Measuring the seroprevalence of antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is central to understanding infection risk and fatality rates. We studied Coronavirus ...Disease 2019 (COVID-19)-antibody seroprevalence in a community sample drawn from Santa Clara County.
On 3 and 4 April 2020, we tested 3328 county residents for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to SARS-CoV-2 using a rapid lateral-flow assay (Premier Biotech). Participants were recruited using advertisements that were targeted to reach county residents that matched the county population by gender, race/ethnicity and zip code of residence. We estimate weights to match our sample to the county by zip, age, sex and race/ethnicity. We report the weighted and unweighted prevalence of antibodies to SARS-CoV-2. We adjust for test-performance characteristics by combining data from 18 independent test-kit assessments: 14 for specificity and 4 for sensitivity.
The raw prevalence of antibodies in our sample was 1.5% exact binomial 95% confidence interval (CI) 1.1-2.0%. Test-performance specificity in our data was 99.5% (95% CI 99.2-99.7%) and sensitivity was 82.8% (95% CI 76.0-88.4%). The unweighted prevalence adjusted for test-performance characteristics was 1.2% (95% CI 0.7-1.8%). After weighting for population demographics, the prevalence was 2.8% (95% CI 1.3-4.2%), using bootstrap to estimate confidence bounds. These prevalence point estimates imply that 53 000 95% CI 26 000 to 82 000 using weighted prevalence; 23 000 (95% CI 14 000-35 000) using unweighted prevalence people were infected in Santa Clara County by late March-many more than the ∼1200 confirmed cases at the time.
The estimated prevalence of SARS-CoV-2 antibodies in Santa Clara County implies that COVID-19 was likely more widespread than indicated by the number of cases in late March, 2020. At the time, low-burden contexts such as Santa Clara County were far from herd-immunity thresholds.
Epidermal growth factor receptor (EGFR) regulates multiple signaling cascades essential for cell proliferation, growth and differentiation. Using a genetic approach, we found that Drosophila FERM and ...PDZ domain-containing protein tyrosine phosphatase, dPtpmeg, negatively regulates border cell migration and inhibits the EGFR/Ras/mitogen-activated protein kinase signaling pathway during wing morphogenesis. We further identified EGFR pathway substrate 15 (Eps15) as a target of dPtpmeg and its human homolog PTPN3. Eps15 is a scaffolding adaptor protein known to be involved in EGFR endocytosis and trafficking. Interestingly, PTPN3-mediated tyrosine dephosphorylation of Eps15 promotes EGFR for lipid raft-mediated endocytosis and lysosomal degradation. PTPN3 and the Eps15 tyrosine phosphorylation-deficient mutant suppress non-small-cell lung cancer cell growth and migration in vitro and reduce lung tumor xenograft growth in vivo. Moreover, depletion of PTPN3 impairs the degradation of EGFR and enhances proliferation and tumorigenicity of lung cancer cells. Taken together, these results indicate that PTPN3 may act as a tumor suppressor in lung cancer through its modulation of EGFR signaling.
Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or ...neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.
Endocytosis mediates the cellular uptake of micronutrients and the turnover of plasma membrane proteins. Clathrin-mediated endocytosis is the major uptake pathway in resting cells
, but several ...clathrin-independent endocytic routes exist in parallel
. One such pathway, fast endophilin-mediated endocytosis (FEME), is not constitutive but triggered upon activation of certain receptors, including the β
adrenergic receptor
. FEME activates promptly following stimulation as endophilin is pre-enriched by the phosphatidylinositol-3,4-bisphosphate-binding protein lamellipodin
. However, in the absence of stimulation, endophilin foci abort and disassemble after a few seconds. Looking for additional proteins involved in FEME, we found that 20 out of 65 BAR domain-containing proteins tested colocalized with endophilin spots. Among them, FBP17 and CIP4 prime the membrane of resting cells for FEME by recruiting the 5'-lipid phosphatase SHIP2 and lamellipodin to mediate the local production of phosphatidylinositol-3,4-bisphosphate and endophilin pre-enrichment. Membrane-bound GTP-loaded Cdc42 recruits FBP17 and CIP4, before being locally deactivated by RICH1 and SH3BP1 GTPase-activating proteins. This generates the transient assembly and disassembly of endophilin spots, which lasts 5-10 seconds. This mechanism periodically primes patches of the membrane for prompt responses upon FEME activation.
In 1995, the Global Initiative for Asthma (GINA) guidelines recommended goals for the management of asthma, which were updated in 2002. However, there are no recent international surveys on the real ...management of asthma.
The Asthma Insights and Reality surveys are the first large-scale surveys aimed at determining international variations in the severity, control, and management of asthma in children and adults.
A cross-section of households in 29 countries in North America, Europe, and Asia were surveyed to identify from the general population asthmatic patients with symptoms within the last year or who were taking current asthma medication. A standard questionnaire was administered to 7786 adults, and, through a proxy, to 3153 children with asthma. Objective and subjective patient perception of asthma control and severity were assessed, including access to medical care, health care use, missed work-school, and medication use.
Despite variations at a country level, a substantial effect of asthma on patients' lives was observed, with considerable loss of schooldays and workdays. The current level of asthma control worldwide falls far short of the goals for long-term management in international guidelines. A significant proportion of patients continue to have symptoms and lifestyle restrictions and to require emergency care. The proportion of adult asthmatic patients who were current smokers was also high. However, the use of anti-inflammatory preventative medication, even in patients with severe persistent asthma, was low, ranging from 26% in Western Europe to 9% in Japan, as was the use of objective lung function testing. The correlation between self-perceived severity of asthma and objective assessment of severity on the basis of GINA criteria was consistently poor in all areas.
We conclude that there is direct evidence for suboptimal asthma control in many patients worldwide, despite the availability of effective therapies, with long-term management falling far short of the goals set in the GINA guidelines.
Background (aims, hypotheses, or objectives)
Emergency laparotomy (EL) is a high-risk surgical procedure associated with considerable morbidity and mortality around the world. A reliable ...risk-assessment tool that is specific to patients undergoing EL allows the early identification of high-risk patients and enables appropriate healthcare resource allocation. The objective of this study was to compare the commonly used Portsmouth-physiologic and operative severity score for the enumeration of mortality and morbidity (P-POSSUM) with the recently developed National Emergency Laparotomy Audit (NELA) score in terms of their accuracy for identifying patients at increased risk of 30-day mortality in a predominantly Asian population.
Methods
Physiological and operative data from a prospectively collected audit of adult patients undergoing EL in 2018 and 2019 across two tertiary hospitals in Singapore were used to retrospectively calculate both the P-POSSUM and NELA scores for each patient encounter. This was then compared to actual mortality rates to determine each model’s accuracy and precision.
Results
830 patients were included in the study with a 30-day mortality of 5.66%. The area under the receiver operating characteristics curve (AUROC) was similar for both the NELA (0.86,
p
< 0.001, 95% CI 0.81–0.91) and the P-POSSUM models (0.84,
p
< 0.001, 95% CI 0.78–0.89). While the models over-predicted mortality, overall O:E ratios showed that the NELA model performance was superior to that of P-POSSUM (0.58 95% CI 0.43–0.77 compared to 0.34 95% CI 0.26–0.46).
Conclusion
The NELA risk-prediction model accurately predicts 30-day mortality in this large cohort of patients undergoing EL and outperforms the current P-POSSUM model. We recommend that the NELA score should replace the P-POSSUM score as a model to distinguish between high- and low-risk patients undergoing EL.
Electron heating at Earth's quasiperpendicular bow shock has been surmised to be due to the combined effects of a quasistatic electric potential and scattering through wave-particle interaction. Here ...we report the observation of electron distribution functions indicating a new electron heating process occurring at the leading edge of the shock front. Incident solar wind electrons are accelerated parallel to the magnetic field toward downstream, reaching an electron-ion relative drift speed exceeding the electron thermal speed. The bulk acceleration is associated with an electric field pulse embedded in a whistler-mode wave. The high electron-ion relative drift is relaxed primarily through a nonlinear current-driven instability. The relaxed distributions contain a beam traveling toward the shock as a remnant of the accelerated electrons. Similar distribution functions prevail throughout the shock transition layer, suggesting that the observedacceleration and thermalization is essential to the cross-shock electron heating.
NMR analysis of (13)C-labelling patterns showed that the Embden-Meyerhof (EM) pathway is the main route for glycolysis in the extreme thermophile Caldicellulosiruptor saccharolyticus. Glucose ...fermentation via the EM pathway to acetate results in a theoretical yield of 4 mol of hydrogen and 2 mol of acetate per mole of glucose. Previously, approximately 70% of the theoretical maximum hydrogen yield has been reached in batch fermentations. In this study, hydrogen and acetate yields have been determined at different dilution rates during continuous cultivation. The yields were dependent on the growth rate. The highest hydrogen yields of 82 to 90% of theoretical maximum (3.3 to 3.6 mol H(2) per mol glucose) were obtained at low growth rates when a relatively larger part of the consumed glucose is used for maintenance. The hydrogen productivity showed the opposite effect. Both the specific and the volumetric hydrogen production rates were highest at the higher growth rates, reaching values of respectively 30 mmol g(-1) h(-1) and 20 mmol l(-1) h(-1). An industrial process for biohydrogen production will require a bioreactor design, which enables an optimal mix of high productivity and high yield.
The liver is positioned at the interface between two routes traversed by pathogens in disseminating infection. Whereas blood-borne pathogens are efficiently cleared in hepatic sinusoids by Kupffer ...cells (KCs), it is unknown how the liver prevents dissemination of peritoneal pathogens accessing its outer membrane. We report here that the hepatic capsule harbors a contiguous cellular network of liver-resident macrophages phenotypically distinct from KCs. These liver capsular macrophages (LCMs) were replenished in the steady state from blood monocytes, unlike KCs that are embryonically derived and self-renewing. LCM numbers increased after weaning in a microbiota-dependent process. LCMs sensed peritoneal bacteria and promoted neutrophil recruitment to the capsule, and their specific ablation resulted in decreased neutrophil recruitment and increased intrahepatic bacterial burden. Thus, the liver contains two separate and non-overlapping niches occupied by distinct resident macrophage populations mediating immunosurveillance at these two pathogen entry points to the liver.
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•A distinct subset of resident macrophages (LCMs) occupies the hepatic capsule•LCMs are replenished from blood monocytes in the steady state•LCMs recruit neutrophils in response to bacteria reaching the liver capsule•LCM depletion decreases neutrophil recruitment and increases liver pathogen load
The hepatic sinusoids harbor a well-characterized resident macrophage population, Kupffer cells. Sierro et al. report an additional liver-resident macrophage population occupying the hepatic capsule, phenotypically and developmentally distinct from Kupffer cells, which plays a role in immunosurveillance by sensing peritoneal pathogens and recruiting neutrophils to control intrahepatic bacterial dissemination.
With a combination of adaptive optics imaging and a multi-epoch common proper motion search, we have conducted a large volume-limited (D ≤ 75 pc) multiplicity survey of A-type stars, sensitive to ...companions beyond 30 au. The sample for the Volume-limited A-STar (VAST) survey consists of 435 A-type stars: 363 stars were observed with adaptive optics, 228 stars were searched for wide common proper motion companions and 156 stars were measured with both techniques. The projected separation coverage of the VAST survey extends from 30 to 45 000 au. A total of 137 stellar companions were resolved, including 64 new detections from the VAST survey, and the companion star fraction, projected separation distribution and mass ratio distribution were measured. The separation distribution forms a log-normal distribution similar to the solar-type binary distribution, but with a peak shifted to a significantly wider value of
au. Integrating the fit to the distribution over the 30 to 10 000 au observed range, the companion star fraction for A-type stars is estimated as 33.8 ± 2.6 per cent. The mass ratio distribution of closer (<125 au) binaries is distinct from that of wider systems, with a flat distribution for close systems and a distribution that tends towards smaller mass ratios for wider binaries. Combining this result with previous spectroscopic surveys of A-type stars gives an estimate of the total companion star fraction of 68.9 ± 7.0 per cent. The most complete assessment of higher order multiples was estimated from the 156 star subset of the VAST sample with both adaptive optics and common proper motion measurements, combined with a thorough literature search for companions, yielding a lower limit on the frequency of single, binary, triple, quadruple and quintuple A-type star systems of
,
,
,
and
per cent, respectively.
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