus goodladi) and leatherjackets (Monacanthidae). This study provides circumstantial evidence that eggs and larvae of P. auratus and other teleosts are retained in the sheltered waters of Cockburn and Warnbro Sounds during spring/summer

Risk factors associated with poorer experiences of end-of-life care and challenges in early bereavement : results of a national online survey of people bereaved during the COVID-19 pandemic

Background: Experiences of end-of-life care and early bereavement during the COVID-19 pandemic are poorly understood. Aim: To identify clinical and demographic risk factors for sub-optimal end-of-life care and pandemic-related challenges prior to death and in early bereavement, to inform clinical practice, policy and bereavement support. Design: Online national survey of adults bereaved in the UK (deaths between 16 March 2020 and 2 January 2021), recruited via media, social media, national associations and organisations. Setting/participants: 711 participants, mean age 49.5 (SD 12.9, range 18–90). 628 (88.6%) were female. Mean age of the deceased was 72.2 (SD 16.1, range miscarriage to 102 years). 311 (43.8%) deaths were from confirmed/suspected COVID-19. Results: Deaths in hospital/care home increased the likelihood of poorer experiences at the end of life; for example, being unable to visit or say goodbye as wanted (p < 0.001). COVID-19 was also associated with worse experiences before and after death; for example, feeling unsupported by healthcare professionals (p < 0.001), social isolation/loneliness (OR = 0.439; 95% CI: 0.261–0.739), and limited contact with relatives/friends (OR = 0.465; 95% CI: 0.254–0.852). Expected deaths were associated with a higher likelihood of positive end-of-life care experiences. The deceased being a partner or child also increased the likelihood of positive experiences, however being a bereaved partner strongly increased odds of social isolation/loneliness, for example, OR = 0.092 (95% CI: 0.028–0.297) partner versus distant family member. Conclusions: Four clear risk factors were found for poorer end-of-life care and pandemic-related challenges in bereavement: place, cause and expectedness of death, and relationship to the deceased

Place, cause and expectedness of death and relationship to the deceased are associated with poorer experiences of end-of-life care and challenges in early bereavement : risk factors from an online survey of people bereaved during the COVID-19 pandemic

Objectives: To identify clinical and demographic risk factors for sub-optimal end-of-life care and pandemic-related challenges prior to death and in early bereavement. Design: Online open national survey of adults bereaved in the UK from 16 March 2020-5 January 2021, recruited via media, social media, national associations and organisations. Setting: General population, UK. Participants: 711 participants, mean age 49.5 (SD 12.9, range 18-90). 395 (55.6%) had experienced the death of a parent, 152 (21.4%) a partner. 628 (88.6%) were female and 33 (4.7%) from a minority ethnic background. The mean age of the person who died was 72.2 (SD 16.1, range miscarriage to 102 years). 311 (43.8%) deaths were from confirmed/suspected COVID-19, and 410 (57.8%) deaths occurred in hospital. Main outcome measures: End-of-life care experiences (six items, e.g. involvement in care decisions) and pandemic-related challenges before and after death (six items, e.g. unable to visit prior to death). Results: Deaths in hospital/care home increased the likelihood of: unable to visit prior to death, unable to say goodbye as wanted, limited contact in last days of life (all P<0.001). Deaths in hospice/at home increased the likelihood of: involved in care decisions (P<0.001), well supported by healthcare professionals (HCPs) after the death (P=0.003). Hospice deaths increased the likelihood of being given bereavement support information, which was least likely for care home deaths (P<0.001). Hospital deaths decreased the likelihood of knowing the contact details for the responsible care professional (P=0.001). Bereavement due to COVID-19 decreased the likelihood of: involvement in care decisions (P<0.001), feeling well supported by HCPs after the death (P<0.001), and increased the likelihood of: being unable to say goodbye (OR=0.348; 95% CI: 0.2 to 0.605), social isolation and loneliness (OR=0.439; 95% CI: 0.261 to 0.739), limited contact with relatives/friends (OR=0.465; 95% CI: 0.254 to 0.852). Expected deaths were associated with higher likelihood of feeling involved, informed, and well supported by HCPs (all P<0.001). The deceased being a partner or child increased the likelihood of knowing the contact details for the responsible care professional (P=0.001), being able to visit (P<0.001) and given bereavement support information (P<0.001). Being a bereaved partner strongly increased odds of social isolation and loneliness, e.g. OR = 0.092 (95% CI: 0.028 to 0.297) partner versus distant family member. Conclusions: Four clear risk factors were found for poorer end-of-life care and pandemic-related challenges in bereavement: place, cause and expectedness of death, and relationship to the deceased

The effects of rain on the erosion threshold of intertidal cohesive sediments

Intertidal sedimentary environments are complex systems governed by interactions between physical, chemical and biological processes and parameters. Tidally induced flow and wave action are known to be an integral driving force behind the erosion, transport, deposition and consolidation cycle (ETDC) of intertidal sediments. Whilst considerable advances have been made in understanding both the physical and biological processes and their interactions in these systems, it is clear that there are gaps in our understanding. One factor that has been largely ignored to date is that of rain. Visual observations in the field and associated data indicated that rain showers during low tide are correlated with a reduction in the erosion threshold of intertidal cohesive sediments. This paper presents preliminary field and laboratory data showing the importance of rain in reducing the erosion threshold of cohesive intertidal sediments. The implications for our knowledge of, and modelling of the ETDC cycle of cohesive intertidal sediments are discussed