Unfortunately, post-withdrawal outbreaks of cVDPV2 required responses using monovalent type OPV2 (mOPV2), leading to more than 70 new emergences of cVDPV2 and cycles of outbreaks and responses.2 ...Since 2016, more than 3000 cVDPV2 cases have been reported, more than 75% linked to outbreak responses with Sabin OPV.2 Novel OPV2 (nOPV2) was designed with greater genetic stability than Sabin OPV2 to reduce the likelihood of creating future VDPV outbreaks.3 Emergency use listing of nOPV2 was granted in November, 2020, and 1 billion doses have been administered as of the end of December, 2023.2 Although nOPV2 has far greater genetic stability than Sabin OPV2, 11 cVDPV2 outbreaks have been linked to its use.2 Magnus Ochoge and colleagues report, in The Lancet, a phase 3 clinical trial examining the safety and immunogenicity of nOPV2 relative to bivalent OPV in 2345 infants (ie, those aged 18 to <52 weeks) and 600 young children (ie, those aged 1 to <5 years) in The Gambia,4 providing the first clinical data on nOPV2 in a low-income country and on the African continent, where 98% of the vaccine has been used.2 The study, which took place between February and October, 2021, assessed the safety and type 2 immunogenicity of nOPV2 relative to bivalent OPV (bOPV) in infants and young children in The Gambia. Studies in Liberia and Nigeria have documented poorer performance of nOPV2.11,12 These could have been biased by inaccurately reported vaccination history but might also indicate additional challenges not encountered in the clinical trial reported by Ochoge and colleagues, including cold chain disruption, greater interference from enteric infections, or a lack of priming from previous IPV or OPV2. ...recent experiences in Nigeria, where more than ten campaigns were conducted between 2021 and 2023, without stopping cVDPV2 transmission, and the Democratic Republic of the Congo, where 12 months passed from the first cVDPV2 detection in 2022 before completion of two campaigns,2 highlight basic challenges that are not addressed by a new vaccine: locating and reaching inaccessible communities and ensuring effective coordination for timely action. nOPV2 will continue to be an essential tool to stop cVDPV2 circulation, but the Global Polio Eradication Initiative must deliver high-quality and timely outbreak response campaigns to reliably stop poliovirus transmission.
Summary Background In preparation for the introduction of MenAfriVac, a meningococcal group A conjugate vaccine developed for the African meningitis belt, an enhanced meningitis surveillance network ...was established. We analysed surveillance data on suspected and confirmed cases of meningitis to quantify vaccine impact. Methods We compiled and analysed surveillance data for nine countries in the meningitis belt (Benin, Burkina Faso, Chad, Côte d'Ivoire, Ghana, Mali, Niger, Nigeria, and Togo) collected and curated by the WHO Inter-country Support Team between 2005 and 2015. The incidence rate ratios (IRRs) of suspected and confirmed cases in vaccinated and unvaccinated populations were estimated with negative binomial regression models. The relative risk of districts reaching the epidemic threshold of ten per 100 000 per week was estimated according to district vaccination status. Findings The incidence of suspected meningitis cases declined by 57% (95% CI 55–59) in vaccinated compared with unvaccinated populations, with some heterogeneity observed by country. We observed a similar 59% decline in the risk of a district reaching the epidemic threshold. In fully vaccinated populations, the incidence of confirmed group A disease was reduced by more than 99%. The IRR for non-A serogroups was higher after completion of MenAfriVac campaigns (IRR 2·76, 95% CI 1·21–6·30). Interpretation MenAfriVac introduction has led to substantial reductions in the incidence of suspected meningitis and epidemic risk, and a substantial effect on confirmed group A meningococcal meningitis. It is important to continue strengthening surveillance to monitor vaccine performance and remain vigilant against threats from other meningococcal serogroups and other pathogens. Funding World Health Organization.
In this paper, we provide direct evidence of the importance of root hairs on pore structure development at the root–soil interface during the early stage of crop establishment.
This was achieved by ...use of high-resolution (c. 5 μm) synchrotron radiation computed tomography (SRCT) to visualise both the structure of root hairs and the soil pore structure in plant–soil microcosms. Two contrasting genotypes of barley (Hordeum vulgare), with and without root hairs, were grown for 8d in microcosms packed with sandy loam soil at 1.2 g cm−3 dry bulk density. Root hairs were visualised within air-filled pore spaces, but not in the fine-textured soil regions.
We found that the genotype with root hairs significantly altered the porosity and connectivity of the detectable pore space (> 5 μm) in the rhizosphere, as compared with the no-hair mutants. Both genotypes showed decreasing pore space between 0.8 and 0.1mm from the root surface. Interestingly the root-hair-bearing genotype had a significantly greater soil pore volume-fraction at the root–soil interface.
Effects of pore structure on diffusion and permeability were estimated to be functionally insignificant under saturated conditions when simulated using image-based modelling.
Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases that regulate ...viral replication, also dysregulates host immune sensing by binding and deubiquitination of host protein substrates. PLpro is a promising therapeutic target, albeit challenging owing to featureless P1 and P2 sites recognizing glycine. To overcome this challenge, we leveraged the cooperativity of multiple shallow binding sites on the PLpro surface, yielding novel 2-phenylthiophenes with nanomolar inhibitory potency. New cocrystal structures confirmed that ligand binding induces new interactions with PLpro: by closing of the BL2 loop of PLpro forming a novel "BL2 groove" and by mimicking the binding interaction of ubiquitin with Glu167 of PLpro. Together, this binding cooperativity translates to the most potent PLpro inhibitors reported to date, with slow off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells.
Abstract
Serotype 2 oral poliovirus vaccine (OPV2) can revert to regain wild-type neurovirulence and spread to cause emergences of vaccine-derived poliovirus (VDPV2). After its global withdrawal from ...routine immunization in 2016, outbreak response use has created a cycle of VDPV2 emergences that threaten eradication. We implemented a hierarchical model based on VP1 region genetic divergence, time, and location to attribute emergences to campaigns and identify risk factors. We found that a 10 percentage point increase in population immunity in children younger than 5 years at the campaign time and location corresponds to a 18.0% decrease (95% credible interval CrI, 6.3%–28%) in per-campaign relative risk, and that campaign size is associated with emergence risk (relative risk scaling with population size to a power of 0.80; 95% CrI, .50–1.10). Our results imply how Sabin OPV2 can be used alongside the genetically stable but supply-limited novel OPV2 (listed for emergency use in November 2020) to minimize emergence risk.
Outbreaks of vaccine-derived poliovirus from rare reversion of type-2 Sabin vaccine strain inhibit polio eradication efforts. We use a hierarchical model, incorporating VP1 region genetic divergence and population movement, to estimate outbreak origins and risk factors for vaccine campaigns.
Vaccine hesitancy and emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) escaping vaccine-induced immune responses highlight the urgency for new ...COVID-19 therapeutics. Engineered angiotensin-converting enzyme 2 (ACE2) proteins with augmented binding affinities for SARS-CoV-2 spike (S) protein may prove to be especially efficacious against multiple variants. Using molecular dynamics simulations and functional assays, we show that three amino acid substitutions in an engineered soluble ACE2 protein markedly augmented the affinity for the S protein of the SARS-CoV-2 WA-1/2020 isolate and multiple VOCs: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). In humanized K18-hACE2 mice infected with the SARS-CoV-2 WA-1/2020 or P.1 variant, prophylactic and therapeutic injections of soluble ACE2
.v2.4-IgG1 prevented lung vascular injury and edema formation, essential features of CoV-2-induced SARS, and above all improved survival. These studies demonstrate broad efficacy in vivo of an engineered ACE2 decoy against SARS-CoV-2 variants in mice and point to its therapeutic potential.
Expanding outbreaks of circulating vaccine-derived type 2 poliovirus (cVDPV2) across Africa after the global withdrawal of trivalent oral poliovirus vaccine (OPV) in 2016 are delaying global polio ...eradication. We aimed to assess the effect of outbreak response campaigns with monovalent type 2 OPV (mOPV2) and the addition of inactivated poliovirus vaccine (IPV) to routine immunisation.
We used vaccination history data from children under 5 years old with non-polio acute flaccid paralysis from a routine surveillance database (the Polio Information System) and setting-specific OPV immunogenicity data from the literature to estimate OPV-induced and IPV-induced population immunity against type 2 poliomyelitis between Jan 1, 2015, and June 30, 2020, for 51 countries in Africa. We investigated risk factors for reported cVDPV2 poliomyelitis including population immunity, outbreak response activities, and correlates of poliovirus transmission using logistic regression. We used the model to estimate cVDPV2 risk for each 6-month period between Jan 1, 2016, and June 30, 2020, with different numbers of mOPV2 campaigns and compared the timing and location of actual mOPV2 campaigns and the number of mOPV2 campaigns required to reduce cVDPV2 risk to low levels.
Type 2 OPV immunity among children under 5 years declined from a median of 87% (IQR 81–93) in January–June, 2016 to 14% (9–37) in January–June, 2020. Type 2 immunity from IPV among children under 5 years increased from 3% (<1–6%) in January–June, 2016 to 35% (24–47) in January–June, 2020. The probability of cVDPV2 poliomyelitis among children under 5 years was negatively correlated with OPV-induced and IPV-induced immunity and mOPV2 campaigns (adjusted odds ratio: OPV 0·68 95% CrI 0·60−0·76, IPV 0·82 0·68−0·99 per 10% absolute increase in estimated population immunity, mOPV2 0·30 0·20−0·44 per campaign). Vaccination campaigns in response to cVDPV2 outbreaks have been smaller and slower than our model shows would be necessary to reduce risk to low levels, covering only 11% of children under 5 years who are predicted to be at risk within 6 months and only 56% within 12 months.
Our findings suggest that as mucosal immunity declines, larger or faster responses with vaccination campaigns using type 2-containing OPV will be required to stop cVDPV2 transmission. IPV-induced immunity also has an important role in reducing the burden of cVDPV2 poliomyelitis in Africa.
Bill & Melinda Gates Foundation, Medical Research Council Centre for Global Infectious Disease Analysis, and WHO.
For the French translation of the abstract see Supplementary Materials section.
Abstract
Background
Detection of poliovirus outbreaks relies on a complex laboratory algorithm of cell-culture, polymerase chain reaction (PCR), and sequencing to distinguish wild-type and ...vaccine-derived polioviruses (VDPV) from Sabin-like strains. We investigated the potential for direct molecular detection and nanopore sequencing (DDNS) to accelerate poliovirus detection.
Methods
We analyzed laboratory data for time required to analyze and sequence serotype-2 VDPV (VDPV2) in stool collected from children with acute flaccid paralysis in Africa (May 2016–February 2020). Impact of delayed detection on VDPV2 outbreak size was assessed through negative binomial regression.
Results
VDPV2 confirmation in 525 stools required a median of 49 days from paralysis onset (10th–90th percentile, 29–74), comprising collection and transport (median, 16 days), cell-culture (7 days), intratypic differentiation quantitative reverse transcription PCR (3 days), and sequencing, including shipping if required (15 days). New VDPV2 outbreaks were confirmed a median of 35 days (27–60) after paralysis onset, which we estimate could be reduced to 16 days by DDNS (9–37). Because longer delays in confirmation and response were positively associated with more cases (P < .001), we estimate that DDNS could reduce the number of VDPV2 cases before a response by 28% (95% credible interval, 12%–42%).
Conclusions
DDNS could accelerate poliovirus outbreak response, reducing their size and the cost of eradication.
Delays in detecting poliovirus result in larger outbreaks. Direct molecular detection of poliovirus in stool by nanopore sequencing is fast, easy to implement, and could substantially decrease the time taken to respond to poliovirus outbreaks, accelerating eradication.
Layilin (LAYN) is a critical gene that regulates T cell function. However, the correlations of LAYN to prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear.
LAYN ...expression was analyzed via the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. We evaluated the influence of LAYN on clinical prognosis using Kaplan-Meier plotter, the PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA). The correlations between LAYN and cancer immune infiltrates was investigated via TIMER. In addition, correlations between LAYN expression and gene marker sets of immune infiltrates were analyzed by TIMER and GEPIA.
A cohort (GSE17536) of colorectal cancer patients showed that high LAYN expression was associated with poorer overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). In addition, high LAYN expression was significantly correlated with poor OS and progression-free survival (PFS) in gastric cancers (OS HR = 1.97,
= 3.6e-10; PFS HR = 2.12,
= 2.3e-10). Moreover, LAYN significantly impacts the prognosis of diverse cancers via The Cancer Genome Atlas (TCGA). Specifically, high LAYN expression was correlated with worse OS and PFS in stage 2 to 4 but not stage 1 and stage N0 gastric cancer patients (
= 0.28, 0.34;
= 0.073, 0.092). LAYN expression was positively correlated with infiltrating levels of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in colon adenocarcinoma (COAD) and stomach adenocarcinoma (STAD). LAYN expression showed strong correlations with diverse immune marker sets in COAD and STAD.
These findings suggest that LAYN is correlated with prognosis and immune infiltrating levels of, including those of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in multiple cancers, especially in colon and gastric cancer patients. In addition, LAYN expression potentially contributes to regulation of tumor-associated macrophages (TAMs), DCs, T cell exhaustion and Tregs in colon and gastric cancer. These findings suggest that LAYN can be used as a prognostic biomarker for determining prognosis and immune infiltration in gastric and colon cancers.
Airway clearance interventions are recommended for people with chronic lung conditions and mucus hypersecretion, but there are few published models of care or descriptions of airway clearance service ...provision. This evaluation describes a dedicated, physiotherapy-led, community-based airway clearance service in a metropolitan local health network.
Retrospective evaluation using existing airway clearance service administrative database.
All first referrals to the airway clearance service in a 5-year period (1/1/2017 to 31/12/2021).
Available service data grouped into four domains: participant demographics, referral demographics, service provision and outcomes.
Of the 1335 first referrals eligible for inclusion, 1157 (87%) people attended. Bronchiectasis was the commonest condition (n = 649/1135, 49%). A total of 2996 occasions of service (face to face clinic n = 2108, 70%, phone n = 736, 25%, telehealth n = 99, 3%, home visit n = 53, 2%) were delivered. Airway clearance devices frequently prescribed were the Aerobika (525/1157, 45%), bubble-positive expiratory pressure (263/1157, 23%) and the Acapella (127/1157, 11%). On average, initial appointment with the airway clearance service occurred within 36 days of referral and people attended the service three times. Individuals voluntarily completed both pre/post service questionnaires around a third of the time. At least half of responders reported an improvement in respiratory symptom outcome measures consistent with the minimum clinically important difference.
This evaluation describes an airway clearance service as it exists, providing an example from which airway clearance services can be planned, implemented and improved.
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