Rapid Epidemiological Analysis of Comorbidities and Treatments as risk factors for COVID-19 in Scotland (REACT-SCOT): a population-based case-control study

Background The objectives of this study were to identify risk factors for severe coronavirus disease 2019 (COVID-19) and to lay the basis for risk stratification based on demographic data and health records. Methods and findings The design was a matched case-control study. Severe COVID-19 was defined as either a positive nucleic acid test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the national database followed by entry to a critical care unit or death within 28 days or a death certificate with COVID-19 as underlying cause. Up to 10 controls per case matched for sex, age, and primary care practice were selected from the national population register. For this analysis—based on ascertainment of positive test results up to 6 June 2020, entry to critical care up to 14 June 2020, and deaths registered up to 14 June 2020—there were 36,948 controls and 4,272 cases, of which 1,894 (44%) were care home residents. All diagnostic codes from the past 5 years of hospitalisation records and all drug codes from prescriptions dispensed during the past 240 days were extracted. Rate ratios for severe COVID-19 were estimated by conditional logistic regression. In a logistic regression using the age-sex distribution of the national population, the odds ratios for severe disease were 2.87 for a 10-year increase in age and 1.63 for male sex. In the case-control analysis, the strongest risk factor was residence in a care home, with rate ratio 21.4 (95% CI 19.1–23.9, p = 8 × 10−644). Univariate rate ratios for conditions listed by public health agencies as conferring high risk were 2.75 (95% CI 1.96–3.88, p = 6 × 10−9) for type 1 diabetes, 1.60 (95% CI 1.48–1.74, p = 8 × 10−30) for type 2 diabetes, 1.49 (95% CI 1.37–1.61, p = 3 × 10−21) for ischemic heart disease, 2.23 (95% CI 2.08–2.39, p = 4 × 10−109) for other heart disease, 1.96 (95% CI 1.83–2.10, p = 2 × 10−78) for chronic lower respiratory tract disease, 4.06 (95% CI 3.15–5.23, p = 3 × 10−27) for chronic kidney disease, 5.4 (95% CI 4.9–5.8, p = 1 × 10−354) for neurological disease, 3.61 (95% CI 2.60–5.00, p = 2 × 10−14) for chronic liver disease, and 2.66 (95% CI 1.86–3.79, p = 7 × 10−8) for immune deficiency or suppression. Seventy-eight percent of cases and 52% of controls had at least one listed condition (51% of cases and 11% of controls under age 40). Severe disease was associated with encashment of at least one prescription in the past 9 months and with at least one hospital admission in the past 5 years (rate ratios 3.10 [95% CI 2.59–3.71] and 2.75 [95% CI 2.53–2.99], respectively) even after adjusting for the listed conditions. In those without listed conditions, significant associations with severe disease were seen across many hospital diagnoses and drug categories. Age and sex provided 2.58 bits of information for discrimination. A model based on demographic variables, listed conditions, hospital diagnoses, and prescriptions provided an additional 1.07 bits (C-statistic 0.804). A limitation of this study is that records from primary care were not available. Conclusions We have shown that, along with older age and male sex, severe COVID-19 is strongly associated with past medical history across all age groups. Many comorbidities beyond the risk conditions designated by public health agencies contribute to this. A risk classifier that uses all the information available in health records, rather than only a limited set of conditions, will more accurately discriminate between low-risk and high-risk individuals who may require shielding until the epidemic is over

Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study

Background: The objective of this study was to investigate the relation of severe COVID-19 to prior drug prescribing. Methods: Severe cases were defined by entry to critical care or fatal outcome. For this matched case-control study (REACT-SCOT), all 4251 cases of severe COVID-19 in Scotland since the start of the epidemic were matched for age, sex and primary care practice to 36,738 controls from the population register. Records were linked to hospital discharges since June 2015 and dispensed prescriptions issued in primary care during the last 240 days. Results: Severe COVID-19 was strongly associated with the number of non-cardiovascular drug classes dispensed. This association was strongest in those not resident in a care home, in whom the rate ratio (95% CI) associated with dispensing of 12 or more drug classes versus none was 10.8 (8.8, 13.3), and in those without any of the conditions designated as conferring increased risk of COVID-19. Of 17 drug classes postulated at the start of the epidemic to be “ "medications compromising COVID", all were associated with increased risk of severe COVID-19 and these associations were present in those without any of the designated risk conditions. The fraction of cases in the population attributable to exposure to these drug classes was 38%. The largest effect was for antipsychotic agents: rate ratio 4.18 (3.42, 5.11). Other drug classes with large effects included proton pump inhibitors (rate ratio 2.20 (1.72, 2.83) for = 2 defined daily doses/day), opioids (3.66 (2.68, 5.01) for = 50 mg morphine equivalent/day) and gabapentinoids. These associations persisted after adjusting for covariates and were stronger with recent than with non-recent exposure. Conclusions: Severe COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression, or dyskinesia; have anticholinergic effects; or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. Measures to reduce the burden of mortality and morbidity from COVID-19 should include reinforcing existing guidance on reducing overprescribing of these drug classes and limiting inappropriate polypharmacy. Registration: ENCEPP number EUPAS3555

Reduction of astrogliosis and microgliosis by cerebrospinal fluid shunting in experimental hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Reactive gliosis has the potential to alter biomechanical properties of the brain, impede neuronal regeneration and affect plasticity. Determining the onset and progression of reactive astrogliosis and microgliosis due to hydrocephalus is important for designing better clinical treatments.</p> <p>Methods</p> <p>Reactive astrogliosis and microgliosis were evaluated as the severity of hydrocephalus increased with age in hydrocephalic H-Tx rats and control littermates. Previous studies have suggested that gliosis may persist after short-term drainage (shunt treatment) of the cerebrospinal fluid. Therefore shunts were placed in 15d hydrocephalic rats that were sacrificed after 6d (21d of age) or after 21d (36d of age). Tissue was processed for Western blot procedures and immunohistochemistry, and probed for the astrocytic protein, Glial Fibrillary Acidic Protein (GFAP) and for microglial protein, Isolectin B4 (ILB4).</p> <p>Results</p> <p>In the parietal cortex of untreated hydrocephalic animals, GFAP levels increased significantly at 5d and at 12d compared to age-matched control rats. There was a continued increase in GFAP levels over control at 21d and at 36d. Shunting prevented some of the increase in GFAP levels in the parietal cortex. In the occipital cortex of untreated hydrocephalic animals, there was a significant increase over control in levels of GFAP at 5d. This trend continued in the 12d animals, although not significantly. Significant increases in GFAP levels were present in 21d and in 36d animals. Shunting significantly reduced GFAP levels in the 36d shunted group. Quantitative grading of immuno-stained sections showed similar changes in GFAP stained astrocytes.</p> <p>Immuno-stained microglia were altered in shape in hydrocephalic animals. At 5d and 12d, they appeared to be developmentally delayed with a lack of processes. Older 21d and 36d hydrocephalic animals exhibited the characteristics of activated microglia, with thicker processes and enlarged cell bodies. Following shunting, fewer activated microglia were present.</p> <p>Histologic examination of the periventricular area and the periaqueductal area showed similar findings with the 21d and 36d animals having increased populations of both astrocytes and microglia which were reduced following shunting with a more dramatic reduction in the long term shunted animals.</p> <p>Conclusion</p> <p>Overall, these results suggest that reactive astrocytosis and microgliosis are associated with progressive untreated ventriculomegaly, but that shunt treatment can reduce the gliosis occurring with hydrocephalus.</p

A statistical comparison of solar wind sources of moderate and intense geomagnetic storms at solar minimum and maximum

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95223/1/jgra17913.pd

Snapshot of the Eukaryotic Gene Expression in Muskoxen Rumen—A Metatranscriptomic Approach

BACKGROUND: Herbivores rely on digestive tract lignocellulolytic microorganisms, including bacteria, fungi and protozoa, to derive energy and carbon from plant cell wall polysaccharides. Culture independent metagenomic studies have been used to reveal the genetic content of the bacterial species within gut microbiomes. However, the nature of the genes encoded by eukaryotic protozoa and fungi within these environments has not been explored using metagenomic or metatranscriptomic approaches. METHODOLOGY/PRINCIPAL FINDINGS: In this study, a metatranscriptomic approach was used to investigate the functional diversity of the eukaryotic microorganisms within the rumen of muskoxen (Ovibos moschatus), with a focus on plant cell wall degrading enzymes. Polyadenylated RNA (mRNA) was sequenced on the Illumina Genome Analyzer II system and 2.8 gigabases of sequences were obtained and 59129 contigs assembled. Plant cell wall degrading enzyme modules including glycoside hydrolases, carbohydrate esterases and polysaccharide lyases were identified from over 2500 contigs. These included a number of glycoside hydrolase family 6 (GH6), GH48 and swollenin modules, which have rarely been described in previous gut metagenomic studies. CONCLUSIONS/SIGNIFICANCE: The muskoxen rumen metatranscriptome demonstrates a much higher percentage of cellulase enzyme discovery and an 8.7x higher rate of total carbohydrate active enzyme discovery per gigabase of sequence than previous rumen metagenomes. This study provides a snapshot of eukaryotic gene expression in the muskoxen rumen, and identifies a number of candidate genes coding for potentially valuable lignocellulolytic enzymes

Minocycline inhibits glial proliferation in the H-Tx rat model of congenital hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Reactive astrocytosis and microgliosis are important features of the pathophysiology of hydrocephalus, and persistent glial "scars" that form could exacerbate neuroinflammation, impair cerebral perfusion, impede neuronal regeneration, and alter biomechanical properties. The purpose of this study was to determine the efficacy of minocycline, an antibiotic known for its anti-inflammatory properties, to reduce gliosis in the H-Tx rat model of congenital hydrocephalus.</p> <p>Methods</p> <p>Minocycline (45 mg/kg/day i.p. in 5% sucrose at a concentration of 5-10 mg/ml) was administered to hydrocephalic H-Tx rats from postnatal day 15 to day 21, when ventriculomegaly had reached moderate to severe stages. Treated animals were compared to age-matched non-hydrocephalic and untreated hydrocephalic littermates. The cerebral cortex (both gray matter laminae and white matter) was processed for immunohistochemistry (glial fibrillary acidic protein, GFAP, for astrocytes and ionized calcium binding adaptor molecule, Iba-1, for microglia) and analyzed by qualitative and quantitative light microscopy.</p> <p>Results</p> <p>The mean number of GFAP-immunoreactive astrocytes was significantly higher in untreated hydrocephalic animals compared to both types of controls (<it>p </it>< 0.001). Minocycline treatment of hydrocephalic animals reduced the number of GFAP immunoreactive cells significantly (<it>p </it>< 0.001). Likewise, the mean number of Iba-1 immunoreactive microglia was significantly higher in untreated hydrocephalic animals compared to both types of controls (<it>p </it>< 0.001). Furthermore, no differences in the numbers of GFAP-positive astrocytes or Iba-1-positive microglia were noted between control animals receiving no minocycline and control animals receiving minocycline, suggesting that minocycline does not produce an effect under non-injury conditions. Additionally, in six out of nine regions sampled, hydrocephalic animals that received minocycline injections had significantly thicker cortices when compared to their untreated hydrocephalic littermates.</p> <p>Conclusions</p> <p>Overall, these data suggest that minocycline treatment is effective in reducing the gliosis that accompanies hydrocephalus, and thus may provide an added benefit when used as a supplement to ventricular shunting.</p

Molecular surveillance of norovirus, 2005-16: an epidemiological analysis of data collected from the NoroNet network.

BACKGROUND: The development of a vaccine for norovirus requires a detailed understanding of global genetic diversity of noroviruses. We analysed their epidemiology and diversity using surveillance data from the NoroNet network. METHODS: We included genetic sequences of norovirus specimens obtained from outbreak investigations and sporadic gastroenteritis cases between 2005 and 2016 in Europe, Asia, Oceania, and Africa. We genotyped norovirus sequences and analysed sequences that overlapped at open reading frame (ORF) 1 and ORF2. Additionally, we assessed the sampling date and country of origin of the first reported sequence to assess when and where novel drift variants originated. FINDINGS: We analysed 16 635 norovirus sequences submitted between Jan 1, 2005, to Nov 17, 2016, of which 1372 (8·2%) sequences belonged to genotype GI, 15 256 (91·7%) to GII, and seven (<0·1%) to GIV.1. During this period, 26 different norovirus capsid genotypes circulated and 22 different recombinant genomes were found. GII.4 drift variants emerged with 2-3-year periodicity up to 2012, but not afterwards. Instead, the GII.4 Sydney capsid seems to persist through recombination, with a novel recombinant of GII.P16-GII.4 Sydney 2012 variant detected in 2014 in Germany (n=1) and the Netherlands (n=1), and again in 2016 in Japan (n=2), China (n=8), and the Netherlands (n=3). The novel GII.P17-GII.17, first reported in Asia in 2014, has circulated widely in Europe in 2015-16 (GII.P17 made up a highly variable proportion of all sequences in each country [median 11·3%, range 4·2-53·9], as did GII.17 [median 6·3%, range 0-44·5]). GII.4 viruses were more common in outbreaks in health-care settings (2239 [37·2%] of 6022 entries) compared with other genotypes (101 [12·5%] of 809 entries for GI and 263 [13·5%] of 1941 entries for GII non-GII.Pe-GII.4 or GII.P4-GII.4). INTERPRETATION: Continuous changes in the global norovirus genetic diversity highlight the need for sustained global norovirus surveillance, including assessment of possible immune escape and evolution by recombination, to provide a full overview of norovirus epidemiology for future vaccine policy decisions. FUNDING: European Union's Horizon 2020 grant COMPARE, ZonMw TOP grant, the Virgo Consortium funded by the Dutch Government, and the Hungarian Scientific Research Fund

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits