Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how ...deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase's main subunit (gp91
) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chip-genotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10
; OR = 67.6), as well as reduced height (P = 3.3 × 10
; -8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.
Abstract
A pressing concern in the SARS-CoV-2 epidemic and other viral outbreaks, is the extent to which the containment measures are halting the viral spread. A straightforward way to assess this is ...to tally the active cases and the recovered ones throughout the epidemic. Here, we show how epidemic control can be assessed with molecular information during a well characterized epidemic in Iceland. We demonstrate how the viral concentration decreased in those newly diagnosed as the epidemic transitioned from exponential growth phase to containment phase. The viral concentration in the cases identified in population screening decreased faster than in those symptomatic and considered at high risk and that were targeted by the healthcare system. The viral concentration persists in recovering individuals as we found that half of the cases are still positive after two weeks. We demonstrate that accumulation of mutations in SARS-CoV-2 genome can be exploited to track the rate of new viral generations throughout the different phases of the epidemic, where the accumulation of mutations decreases as the transmission rate decreases in the containment phase. Overall, the molecular signatures of SARS-CoV-2 infections contain valuable epidemiological information that can be used to assess the effectiveness of containment measures.
The spread of SARS-CoV-2 is dependent on several factors, both biological and behavioural. The effectiveness of nonpharmaceutical interventions can be attributed largely to changes in human ...behaviour, but quantifying this effect remains challenging. Reconstructing the transmission tree of the third wave of SARS-CoV-2 infections in Iceland using contact tracing and viral sequence data from 2522 cases enables us to directly compare the infectiousness of distinct groups of persons.
The transmission tree enables us to model the effect that a given population prevalence of vaccination would have had on the third wave had one of three different vaccination strategies been implemented before that time. This allows us to compare the effectiveness of the strategies in terms of minimizing the number of cases, deaths, critical cases, and severe cases.
We found that people diagnosed outside of quarantine (Rˆ=1.31) were 89% more infectious than those diagnosed while in quarantine (Rˆ=0.70) and that infectiousness decreased as a function of time spent in quarantine before diagnosis, with people diagnosed outside of quarantine being 144% more infectious than those diagnosed after ≥3 days in quarantine (Rˆ=0.54). People of working age, 16 to 66 years (Rˆ=1.08), were 46% more infectious than those outside of that age range (Rˆ=0.74).
We found that vaccinating the population in order of ascending age or uniformly at random would have prevented more infections per vaccination than vaccinating in order of descending age, without significantly affecting the expected number of deaths, critical cases, or severe cases.
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Since 1974 we have attempted to ascertain all cases of MS beginning 1900-1975 in Iceland. As of October 1979 they numbered 168; all but 5 met all diagnostic criteria of the Schumacher Committee. ...Virtually all cases had been examined by a least one of the authors. Cases were few and sporadic from 1900 to 1922, then increased to a plateau for 1923-44, then again increased in 1945 with an irregular plateau thereafter. Average annual incidence rate for 1945-1954 was 3.2 per 100,000 population, significantly higher than the 1.6 for 1923-1944 or the 1.9 for 1955-1974. Age at onset was significantly decreased for cases with onset 1945-1949 and then sharply increased for those with 1950-1954 onsets. The occurrence of MS in 1945-1954 meets the criteria for a point-source epidemic, whose tail thereafter mérged into what may be "baseline" for Iceland. This postwar epidemic is then similar to that recently described for the Faroe Islands, a land that shares its history, culture, and peoples with Iceland.
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