Predictions of COVID-19 dynamics in the UK: Short-term forecasting and analysis of potential exit strategies

Efforts to suppress transmission of SARS-CoV-2 in the UK have seen non-pharmaceutical interventions being invoked. The most severe measures to date include all restaurants, pubs and cafes being ordered to close on 20th March, followed by a “stay at home” order on the 23rd March and the closure of all non-essential retail outlets for an indefinite period. Government agencies are presently analysing how best to develop an exit strategy from these measures and to determine how the epidemic may progress once measures are lifted. Mathematical models are currently providing short and long term forecasts regarding the future course of the COVID-19 outbreak in the UK to support evidence-based policymaking. We present a deterministic, age-structured transmission model that uses real-time data on confirmed cases requiring hospital care and mortality to provide up-to-date predictions on epidemic spread in ten regions of the UK. The model captures a range of age-dependent heterogeneities, reduced transmission from asymptomatic infections and produces a good fit to the key epidemic features over time. We simulated a suite of scenarios to assess the impact of differing approaches to relaxing social distancing measures from 7th May 2020 on the estimated number of patients requiring inpatient and critical care treatment, and deaths. With regard to future epidemic outcomes, we investigated the impact of reducing compliance, ongoing shielding of elder age groups, reapplying stringent social distancing measures using region based triggers and the role of asymptomatic transmission. We find that significant relaxation of social distancing measures from 7th May onwards can lead to a rapid resurgence of COVID-19 disease and the health system being quickly overwhelmed by a sizeable, second epidemic wave. In all considered age-shielding based strategies, we projected serious demand on critical care resources during the course of the pandemic. The reintroduction and release of strict measures on a regional basis, based on ICU bed occupancy, results in a long epidemic tail, until the second half of 2021, but ensures that the health service is protected by reintroducing social distancing measures for all individuals in a region when required. Our work confirms the effectiveness of stringent non-pharmaceutical measures in March 2020 to suppress the epidemic. It also provides strong evidence to support the need for a cautious, measured approach to relaxation of lockdown measures, to protect the most vulnerable members of society and support the health service through subduing demand on hospital beds, in particular bed occupancy in intensive care units.     

Detection of toxoplasmic encephalitis in HIV positive patients in urine with hydrogel nanoparticles

BackgroundDiagnosis of toxoplasmic encephalitis (TE) is challenging under the best clinical circumstances. The poor clinical sensitivity of quantitative polymerase chain reaction (qPCR) for Toxoplasma in blood and CSF and the limited availability of molecular diagnostics and imaging technology leaves clinicians in resource-limited settings with few options other than empiric treatment.Methology/principle findingsHere we describe proof of concept for a novel urine diagnostics for TE using Poly-N-Isopropylacrylamide nanoparticles dyed with Reactive Blue-221 to concentrate antigens, substantially increasing the limit of detection. After nanoparticle-concentration, a standard western blotting technique with a monoclonal antibody was used for antigen detection. Limit of detection was 7.8pg/ml and 31.3pg/ml of T. gondii antigens GRA1 and SAG1, respectively. To characterize this diagnostic approach, 164 hospitalized HIV-infected patients with neurological symptoms compatible with TE were tested for 1) T. gondii serology (121/147, positive samples/total samples tested), 2) qPCR in cerebrospinal fluid (11/41), 3) qPCR in blood (10/112), and 4) urinary GRA1 (30/164) and SAG1 (12/164). GRA1 appears to be superior to SAG1 for detection of TE antigens in urine. Fifty-one HIV-infected, T. gondii seropositive but asymptomatic persons all tested negative by nanoparticle western blot and blood qPCR, suggesting the test has good specificity for TE for both GRA1 and SAG1. In a subgroup of 44 patients, urine samples were assayed with mass spectrometry parallel-reaction-monitoring (PRM) for the presence of T. gondii antigens. PRM identified antigens in 8 samples, 6 of which were concordant with the urine diagnostic.Conclusion/significancesOur results demonstrate nanoparticle technology’s potential for a noninvasive diagnostic test for TE. Moving forward, GRA1 is a promising target for antigen based diagnostics for TE.     

ATP-dependent substrate occlusion by the human erythrocyte sugar transporter

Human erythrocyte sugar transport presents a functional complexity that is not explained by existing models for carrier-mediated transport. It has been suggested that net sugar uptake is the sum of three serial processes: sugar translocation, sugar interaction with an intracellular binding complex, and the release from this complex into bulk cytosol. The present study was carried out to identify the erythrocyte sugar binding complex, to determine whether sugar binding occurs inside or outside the cell, and to determine whether this binding complex is affected by cytosolic ATP or transporter quaternary structure. Sugar binding assays using cells and membrane protein fractions indicate that sugar binding to erythrocytes is quantitatively accounted for by sugar binding to the hexose transport protein, GluT1. Kinetic analysis of net sugar fluxes indicates that GluT1 sugar binding sites are cytoplasmic. Intracellular ATP increases GluT1 sugar binding capacity from 1 to 2 mol of 3-O-methylglucose/mol GluT1 and inhibits the release of bound sugar into cytosol. Reductant-mediated, tetrameric GluT1 dissociation into dimeric GluT1 is associated with the loss of ATP and 3-O-methylglucose binding. We propose that sugar uptake involves GluT1-mediated, extracellular sugar translocation into an ATP-dependent cage formed by GluT1 cytoplasmic domains. Caged or occluded sugar has three possible fates: (1) transport out of the cell (substrate cycling); (2) interaction with sugar binding sites within the cage, or (3) release into bulk cytosol. We show how this hypothesis can account for the complexity of erythrocyte sugar transport and its regulation by cytoplasmic ATP.     

Virus-specific T-cell immunity correlates with control of GB virus B infection in marmosets

GB virus B (GBV-B) is a hepatotropic virus that is closely related to hepatitis C virus (HCV). GBV-B causes acute hepatitis in infected marmosets and tamarins and is therefore a useful small-animal model for the study of HCV. We investigated virus-specific T-cell responses in marmosets infected with GBV-B. Gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay responses in the peripheral blood of two marmosets were assessed throughout the course of GBV-B infection. These T-cell responses were directed against the GBV-B nonstructural proteins 3 (NS3), 4A (NS4A), and 5B (NS5B), and their appearance was temporally associated with clearance of viremia. These marmosets were then rechallenged with GBV-B at least 3 months after clearance of the primary infection to determine if the animals were protected from reinfection. There was no detectable viremia following reinfection, although a sharp increase in T-cell responses against GBV-B proteins was observed. Epitope mapping of T-cell responses to GBV-B was performed with liver and blood samples from both marmosets after rechallenge with GBV-B. Three shared, immunodominant T-cell epitopes within NS3 were identified in animals with multiple common major histocompatibility complex class I alleles. IFN-gamma ELISPOT responses were also detected in the livers of two marmosets that had resolved a primary GBV-B infection. These responses were high in frequency and were directed against epitopes within GBV-B NS3, NS4A, and NS5B proteins. These results indicate that virus-specific T-cell responses are detectable in the liver and blood of GBV-B-infected marmosets and that the clearance of GBV-B is associated with the appearance of these responses.     

Sex differences in circulating and renal angiotensins of hypertensive mRen(2). Lewis but not normotensive Lewis rats

Sex differences in blood pressure are evident in experimental models and human subjects, yet the mechanisms underlying this disparity remain equivocal. The current study sought to define the extent of male-female differences in the circulating and tissue renin-angiotensin aldosterone systems (RAASs) of congenic mRen(2). Lewis and control Lewis rats. Male congenics exhibited higher systolic blood pressure than females [200 +/- 4 vs. 146 +/- 7 mmHg, P < 0.01] or Lewis males and females [113 +/- 2 vs. 112 +/- 2 mmHg, P > 0.05]. Plasma ANG II levels were twofold higher in male congenics [47 +/- 3 vs. 19 +/- 3 pM, P < 0.01] and fivefold higher than in male or female Lewis rats [6 +/- 1 vs. 6 +/- 1 pM]. ANG I levels were also highest in the males; however, plasma ANG-(1-7) was higher in female congenics. Male congenics exhibited greater circulating renin and angiotensin-converting enzyme (ACE) activities, as well as angiotensinogen, than female littermates. Renal cortical and medullary ANG II levels were also higher in the male congenics versus all the other groups; ANG I was lower in the males. Cortical ACE2 activity was higher in male congenics, yet neprilysin activity and protein were greater in the females, which may contribute to reduced renal levels of ANG II. These data reveal that sex differences in both the circulating and renal RAAS are apparent primarily in the hypertensive group. The enhanced activity of the RAAS in male congenics may contribute to the higher pressure and tissue injury evident in the strain.     

What constitutes fair shared decision-making in global health research collaborations?

Funders (located primarily in high-income countries) and high-income country researchers have historically dominated decision-making within global health research collaborations: from setting agendas and research design to determining how data are collected and analysed and what happens with findings and outputs. The ethical principle of shared decision-making has been proposed as a way to help address these imbalances within collaborations and to reduce semicolonial and exploitative forms of global health research. It is important to be clear about what shared decision-making means in order to ensure that it is not done in a tokenistic, shallow way. Thus far, the principle’s content has not been examined and articulated in detail. This paper aims to start the process of delineating a concept of fair shared decision-making as a minimum standard for global health research. Using two hypothetical case examples, the paper will demonstrate that global health research practice is often inconsistent with ideal shared decision-making. In such instances, it can be difficult to decide whether shared decision-making within collaborations is fair. The paper describes how the two cases do not meet criteria for unfair or non-ideal shared decision-making, despite having potentially morally troubling features. The nuances of these examples of research practice help to generate clearer ideas about how to judge fairness in shared decision-making. The paper concludes by presenting ideas about when soft power can be fairly employed between high-income-country and low- and middle-income-country partners and what fair compromise agreements may look like in shared decision-making.     

Comparison of the mating systems and breeding behavior of a resident and a migratory tropical flycatcher

ABSTRACT.   Little is known about the genetic mating systems of tropical passerines and how they vary among species. We studied the Lesser Elaenia ( Elaenia chiriquensis ) and the Yellow-bellied Elaenia ( E. flavogaster ) near Gamboa, Panama. These species breed in the same habitat, but Lesser Elaenias are intratropical migrants with seasonal territories and Yellow-bellied Elaenias are permanent residents that remain paired and defend territories throughout the year. Lesser Elaenias exhibited greater breeding synchrony (15–18 %) than Yellow-bellied Elaenias (9–10%). For Lesser Elaenias, 10 of 15 (67%) nests contained extra-pair young and 14 of 38 (37%) young resulted from extra-pair fertilizations (EPFs). In contrast, only one extra-pair nestling (4%, N = 24 nestlings) was found in 13 Yellow-bellied Elaenia nests. Neither species exhibited strong mate guarding. The higher rate of EPFs in Lesser Elaenias is consistent with the hypothesis that year-round territorial tropical passerines with low breeding synchrony have little or no extra-pair behavior compared with species that breed seasonally. Although the low singing rates of Lesser Elaenias (7 songs/h) suggest that this not an important cue for female extra-pair mate choice, the role of conspicuous male dawn song remains to be investigated. Further studies of tropical passerines are needed to help disentangle the effects of synchrony, density, and other ecological and behavioral factors that have influenced the evolution of extra-pair mating systems in passerines.     

Equol producer status, salivary estradiol profile and urinary excretion of isoflavones in Irish Caucasian women, following ingestion of soymilk

Equol production, isoflavone excretion, and the salivary estradiol profile among 36 females, native Irish Caucasian volunteers following ingestion of 200mL soymilk is reported. The soymilk contained daidzein (73+/-6.7mg) and genistein (86+/-10.2mg). Volunteers provided personal and family medical history. Dietary analysis revealed that all volunteers regularly consumed soy-based or soy-supplemented food products. The mean age, mean age at menarche, and body mass index of volunteers were 46.6+/-12.3 years, 13.1 years and 26.1, respectively. The average number of children per volunteer was 2.13. Twelve (34%) of the volunteers were found to be first-degree relatives of breast cancer patients. Following consumption of the soymilk, equol was detected in the urine of 18 (51%) of the volunteers. Mean urinary daidzein and genistein concentrations during the hours following soymilk ingestion were 13.5 and 16.7microg/mg creatinine, respectively, however, some volunteers excreted little (less than 4.0microg/mg) or no isoflavone. Salivary estradiol in most (24) volunteers had decreased from 51.5+/-28.67pmol/L pre-ingestion to 29.75+/-16.13pmol/L 5h after drinking the soymilk. However, the salivary estradiol in 12 subjects (34%) increased from 33.76+/-13.4pmol/L to 137.4+/-65.64pmol/L over the same period. Individuals whose salivary estradiol increased had significantly less children (1.58 (P<0.05)), were more likely to (a) return urine samples with low isoflavone content (50.3% compared to 25%), (b) to be equol producers (67% compared to 41.7%), and (c) to be first-degree relatives of breast cancer patients (41.7% compared to 25%). Volunteers who reported a first-degree link to breast cancer were more likely to have a higher body mass index (29.0 compared to 26.1 (P<0.05)), to be equol producers (75% compared to 51%), and to excrete isoflavones in low quantities only (60% compared to 50%). First-degree relatives also had fewer children (1.75 (P<0.05)). The results indicate a significant, distinctive variation in equol production, isoflavone excretion and salivary estradiol profile among individual volunteers following ingestion of soymilk.     

Role of the GALT in scrapie agent neuroinvasion from the intestine

Following oral exposure, some transmissible spongiform encephalopathy (TSE) agents accumulate first upon follicular dendritic cells (FDCs) in the GALT. Studies in mice have shown that this accumulation is obligatory for the efficient delivery of the TSE agent to the brain. However, which GALTs are crucial for disease pathogenesis is uncertain. Mice deficient in specific GALT components were used here to determine their separate involvement in scrapie agent neuroinvasion from the intestine. In the combined absence of the GALTs and FDCs (lymphotoxin (LT)alpha(-/-) mice and LTbeta(-/-) mice), scrapie agent transmission was blocked. When FDC maturation was induced in remaining lymphoid tissues, mice that lacked both Peyer's patches (PPs) and mesenteric lymph nodes (wild-type (WT)-->LTalpha(-/-) mice) or PPs alone (WT-->LTbeta(-/-) mice) remained refractory to disease, demonstrating an important role for the PPs. Although early scrapie agent accumulation also occurs within the mesenteric lymph nodes, their presence in WT-->LTbeta(-/-) mice did not restore disease susceptibility. We have also shown that isolated lymphoid follicles (ILFs) are important novel sites of TSE agent accumulation in the intestine. Mice that lacked PPs but contained numerous FDC-containing mature ILFs succumbed to scrapie at similar times to control mice. Because the formation and maturation status of ILFs is inducible and influenced by the gut flora, our data suggest that such factors could dramatically affect susceptibility to orally acquired TSE agents. In conclusion, these data demonstrate that following oral exposure TSE agent accumulation upon FDCs within lymphoid tissue within the intestine itself is critically required for efficient neuroinvasion.