Time is of the essence: containment of the SARS-CoV-2 epidemic in Switzerland from February to May 2020

AIM: In late February and early March 2020, Switzerland experienced rapid growth of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections with 30,243 confirmed cases and 1,860 deaths as of 10 May 2020. The sequential introduction of non-pharmaceutical interventions (NPIs) resulted in successful containment of the epidemic. A better understanding of how the timing of implementing NPIs influences the dynamics and outcome of SARS-CoV-2 epidemics will be crucial for the management of a potential resurgence in Switzerland. METHODS: We developed a dynamic transmission model that describes infection, hospitalization, recovery and death due to SARS-CoV-2 in Switzerland. Using a maximum likelihood framework, we fitted the model to aggregated daily numbers of hospitalized patients, ICU occupancy and death from 25 February to 10 May 2020. We estimated critical parameters of SARS-CoV-2 transmission in Switzerland and explored counterfactual scenarios of an earlier and later implementation of NPIs. RESULTS: We estimated the basic reproduction number R0 = 2.61 (95% compatibility interval, CI: 2.51-2.71) during the early exponential phase of the SARS-CoV-2 epidemic in Switzerland. After the implementation of NPIs, the effective reproduction number approached Re = 0.64 (95% CI: 0.61-0.66). Based on the observed doubling times of the epidemic before and after the implementation of NPIs, we estimated that one week of early exponential spread required 3.1 weeks (95% CI: 2.8-3.3 weeks) of 'lockdown' to reduce the number of infections to the same level. Introducing the same sequence of NPIs one week earlier or later would have resulted in substantially lower (399, 95% prediction interval, PI: 347-458) and higher (8,683, 95% PI: 8,038-9,453) numbers of deaths, respectively. CONCLUSIONS: The introduction of NPIs in March 2020 prevented thousands of SARS-CoV-2-related deaths in Switzerland. Early implementation of NPIs during SARS-CoV-2 outbreaks can reduce the number of deaths and the necessary duration of strict control measures considerably.

Releasing the lockdown in the UK Covid-19 epidemic: a stochastic model

BackgroundIn a classic epidemic, the infected population has an early exponential phase, before slowing and fading to its peak. Mitigating interventions may change the exponent during the rising phase and a plateau can replace a peak. With interventions comes the risk that relaxation causes a second-wave. In the UK Covid-19 epidemic, infections cannot be counted, but their influence is seen in the curve of the mortality data. This work simulated social distancing and the lockdown in the UK Covid-19 epidemic to explore strategies for relaxation.MethodsCumulative mortality data was transposed 20 days earlier to identify three doubling periods separated by the 17th March—social distancing, and 23rd March—lockdown. A set of stochastic processes simulated viral transmission between interacting individuals using Covid-19 incubation and illness durations. Social distancing and restrictions on interactions were imposed and later relaxed.Principal FindingsDaily mortality data, consistent with that seen in the UK Covid-19 epidemic to 24th April 2020 was simulated. This output predicts that under a lockdown maintained till early July 2020, UK deaths will exceed 31,000, but leave a large susceptible population and a requirement for vaccination or quarantine. An earlier staged relaxation carries a risk of a second-wave. The model allows exploration of strategies for lifting the lockdown.InterpretationSocial distancing and the lockdown have had an impressive impact on the UK Covid-19 epidemic and saved lives, caution is now needed in planning its relaxation.FundingUnfunded research.Research in contextEvidence before this studyThe classical Susceptible, Infected, Recovered, (SIR) epidemiological model with additional compartments and sophistications have been widely used to make forecasts in the Covid-19 pandemic but are not easily accessible.Added value of this studyThis study adds reassurance that the interventions of social distancing introduced on the 17th March and the lockdown of the 23rd March 2020 have reduced mortality. The risks of a second-wave on their relaxation are real and illustrated graphically.Implications of all the available evidenceTogether with other models, credence is given to the risks of a second-wave in the UK Covid-19 epidemic on the relaxation of restrictions.

Dynamics of COVID-19 pandemic at constant and time-dependent contact rates

We constructed a simple Susceptible–Infected–Infectious–Excluded model of the spread of COVID-19. The model is parametrised only by the average incubation period, τ, and two rate parameters: contact rate, rC, and exclusion rate, rE. The rates can be manipulated by non-therapeutic interventions and determine the basic reproduction number, R = rC/rE, and, together with τ, the daily multiplication coefficient at the early exponential phase, β. Initial β determines the reduction of rC required to contain epidemic spread. In the long-term, we consider a scenario based on typical social behaviours, in which rC first decreases in response to a surge of daily new cases, forcing people to self-isolate, and then slowly increases when people gradually accept higher risk. Consequently, initial abrupt epidemic spread is followed by a plateau and slow regression. This scenario, although economically and socially devastating, will grant time to develop, produce, and distribute a vaccine, or at least limit daily cases to a manageable number.

Dynamics of COVID-19 pandemic at constant and time-dependent contact rates

We constructed a simple Susceptible−Exposed–Infectious–Removed model of the spread of COVID-19. The model is parametrised only by the average incubation period, τ, and two rate parameters: contact rate, β, and exclusion rate, γ. The rates depend on nontherapeutic interventions and determine the basic reproduction number, R0 = β/γ, and, together with τ, the daily multiplication coefficient in the early exponential phase, θ. Initial R0 determines the reduction of β required to contain the spread of the epidemic. We demonstrate that introduction of a cascade of multiple exposed states enables the model to reproduce the distributions of the incubation period and the serial interval reported by epidemiologists. Using the model, we consider a hypothetical scenario in which β is modulated solely by anticipated changes of social behaviours: first, β decreases in response to a surge of daily new cases, pressuring people to self-isolate, and then, over longer time scale, β increases as people gradually accept the risk. In this scenario, initial abrupt epidemic spread is followed by a plateau and slow regression, which, although economically and socially devastating, grants time to develop and deploy vaccine or at least limit daily cases to a manageable number.

Influence of muscle metabolic heterogeneity in determining the V̇o2p kinetic response to ramp-incremental exercise

The pulmonary O2 uptake (V̇o2p) response to ramp-incremental (RI) exercise increases linearly with work rate (WR) after an early exponential phase, implying that a single time constant (τ) and gain (G) describe the response. However, variability in τ and G of V̇o2p kinetics to different step increments in WR is documented. We hypothesized that the “linear” V̇o2p-WR relationship during RI exercise results from the conflation between WR-dependent changes in τ and G. Nine men performed three or four repeats of RI exercise (30 W/min) and two step-incremental protocols consisting of four 60-W increments beginning from 20 W or 50 W. During testing, breath-by-breath V̇o2p was measured by mass spectrometry and volume turbine. For each individual, the V̇o2p RI response was characterized with exponential functions containing either constant or variable τ and G values. A relationship between τ and G vs. WR was determined from the step-incremental protocols to derive the variable model parameters. τ and G increased from 21 ± 5 to 98 ± 20 s and from 8.7 ± 0.6 to 12.0 ± 1.9 ml·min−1·W−1 for WRs of 20-230 W, respectively, and were best described by a second-order (τ) and a first-order (G) polynomial function of WR (lowest Akaike information criterion score). The sum of squared residuals was not different ( P > 0.05) when the V̇o2p RI response was characterized with either the constant or variable models, indicating that they described the response equally well. Results suggest that τ and G increase progressively with WR during RI exercise. Importantly, these relationships may conflate to produce a linear V̇o2p-WR response, emphasizing the influence of metabolic heterogeneity in determining the apparent V̇o2p-WR relationship during RI exercise.

Effects of Growth Phase and Temperature onσBActivity within aListeria monocytogenesPopulation: Evidence for RsbV-Independent Activation ofσBat Refrigeration Temperatures

The alternative sigma factorσBofListeria monocytogenesis responsible for regulating the transcription of many of the genes necessary for adaptation to both food-related stresses and to conditions found within the gastrointestinal tract of the host. The present study sought to investigate the influence of growth phase and temperature on the activation ofσBwithin populations ofL.monocytogenesEGD-e wild-type, ΔsigB,and ΔrsbVthroughout growth at both 4°C and 37°C, using a reporter fusion that couples expression of EGFP to the stronglyσB-dependent promoter oflmo2230. A similarσBactivation pattern within the population was observed in wt-egfpat both temperatures, with the highest induction ofσBoccurring in the early exponential phase of growth when the fluorescent population rapidly increased, eventually reaching the maximum in early stationary phase. Interestingly, induction ofσBactivity was heterogeneous, with only a proportion of the cells in the wt-egfppopulation being fluorescent above the background autofluorescence level. Moreover, significant RsbV-independent activation ofσBwas observed during growth at 4°C. This result suggests that an alternative route toσBactivation exists in the absence of RsbV, a finding that is not explained by the current model forσBregulation.

Localization Pattern of Conjugation Machinery in a Gram-Positive Bacterium

Conjugation is an efficient way for transfer of genetic information between bacteria, even between highly diverged species, and a major cause for the spreading of resistance genes. We have investigated the subcellular localization of several conserved conjugation proteins carried on plasmid pLS20 found inBacillus subtilis. We show that VirB1, VirB4, VirB11, VirD2, and VirD4 homologs assemble at a single cell pole, but also at other sites along the cell membrane, in cells during the lag phase of growth. Bimolecular fluorescence complementation analyses showed that VirB4 and VirD4 interact at the cell pole and, less frequently, at other sites along the membrane. VirB1 and VirB11 also colocalized at the cell pole. Total internal reflection fluorescence microscopy showed that pLS20 is largely membrane associated and is frequently found at the cell pole, indicating that transfer takes place at the pole, which is a preferred site for the assembly of the active conjugation apparatus, but not the sole site. VirD2, VirB4, and VirD4 started to localize to the pole or the membrane in stationary-phase cells, and VirB1 and VirB11 were observed as foci in cells resuspended in fresh medium but no longer in cells that had entered exponential growth, although at least VirB4 was still expressed. These data reveal an unusual assembly/disassembly timing for the pLS20 conjugation machinery and suggest that specific localization of conjugation proteins in lag-phase cells and delocalization during growth are the reasons why pLS20 conjugation occurs only during early exponential phase.

Ferrous iron oxidation in moderately thermophilic acidophile Sulfobacillus sibiricus N1T

The iron-oxidizing system of a moderately thermophilic, extremely acidophilic, gram-positive mixotroph, Sulfobacillus sibiricus N1T, was studied by spectroscopic, high-performance liquid chromatography and inhibitory analyses. Hemes B, A, and O were detected in membranes of S. sibiricus N1T. It is proposed that the electron transport chain from Fe2+ to O2 is terminated by 2 physiological oxidases: aa3-type cytochrome, which dominates in the early-exponential phase of growth, and bo3-type cytochrome, whose role in iron oxidation becomes more prominent upon growth of the culture. Both oxidases were sensitive to cyanide and azide. Cytochrome aa3 was more sensitive to cyanide and azide, with Ki values of 4.1 and 2.5 µmol·L–1, respectively, compared with Ki values for cytochrome bo3, which were 9.5 µmol·L–1 for cyanide and 7.0 µmol·L–1 for azide. This is the first evidence for the participation of a bo3-type oxidase in ferrous iron oxidation. The respiratory chain of the mixotroph contains, in addition to the 2 terminal oxidases, a membrane-bound cytochrome b573.

Gene expression of Pseudomonas aeruginosa in a mucin-containing synthetic growth medium mimicking cystic fibrosis lung sputum

Pseudomonas aeruginosa airway infection is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. Various in vitro models have been developed to study P. aeruginosa pathobiology in the CF lung. In this study we produced a modified artificial-sputum medium (ASMDM) more closely resembling CF sputum than previous models, and extended previous work by using strain PAO1 arrays to examine the global transcription profiles of P. aeruginosa strain UCBPP-PA14 under early exponential-phase and stationary-phase growth. In early exponential phase, 38/39 nutrition-related genes were upregulated in line with data from previous in vitro models using UCBPP-PA14. Additionally, 23 type III secretion system (T3SS) genes, several anaerobic respiration genes and 24 quorum-sensing (QS)-related genes were upregulated in ASMDM, suggesting enhanced virulence factor expression and priming for anaerobic growth and biofilm formation. Under stationary phase growth in ASMDM, macroscopic clumps resembling microcolonies were evident in UCBPP-PA14 and CF strains, and over 40 potentially important genes were differentially expressed relative to stationary-phase growth in Luria broth. Most notably, QS-related and T3SS genes were downregulated in ASMDM, and iron-acquisition and assimilatory nitrate reductase genes were upregulated, simulating the iron-depleted, microaerophilic/anaerobic environment of CF sputum. ASMDM thus appears to be highly suitable for gene expression studies of P. aeruginosa in CF.