A systematic literature review of the clinical signs and symptoms of veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation in adults and children.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a rare, serious complication following haematopoietic cell transplantation (HCT). This systematic literature review evaluated differences in clinical manifestations of VOD/SOS post-HCT in adults and children. Medline and Embase were searched up to 4 March 2021 for reports of VOD/SOS post-HCT; VOD/SOS diagnostic guidelines were included. Publications were evaluated based on inclusion of five cardinal clinical features of VOD/SOS (ascites, hepatomegaly, hyperbilirubinaemia, right upper quadrant [RUQ] pain and weight gain ≥5%). Overall, 204 publications were included. At diagnosis, hyperbilirubinaemia was more common in adults (93%) versus children (82%), weight gain ≥5% and hepatomegaly were more common in children (86%, 89%) versus adults (73%, 76%) and ascites and RUQ pain were similar between age groups. While 40% of cases had all five cardinal features, age was not a substantial determinant of the likelihood of missing any single specific feature. The proportion of cases, where hyperbilirubinaemia was the first recorded feature, was higher in children versus adults; weight gain and RUQ pain appeared first in a greater proportion of adults versus children. VOD/SOS diagnosis can be challenging; features may not present in a distinct sequence. This necessitates continuous vigilance by those involved in patient monitoring post-HCT.

A model framework for projecting the prevalence and impact of Long-COVID in the UK.

The objective of this paper is to model lost Quality Adjusted Life Years (QALYs) from symptoms arising from COVID-19 disease in the UK population, including symptoms of 'long-COVID'. The scope includes QALYs lost to symptoms, but not deaths, due to acute COVID-19 and long-COVID. The prevalence of symptomatic COVID-19, encompassing acute symptoms and long-COVID symptoms, was modelled using a decay function. Permanent injury as a result of COVID-19 infection, was modelled as a fixed prevalence. Both parts were combined to calculate QALY loss due to COVID-19 symptoms. Assuming a 60% final attack rate for SARS-CoV-2 infection in the population, we modelled 299,730 QALYs lost within 1 year of infection (90% due to symptomatic COVID-19 and 10% permanent injury) and 557,764 QALYs lost within 10 years of infection (49% due to symptomatic COVID-19 and 51% due to permanent injury). The UK Government willingness-to-pay to avoid these QALY losses would be £17.9 billion and £32.2 billion, respectively. Additionally, 90,143 people were subject to permanent injury from COVID-19 (0.14% of the population). Given the ongoing development in information in this area, we present a model framework for calculating the health economic impacts of symptoms following SARS-CoV-2 infection. This model framework can aid in quantifying the adverse health impact of COVID-19, long-COVID and permanent injury following COVID-19 in society and assist the proactive management of risk posed to health. Further research is needed using standardised measures of patient reported outcomes relevant to long-COVID and applied at a population level.

Circadian Clock Synchronization of the Cell Cycle in Zebrafish Occurs through a Gating Mechanism Rather Than a Period-phase Locking Process.

Studies from a number of model systems have shown that the circadian clock controls expression of key cell cycle checkpoints, thus providing permissive or inhibitory windows in which specific cell cycle events can occur. However, a major question remains: Is the clock actually regulating the cell cycle through such a gating mechanism or, alternatively, is there a coupling process that controls the speed of cell cycle progression? Using our light-responsive zebrafish cell lines, we address this issue directly by synchronizing the cell cycle in culture simply by changing the entraining light-dark (LD) cycle in the incubator without the need for pharmacological intervention. Our results show that the cell cycle rapidly reentrains to a shifted LD cycle within 36 h, with changes in p21 expression and subsequent S phase timing occurring within the first few hours of resetting. Reentrainment of mitosis appears to lag S phase resetting by 1 circadian cycle. The range of entrainment of the zebrafish clock to differing LD cycles is large, from 16 to 32 hour periods. We exploited this feature to explore cell cycle entrainment at both the population and single cell levels. At the population level, cell cycle length is shortened or lengthened under corresponding T-cycles, suggesting that a 1:1 coupling mechanism is capable of either speeding up or slowing down the cell cycle. However, analysis at the single cell level reveals that this, in fact, is not true and that a gating mechanism is the fundamental method of timed cell cycle regulation in zebrafish. Cell cycle length at the single cell level is virtually unaltered with varying T-cycles.

Mislocalisation of BEST1 in iPSC-derived retinal pigment epithelial cells from a family with autosomal dominant vitreoretinochoroidopathy (ADVIRC).

Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare, early-onset retinal dystrophy characterised by distinct bands of circumferential pigmentary degeneration in the peripheral retina and developmental eye defects. ADVIRC is caused by mutations in the Bestrophin1 (BEST1) gene, which encodes a transmembrane protein thought to function as an ion channel in the basolateral membrane of retinal pigment epithelial (RPE) cells. Previous studies suggest that the distinct ADVIRC phenotype results from alternative splicing of BEST1 pre-mRNA. Here, we have used induced pluripotent stem cell (iPSC) technology to investigate the effects of an ADVIRC associated BEST1 mutation (c.704T > C, p.V235A) in patient-derived iPSC-RPE. We found no evidence of alternate splicing of the BEST1 transcript in ADVIRC iPSC-RPE, however in patient-derived iPSC-RPE, BEST1 was expressed at the basolateral membrane and the apical membrane. During human eye development we show that BEST1 is expressed more abundantly in peripheral RPE compared to central RPE and is also expressed in cells of the developing retina. These results suggest that higher levels of mislocalised BEST1 expression in the periphery, from an early developmental stage, could provide a mechanism that leads to the distinct clinical phenotype observed in ADVIRC patients.