During the COVID-19 lockdown, referrals via the 2-week-wait urgent pathway for suspected cancer in England, UK, are reported to have decreased by up to 84%. We aimed to examine the impact of ...different scenarios of lockdown-accumulated backlog in cancer referrals on cancer survival, and the impact on survival per referred patient due to delayed referral versus risk of death from nosocomial infection with severe acute respiratory syndrome coronavirus 2.
In this modelling study, we used age-stratified and stage-stratified 10-year cancer survival estimates for patients in England, UK, for 20 common tumour types diagnosed in 2008–17 at age 30 years and older from Public Health England. We also used data for cancer diagnoses made via the 2-week-wait referral pathway in 2013–16 from the Cancer Waiting Times system from NHS Digital. We applied per-day hazard ratios (HRs) for cancer progression that we generated from observational studies of delay to treatment. We quantified the annual numbers of cancers at stage I–III diagnosed via the 2-week-wait pathway using 2-week-wait age-specific and stage-specific breakdowns. From these numbers, we estimated the aggregate number of lives and life-years lost in England for per-patient delays of 1–6 months in presentation, diagnosis, or cancer treatment, or a combination of these. We assessed three scenarios of a 3-month period of lockdown during which 25%, 50%, and 75% of the normal monthly volumes of symptomatic patients delayed their presentation until after lockdown. Using referral-to-diagnosis conversion rates and COVID-19 case-fatality rates, we also estimated the survival increment per patient referred.
Across England in 2013–16, an average of 6281 patients with stage I–III cancer were diagnosed via the 2-week-wait pathway per month, of whom 1691 (27%) would be predicted to die within 10 years from their disease. Delays in presentation via the 2-week-wait pathway over a 3-month lockdown period (with an average presentational delay of 2 months per patient) would result in 181 additional lives and 3316 life-years lost as a result of a backlog of referrals of 25%, 361 additional lives and 6632 life-years lost for a 50% backlog of referrals, and 542 additional lives and 9948 life-years lost for a 75% backlog in referrals. Compared with all diagnostics for the backlog being done in month 1 after lockdown, additional capacity across months 1–3 would result in 90 additional lives and 1662 live-years lost due to diagnostic delays for the 25% backlog scenario, 183 additional lives and 3362 life-years lost under the 50% backlog scenario, and 276 additional lives and 5075 life-years lost under the 75% backlog scenario. However, a delay in additional diagnostic capacity with provision spread across months 3–8 after lockdown would result in 401 additional lives and 7332 life-years lost due to diagnostic delays under the 25% backlog scenario, 811 additional lives and 14 873 life-years lost under the 50% backlog scenario, and 1231 additional lives and 22 635 life-years lost under the 75% backlog scenario. A 2-month delay in 2-week-wait investigatory referrals results in an estimated loss of between 0·0 and 0·7 life-years per referred patient, depending on age and tumour type.
Prompt provision of additional capacity to address the backlog of diagnostics will minimise deaths as a result of diagnostic delays that could add to those predicted due to expected presentational delays. Prioritisation of patient groups for whom delay would result in most life-years lost warrants consideration as an option for mitigating the aggregate burden of mortality in patients with cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent ...from the COVID-19 pandemic.
We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval.
Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%.
Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required.
The symbiotic partnership of plants and fungi was a critical means of nutrient uptake during colonization of the terrestrial surface. The Lower Devonian Rhynie Chert shows evidence for extensive ...phosphorus mobilization in plant debris that was pervasively colonized by fungi. Sandy sediment entrapped with fungi‐rich phytodebris contains grains of the phosphate mineral monazite which exhibit alteration to highly porous and leached surfaces. Mixed manganese‐iron oxide precipitates contain up to 2% P2O5. The mobilization of Mn, Fe, and P are all features of mycorrhizal nutrient concentration. However, the ecosystem was also exposed to toxic elements from hot spring hydrothermal activity. The oxide precipitates include titanium and iron‐titanium oxide which sequestered potentially toxic tungsten and antimony. Abundant pyrite framboids in the Rhynie Chert indicate that plant decomposition included microbial sulfate reduction. This caused the removal of some of the arsenic from the groundwaters into the pyrite, which reduced toxicity while leaving enough for putative arsenic metabolism. These relationships show the mineral component of the ecosystem modified the geochemistry of ambient waters.
Plain Language Summary
The symbiotic partnership of plants and fungi was a critical means of nutrient uptake during colonization of the terrestrial surface. The Lower Devonian Rhynie Chert shows evidence for extensive phosphorus mobilization in plant debris that was pervasively colonized by fungi. Sandy sediment entrapped with fungi‐rich organic matter contains grains of the phosphate mineral monazite which exhibit alteration to highly porous and leached surfaces. The ecosystem was also exposed to toxic elements from hot springs. Precipitates of oxide minerals sequestered potentially toxic tungsten and antimony. Iron sulfide allowed the removal of excess arsenic from the groundwaters. These relationships show the mineral component of the ecosystem modified the geochemistry of ambient waters.
Key Points
The plant‐bearing Rhynie Chert contains authigenic mineral phases, including pyrite, and manganese‐iron and titanium oxides
Authigenic phases may be products of bacterial and fungal components and sequestered potentially toxic elements, including As, Sb, and W
Detrital monazite was leached to supply phosphate, which was required by fungi in symbiosis with plants
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/404, was tested in phase 1 trials in 114 children, including 37 1–2-month-old infants—a target age for RSV ...vaccines. The cpts-248/404vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children >6 months old. Serum and nasal antibody responses in 1–2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Genetic studies aimed at understanding the molecular basis of complex human phenotypes require the genotyping of many thousands of single-nucleotide polymorphisms (SNPs) across large numbers of ...individuals. Public efforts have so far identified over two million common human SNPs; however, the scoring of these SNPs is labor-intensive and requires a substantial amount of automation. Here we describe a simple but effective approach, termed whole-genome sampling analysis (WGSA), for genotyping thousands of SNPs simultaneously in a complex DNA sample without locus-specific primers or automation. Our method amplifies highly reproducible fractions of the genome across multiple DNA samples and calls genotypes at >99% accuracy. We rapidly genotyped 14,548 SNPs in three different human populations and identified a subset of them with significant allele frequency differences between groups. We also determined the ancestral allele for 8,386 SNPs by genotyping chimpanzee and gorilla DNA. WGSA is highly scaleable and enables the creation of ultrahigh density SNP maps for use in genetic studies.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lamina by lamina measurement of biomarkers at a sub-millimetre resolution within the Achanarras Limestone Member has helped to resolve the changing environmental conditions associated with a fish ...mass mortality horizon. An anomalous proportion of C30 sterane (24-n-propylcholestane) marks the beginning of the horizon and likely corresponds to an influx of marine water. This appears to have been short lived and was likely analogous to a modern day storm tide. The subsequent laminae record an increased incidence of water column stratification and hypoxic bottom waters in the form of an elevated gammacerane index. The mass mortality horizon studied was from an upper interval of the Achanarras Limestone Member with a fossil fish assemblage comprising mostly Dipterus, an early Dipnoan (lungfish). However, lower intervals of the Achanarras Limestone Member have greater assemblage diversity, including species associated with marine conditions such as Coccosteus, and evidence higher proportions of C30 sterane indicating better connection to the marine environment. Therefore, it appears that ingressing seawater in and of itself was not responsible for creating a stressed environment. Rather, disconnection of the lake from marine waters stranded fish in a lake, that when perturbed by storm tides, killed en masse by exposing fish to hypoxic conditions in a similar way to modern water bodies affected by storm tides generated during hurricanes.
•Sub-annual, high resolution biomarker data obtained for a mass mortality horizon (MMH)•Biomarker parameters suggest incursions of marine water varied over time.•For the studied MMH they had become infrequent.•Fish killed by hypoxic conditions subsequent to an incursion of marine water
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report the case of 65-year-old man who developed massive rectal bleeding associated with the use of a fecal collecting device: the Flexi-Seal® Fecal Management System. A colonoscopy showed an ...acute laceration of the anterior rectal wall mucosa, 6 cm from the anal verge, with active bleeding. The tear was most likely the result of an acute event, such as sudden movement of the device within the rectum or trauma sustained during insertion. Massive transfusion was required, and surgical endoscopic treatment was necessary to ensure hemostasis. This is, to our knowledge, the first such case to be reported.
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KISLJ, NUK, OILJ, PNG, SAZU, UL, UM, UPUK
Purpose Infections due to methicillin resistant Staphylococcus aureus are becoming increasingly prevalent in hospitals and in the community. We reviewed our institutional experience to determine ...whether methicillin resistant S. aureus is becoming a more common cause of bacteriuria and to determine if there are specific risk factors that may predict the development of methicillin resistant S. aureus bacteriuria. Materials and Methods We reviewed all urine cultures with a pure growth of a single organism obtained at our institution from 1997 and 2007. Patients with urine cultures positive for methicillin resistant S. aureus were compared to a cohort with cultures positive for methicillin sensitive S. aureus, and to a third cohort with cultures positive for Escherichia coli to determine patient characteristics and associated risk factors. Results We identified 7,100 and 9,985 positive urine cultures performed in 1997 and 2007, respectively. The most common urinary organism was E. coli. The number of patients with methicillin resistant S. aureus bacteriuria increased from 18 (0.3%) to 74 (0.8%) (p <0.001). On multivariate analysis older age (p = 0.004), catheter use (p = 0.004), hospital exposure (p <0.001) and patient comorbidity (p <0.001) were associated with methicillin resistant S. aureus bacteriuria compared with E. coli bacteriuria. Conclusions Methicillin resistant S. aureus remains rare as a cause of bacteriuria but its incidence has increased during the last decade. Risk factors for methicillin resistant S. aureus bacteriuria include increased age, patient comorbidity, hospital exposure and catheter use. For patients with these risk factors and new onset urinary symptoms, methicillin resistant S. aureus should be considered a possible cause of urinary tract infection.
•Putative stromatolites of the Mesoproterozoic Stoer Group show no evidence for biogenicity.•Some are laminated clastic sediment draped over an ancient land surface.•Clastic carbonate is calcite, ...probably derived from weathering of older rocks.•Other possible stromatolites result from soft-sediment deformation.•Crystalline calcite in these is a result of syn-depositional to burial diagenesis.
Putative stromatolites and associated carbonate minerals in 1.1 Ga Stoer Group lacustrine sedimentary rocks were analysed to deduce their likely origins. Potential stromatolite examples included finely laminated and sometimes wrinkled carbonate-siliciclastic rocks of the Clachtoll Formation at Clachtoll and Bay of Stoer, and laminated limestone domes of the Poll a’Mhuilt Member (Bay of Stoer Formation) from Enard Bay.
Petrography shows that the lamination and wrinkling of Clachtoll Formation specimens can most logically be explained by abiotic siliclastic sedimentary processes, namely rippling and soft-sediment deformation probably related to de-watering. Electron backscatter diffraction shows that the carbonate in these laminated Clachtoll Formation specimens was calcite, and petrography combined with clumped isotope palaeothermometry indicates it was likely to be part syn-depositional and part burial diagenetic in origin.
The laminated domes of the Poll a’Mhuilt Member are shown to comprise clasts of limestone interlayered with clay, quartz, Na-rich feldspars and micas. Cathodoluminescence revealed the limestone clasts to be composite and built of sub-grains that must have been derived from an earlier, potentially Palaeoproterozoic, carbonate unit. Support for this hypothesis comes from clumped isotope palaeotemperature measurements that indicate the limestone clasts were precipitated or recrystallized under higher temperature conditions than the burial diagenetic calcite found in the Clachtoll Formation. Raman spectra of an organic carbon particle within a laminated dome of the Poll a’Mhuilt Member at Enard Bay are consistent with the organic carbon having been re-worked from the ∼2 Ga Loch Maree Group, and we speculate that this might also be true of the calcite.
Microbial fossils are well known from elsewhere in the Stoer Group, but no conclusive examples were found within the thin-sections examined herein. No conclusive evidence was found to suggest that any of the examined putative stromatolites were biogenic, leading to the conclusion that they are best considered stromatolite-like sedimentary rocks (pseudostromatolites).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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