Evaluation of ß-lapachone-methyl-ß-cyclodextrin inclusion complex prepared by spray drying and its application against different developmental stages of Schistosoma mansoni in murine model.

BACKGROUND: ß-lapachone (ß-lap) is a naphthoquinone widely found in species of vegetables. However, its poor aqueous solubility limits its systemic administration and clinical applications in vivo. To overcome this limitation, several studies have been carried out in order to investigate techniques that can enhance the solubility and dissolution rate of ß-lap, such as the use of inclusion complexes with cyclodextrin. PURPOSE: To evaluate the in vivo effect of ß-lap complexed in methyl-ß-cyclodextrin (MßCD) on the evolutionary stages of Schistosoma mansoni in a murine model. METHODS: The development and characterization of the physicochemical properties of the inclusion complex of ß-lap in ß-lap:MßCD was prepared by solubility and dissolution tests, FTIR, DSC, X-RD and SEM. The mice were infected and subsequently treated with ß-lap:MßCD orally with 50 mg/kg/day and 100 mg/kg/day for 5 consecutive days, starting therapy on the 1st (skin schistosomula), 14th (pulmonary schistosomula), 28th (young worms) and 45th (adult worms) days after infection. Control groups were also formed; one infected untreated, treated with MßCD, and the other treated with PZQ. RESULTS: The loss of the crystalline form of ß-lap in the ß-lap:MßCD complex obtained by spray drying was proven through physical-chemical characterization analyses. ß-lap:MßCD caused reduction in the number of worms of the 33.56%, 35.7%, 35.45% and 36.45%, when the dose was at 50 mg/kg, and 65.00%, 60.34%, 52.72% and 65.01%, in the dose 100 mg/kg; when treatment was started in the 1st, 14th, 28th and 45th days after infection, respectively. It was also possible to observe a significant reduction in the number of immature eggs and an increase in the number of ripe and dead eggs and, consequently, a reduction in the damage caused by the egg antigens to the host tissue, where we attributed the reduction in the average diameter of the granulomas to the ß-lap. CONCLUSION: The dissolved content of ß-lap:MßCD by spray drying reached almost 100%, serving for future formulations and delineation of the mechanisms of action of ß-lap against S. mansoni.

Historical mercury contamination in a major Latin American industrial and port complex: The case of the Santos estuary, Southeastern Brazil.

The present study determined total mercury (Hg) in four 210Pb dated sediment cores to assess the historical anthropogenic Hg accumulation in the Santos estuary, Southeastern Brazil. Background levels were identified using the deepest sections of the cores, corresponding to pre-industrial ages. Mercury distribution in the sediment cores (0.02-2.64 mg kg-1) presented a large spatial and temporal variation. Contamination is highest in the upper estuary and indicates that the industrial hub, especially a chlor-alkali plant is the primary source of Hg. A contaminant trap effect is observed in this area associated with high fine sediment accumulation and Hg fluxes. The contamination pattern indicates that the regions not affected by direct inputs are influenced by reworking, resuspension, and transport of contaminated sediments by tidal flows. The Hg enrichment in the upper layers of the sediment cores demonstrates that the environmental actions fulfilled in the 1980s were insufficient to control Hg pollution in the Santos estuary.

Thymoma and myasthenia gravis - an observational study at a tertiary center.

INTRODUCTION: Acquired Myasthenia Gravis (MG) is a rare autoimmune neurological disorder characterized by fluctu- ating paresis of the skeletal muscle due to pathogenic antibodies against the acetylcholine receptor or other elements of the neuromuscular plaque. There is a close relation between MG and thymoma. We aimed to characterize a population of patients with Myasthenia Gravis associated thymoma (MGAT). METHODS: Retrospective and longitudinal study in all patients with MGAT observed at a tertiary center between 2009 and 2020. We assessed epidemiological, clinical, laboratory and therapeutic features of both MG and thymoma. RESULTS: We found 18 patients with an average age of 53 ± 16.2, 13 of them females. Most patients (n=15) presented the generalized MG form. Most frequent Masaoka staging was II (n=7). Regarding the WHO histopathological classification of thymoma, most patients (n=11) presented with type B2 or B3. Thirteen patients underwent extended thymectomy (12 by median sternotomy and 1 by VATS). Of the remaining 5 patients, 4 of them underwent a CT scan guided biopsy, and 1 patient did not accept further work-up. Seven patients were classified as R0 for surgical resection margins and only one of them had recurrence of thymoma. Besides surgery, oncological treatment included radiotherapy and chemotherapy. Five patients expe- rienced a myasthenic crisis during the course of the disease. Three deaths occurred in the studied population. CONCLUSIONS: This study helped to pinpoint important aspects concerning therapeutic orientation of MGAT patients, such as the clinical impact of thymectomy in the course of MGAT, the oncological prognostic value of surgical resection mar- gins, and the importance of preoperative intravenous immunoglobulin. Management of MGAT patients is only possible with a multidisciplinary approach.

Natural Killer Cell Receptors and Endometriosis: A Systematic Review.

Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies correlate the immune system with endometriosis, particularly NK receptors (NKR), which have been suggested to play an essential role in the pathogenesis of the disease. This systematic review aims to enlighten the role of NKR in endometriosis. A literature search was performed independently by two reviewers, to identify studies assessing the role of NKR in endometriosis. In total, 18 studies were included. Endometriosis pathogenesis seems to be marked by the overexpression of NK inhibitor receptors (KIRS), namely, CD158a+, KIR2DL1, CD94/NKG2A, PD-1, NKB1, and EB6, and inhibiting ligands such as PD-L1, HLA-E, HLA-G, and HLA-I. Concurrently, there is a decrease in NK-activating receptors and natural cytotoxicity receptors (NCRs), such as NKp46, NKp30, and NKG2D. The immune shift from NK surveillance to NK suppression is also apparent in the greater relative number of ITIM domains compared with ITAM domains in NKRs. In conclusion, NK receptor activity seems to dictate the immunocompetency of women to clear endometriotic cells from the peritoneal cavity. Future research could explore NKRs as therapeutic targets, such as that which is now well established in cancer therapy through immunotherapy.

Previous Disability and Benefit of Acute Phase Therapy in Functional Prognosis of Selected Patients with Ischemic Stroke.

OBJECTIVES: Patients' previous disability (PD) is a key factor when considering acute stroke therapy. PD's exact impact on functional prognosis of patients with acute ischemic stroke remains not entirely clarified. We aimed to analyze PD's influence on functional outcome three months after ischemic stroke. MATERIALS AND METHODS: Retrospective analysis of prospectively collected data concerning patients with acute ischemic stroke admitted to Stroke Unit of a tertiary center who underwent acute phase therapy between 2017 and 2019. Modified Rankin Scale (mRS) was used to define PD (with previous mRS≥3). Patients with PD were selected for treatment based on similar baseline characteristics to patients without PD. Patients were classified into two groups according to previous mRS: mRS<3 and mRS≥3. We defined bad outcome at three months after stroke as mRS≥3 for patients with previous mRS<3, and as a higher score than baseline mRS for patients with previous mRS≥3. RESULTS: We identified 1169 eligible patients - 1016 patients with previous mRS<3 and 153 patients with previous mRS≥3. Most baseline characteristics did not differ significantly between them. For patients ≤75 years old, PD was associated with worse outcome (odds ratio estimate [OR] 4.50, p < 0.001). For patients >75 years old, PD was protective against worse outcome (OR 0.42, p < 0.001). In patients with previous mRS≥3 and >75 years old, there was a higher proportion of women (p = 0.005). CONCLUSIONS: PD might not be a relevant factor when considering acute stroke therapy in selected patients >75 years old, especially women. Further studies are needed to clarify these findings.

Replacement of the Gamma by the Delta variant in Brazil: impact of lineage displacement on the ongoing pandemic

The COVID-19 epidemic in Brazil was driven mainly by the spread of Gamma (P.1), a locally emerged Variant of Concern (VOC) that was first detected in early January 2021. This variant was estimated to be responsible for more than 96% of cases reported between January and June 2021, being associated with increased transmissibility and disease severity, a reduction in neutralization antibodies and effectiveness of treatments or vaccines, as well as diagnostic detection failure. Here we show that, following several importations predominantly from the USA, the Delta variant rapidly replaced Gamma after July 2021. However, in contrast to what was seen in other countries, the rapid spread of Delta did not lead to a large increase in the number of cases and deaths reported in Brazil. We suggest that this was likely due to the relatively successful early vaccination campaign coupled with natural immunity acquired following prior infection with Gamma. Our data reinforces reports of the increased transmissibility of the Delta variant and, considering the increasing concern due to the recently identified Omicron variant, argues for the necessity to strengthen genomic monitoring on a national level to quickly detect and curb the emergence and spread of other VOCs that might threaten global health.

Genomic epidemiology reveals how restriction measures shaped the SARS-CoV-2 epidemic in Brazil

Brazil has experienced some of the highest numbers of COVID-19 cases and deaths globally and from May 2021 made Latin America a pandemic epicenter. Although SARS-CoV-2 established sustained transmission in Brazil early in the pandemic, important gaps remain in our understanding of virus transmission dynamics at the national scale. Here, we describe the genomic epidemiology of SARS-CoV-2 using near-full genomes sampled from 27 Brazilian states and a bordering country - Paraguay. We show that the early stage of the pandemic in Brazil was characterised by the co-circulation of multiple viral lineages, linked to multiple importations predominantly from Europe, and subsequently characterized by large local transmission clusters. As the epidemic progressed under an absence of effective restriction measures, there was a local emergence and onward international spread of Variants of Concern (VOC) and Variants Under Monitoring (VUM), including Gamma (P.1) and Zeta (P.2). In addition, we provide a preliminary genomic overview of the epidemic in Paraguay, showing evidence of importation from Brazil. These data reinforce the usefulness and need for the implementation of widespread genomic surveillance in South America as a toolkit for pandemic monitoring that provides a means to follow the real-time spread of emerging SARS-CoV-2 variants with possible implications for public health and immunization strategies.

Asymptomatic SARS-CoV-2 infection and the demography of COVID-19

Asymptomatic individuals carrying SARS-CoV-2 can transmit the virus and contribute to outbreaks of COVID-19, but it is not yet clear how the proportion of asymptomatic infections varies by age and geographic location. Here we use detailed surveillance data gathered during COVID-19 resurgences in six cities of China at the beginning of 2021 to investigate this question. Data were collected by multiple rounds of city-wide PCR test with detailed contact tracing, where each patient was monitored for symptoms through the whole course of infection. We find that the proportion of asymptomatic infections declines with age (coefficient =-0.006, P<0.01), falling from 56% in age group 0-9 years to 12% in age group >60 years. Using an age-stratified compartment model, we show that this age-dependent asymptomatic pattern together with the age distribution of overall cases can explain most of the geographic differences in reported asymptomatic proportions. Combined with demography and contact matrices from other countries worldwide, we estimate that a maximum of 22%-55% of SARS-CoV-2 infections would come from asymptomatic cases in an uncontrolled epidemic based on asymptomatic proportions in China. Our analysis suggests that flare-ups of COVID-19 are likely if only adults are vaccinated and that surveillance and possibly control measures among children will be still needed in the future to contain epidemic resurgence.

Trace element fluxes during the "Anthropocene" in a large South American industrial and port area (Santos and São Vicente estuarine system, SE, Brazil).

The worldwide evidence of human activities on the environment led the scientific community to recognize a new geologic time unit known as the "Anthropocene." Since the twentieth century, urbanization and industrialization needs driven by population and economic growth have impacted several ecosystems including the estuaries. To assess the contamination, provenance, and fluxes of trace elements (As, Cr, Cu, Ni, Pb, Sc, V, and Zn) over the last century, a geochemical and chemometric technique was employed in sediment cores of an industrial and port region of international importance, the Santos and São Vicente Estuarine System (SSVES). The results indicated low contamination, with the highest enrichment factors (EFs) for Cu (EF = 3.1), Pb (EF = 2.7), Zn (EF = 2.4), and As (EF = 2.3) found next to the harbor area. The Pre-industrial records confirm the relatively high concentrations of As and its naturally enriched occurrence on the Brazilian shelf. Sediment accumulation rates and trace element fluxes showed a general increase over the years, since the early 1960s, associated with the "Great Acceleration" of the mid-twentieth century. These alterations are human-induced and include urbanization and industrialization. Nonetheless, as the contents and enrichment of trace elements indicate that the region is not severely polluted, we hypothesize that the contamination in the SSVES is likely related to the drainage and erosion of the urbanized adjacent area, rather than direct disposal of inorganic contaminants from the industrial activity.

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

It is unclear whether prior endemic coronavirus infections affect COVID-19 severity. Here, we show that in cases of fatal COVID-19, antibody responses to the SARS-COV-2 spike are directed against epitopes shared with endemic beta-coronaviruses in the S2 subunit of the SARS-CoV-2 spike protein. This immune response is associated with the compromised production of a de novo SARS-CoV-2 spike response among individuals with fatal COVID-19 outcomes.

Analysis and visualization of epidemics on the timescale of burden: derivation and application of Epidemic Resistance Lines (ERLs) to COVID-19 outbreaks in the US

The 2020 COVID-19 pandemic produced thousands of well-quantified epidemics in counties, states, and countries around the world. Comparing the dynamics and outcomes of these nested epidemics could improve our understanding of the efficacy of non-pharmaceutical interventions (NPIs) and help managers with risk assessment across multiple geographic levels. However, cross-outbreak comparisons are challenging due to their variable dates of introduction of the SARS-CoV-2 virus, rates of transmission, case detection rates, and asynchronous and diverse management interventions. Here, we present a graphical method for comparing ongoing COVID-19 epidemics by using disease burden as a natural timescale for comparison. Trajectories of growth rates of cases over the timescale of lagged deaths per-capita produces coherent visual comparisons of epidemics that are otherwise incoherent and asynchronous in the timescale of calendar dates or incomparable using non-stationary measures of burden such as cases. Applied to US COVID-19 outbreaks at the county and state level, this approach reveals lockdowns reducing transmission at fewer deaths per-capita early in the epidemic, reopenings causing resurgent summer epidemics, and peaks that while separated in time and place actually occur at points of similar per-capita deaths. Our method uses early and minimally mitigated epidemics, like that in NYC in March-April 2020 and Sweden in later 2020, to define what we call "epidemic resistance lines" (ERLs) or hypothesized upper bounds of epidemic speed and burden. ERLs from less-mitigated epidemics allow benchmarking of resurgent summer epidemics in the US. In particular, the unmitigated NYC epidemic resistance line appears to bound the growth rates of 3,000 US counties and funnel growth rates across counties to their peaks where growth rates equal zero in the fall and winter of 2020. Corroboration of upper-bounds on epidemic trajectories allowed early predictions of mortality burden for unmitigated COVID-19 epidemics in these populations, predictions that were more accurate for counties in states without mask-wearing mandates. We discuss how this method could be used for future epidemics, including seasonal epidemics caused by influenza or ongoing epidemics caused by new SARS-CoV-2 variants. Press SummaryWhy, despite no statewide mask-wearing mandates or other restrictions like restaurant closures, did South Dakotas COVID-19 epidemic peak not in January, when seasonal forcing wanes, but in early November? Why are we not seeing a resurgent epidemic in Florida or Texas, where non-pharmaceutical interventions have been relaxed for months? How can we compare the current outbreak in India with other countries epidemics to contextualize the speed of the Indian outbreak and estimate the potential loss of life? We have developed a new method of visualizing epidemics in progress that can help to compare distinct COVID-19 outbreaks to understand, in specific cases like South Dakota, why they peaked when they did. The "when" in this case does not refer to prediction of a calendar date, but rather a point in the accumulation of deaths in a given locale due to the disease in question. The method presented in this paper therefore essentially uses population-based burden of disease as a timescale for measuring epidemics. Just as the age of a car can be measured in years or miles, the age of a COVID-19 epidemic can be measured in days or deaths per-capita. Plotting growth rates of cases as a function of per-capita deaths 11 days later produces a real-time visual comparison of epidemics that are otherwise asynchronous in time. This approach permits both direct comparison across local outbreaks that may be disparate in time and/or place, as well as benchmarking of any outbreak against known exemplars of archetypal response strategies, such as New York Citys unmitigated urban outbreak in Spring 2020 and Swedens uncontained summer 2020 epidemic. Whether comparing the speed of resurgent outbreaks following relaxation in US states like Florida or the peak mortality burden in fall outbreaks across thousands of US counties with and without statewide mask-wearing mandates, this method offers a simple, intuitive tool for real-time monitoring and prediction capability connecting epidemic speed, burden, and management interventions. While our findings point to compelling epidemiological hypotheses for peaks in less-regulated states, future work is needed to confirm and extend our results predicting mortality burden at the peak of confirmed cases in the ongoing and evolving COVID-19 pandemic.

Early genomic detection of SARS-CoV-2 P.1 variant in Northeast Brazil

Tracking the spread of SARS-CoV-2 variants of concern is crucial to inform public health efforts and control the ongoing pandemic. Here, we report genetic evidence for circulation of the P.1 variant in Northeast Brazil. We advocate for increased active surveillance to ensure adequate control of this variant throughout the country. Article Summary LineActive genomic surveillance of SARS- CoV-2 suspected cases from recent travelers reveals the circulation of the P1 variant of concern in Bahia state, Northeast Brazil.

Insights into leaded gasoline registered in mud depocenters derived from multivariate statistical tool: southeastern Brazilian coast.

Lead has been widely used since antiquity, but its uses drastically increased during the Industrial Revolution. The global emission of Pb into the environment was mainly due to tetraethyl lead added to gasoline as an antiknock additive. Because of its toxicity and neurological effects, the compound was phased out in the 1980s. Isotopic signatures are widely applied to differentiate sources of Pb; however, this is an expensive and sophisticated analysis compared to elemental analysis. Thus, this study aims to gain insight into leaded gasoline registered in mud depocenters from the southeastern Brazilian coast using multivariate statistical tools on elemental analysis data of trace elements. Seven multiple cores were collected on board the Research Vessel Alpha Crucis. Al, As, Ba, Ca, Cd, Cr, Cu, Fe, K, Mg, Mn, Ni, P, Pb, Sc, Sr, V and Zn were analyzed by acid digestion and quantified by ICP-OES. Levels and enrichment factors of Pb resulted in homogeneous columns, indicating that small variations in concentrations can be attributed to grain size differences, not presenting contaminated levels. From statistical results, the highest contribution on the first component was represented by a lithogenic source with the leaching of continental rocks. Lead content was notable in its high loadings in other components, which suggests atmospheric deposition. An increase in these components in subsurface samples from vertical profiles between 1935 and 1996 could represent a fingerprint of the consumption of leaded gasoline in Brazil between 1923 and 1989. Thus, statistical analysis of elemental data enabled to infer possible sources and pathways of Pb to the environment, without isotopic analysis.

Thirty years of recombinant BCG: new trends for a centenary vaccine

Introduction: Global perception of the potential for Bacille Calmette-Guérin (BCG), and consequently recombinant BCG (rBCG), in a variety of prophylactic and therapeutic applications has been increasing. A century of information on BCG, and three decades of experience with rBCG, has generated solid knowledge in this field. Area covered: Here, we review the current state of knowledge of BCG and rBCG development. Molecular tools have facilitated the expression of a variety of molecules in BCG, with the aim of improving its efficacy as a tuberculosis vaccine, generating polyvalent vaccines against other pathogens, including viruses, bacteria, and parasites, and developing immunotherapy approaches against noninvasive bladder cancer. BCG’s recently appraised heterologous effects and prospects for expanding its application to other diseases are also addressed. Expert opinion: There are high expectations for new tuberculosis vaccines currently undergoing advanced clinical trials, which could change the prospects of the field. Systems biology could reveal effective biomarkers of protection, which would greatly support vaccine development. The development of appropriate large-scale production processes would further support implementation of new vaccines and rBCG products. The next few years should consolidate the broader applications of BCG and produce insights into improvements using the recombinant BCG technology.

Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa

Continued uncontrolled transmission of the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in many parts of the world is creating the conditions for significant virus evolution. Here, we describe a new SARS-CoV-2 lineage (501Y.V2) characterised by eight lineage-defining mutations in the spike protein, including three at important residues in the receptor-binding domain (K417N, E484K and N501Y) that may have functional significance. This lineage emerged in South Africa after the first epidemic wave in a severely affected metropolitan area, Nelson Mandela Bay, located on the coast of the Eastern Cape Province. This lineage spread rapidly, becoming within weeks the dominant lineage in the Eastern Cape and Western Cape Provinces. Whilst the full significance of the mutations is yet to be determined, the genomic data, showing the rapid displacement of other lineages, suggest that this lineage may be associated with increased transmissibility.

SARS-CoV-2 shifting transmission dynamics and hidden reservoirs limited the efficacy of public health interventions in Italy

We investigated SARS-CoV-2 transmission dynamics in Italy, one of the countries hit hardest by the pandemic, using phylodynamic analysis of viral genetic and epidemiological data. We observed the co-circulation of at least 13 different SARS-CoV-2 lineages over time, which were linked to multiple importations and characterized by large transmission clusters concomitant with a high number of infections. Subsequent implementation of a three-phase nationwide lockdown strategy greatly reduced infection numbers and hospitalizations. Yet we present evidence of sustained viral spread among sporadic clusters acting as "hidden reservoirs" during summer 2020. Mathematical modelling shows that increased mobility among residents eventually catalyzed the coalescence of such clusters, thus driving up the number of infections and initiating a new epidemic wave. Our results suggest that the efficacy of public health interventions is, ultimately, limited by the size and structure of epidemic reservoirs, which may warrant prioritization during vaccine deployment.

Major new lineages of SARS-CoV-2 emerge and spread in South Africa during lockdown.

In March 2020, the first cases of COVID-19 were reported in South Africa. The epidemic spread very fast despite an early and extreme lockdown and infected over 600,000 people, by far the highest number of infections in an African country. To rapidly understand the spread of SARS-CoV-2 in South Africa, we formed the Network for Genomics Surveillance in South Africa (NGS-SA). Here, we analyze 1,365 high quality whole genomes and identify 16 new lineages of SARS-CoV-2. Most of these unique lineages have mutations that are found hardly anywhere else in the world. We also show that three lineages spread widely in South Africa and contributed to [~]42% of all of the infections in the country. This included the first identified C lineage of SARS-CoV-2, C.1, which has 16 mutations as compared with the original Wuhan sequence. C.1 was the most geographically widespread lineage in South Africa, causing infections in multiple provinces and in all of the eleven districts in KwaZulu-Natal (KZN), the most sampled province. Interestingly, the first South-African specific lineage, B.1.106, which was identified in April 2020, became extinct after nosocomial outbreaks were controlled. Our findings show that genomic surveillance can be implemented on a large scale in Africa to identify and control the spread of SARS-CoV-2.

Development of Pediatric Orodispersible Tablets Based on Efavirenz as a New Therapeutic Alternative.

BACKGROUND: Efavirenz is the most used medication in the treatment of Acquired Immunodeficiency Syndrome (AIDS). The limited number of pediatric antiretroviral formulations approved by regulatory agencies is the most significant obstacle to adequate and efficient pharmacotherapy for this group of patients. The efavirenz has excellent therapeutic potential, but has low aqueous solubility/bioavailability. METHODS: To minimize these limitations, multicomponent systems with ß-cyclodextrin and polyvinylpyrrolidone K-30 were obtained. Due to the limited number of pediatric antiretroviral formulations, the development of a pediatric orodispersible tablet is an alternative that is thought easy to administer, since it disintegrates rapidly in the oral cavity. The multicomponent systems were obtained by the method of kneading and characterized by solubility test, X-ray diffraction, differential scanning calorimetry and infrared absorption spectroscopy by Fourier transform. The orodispersible tablets were prepared by direct compression. The quality control of hardness, friability, disintegration, and dissolution was performed. The influence of the components of the formulation on the characteristics of the tablets was evaluated through a 22 factorial design added with three central points, to compare the effect of the dependent variables on the responses. RESULTS: An increase in drug solubility was observed, with a decrease in crystallinity. Besides that, an excellent dissolution profile presented with more than 83% of the drug's content dissolved in less than 15 minutes. Satisfactory disintegration time and friability were observed. CONCLUSION: It was observed that reduced concentrations of mannitol decreased the hardness and disintegration time of the formulations. The orodispersible tablet composed of efavirenz: ß- cyclodextrin: polyvinylpyrrolidone, favors greater absorption and bioavailability. It has several advantages for pediatric patients, as the dosage form disintegrates quickly in the mouth and does not require water for administration, thereby improving patient compliance with the treatment.

Potential impact of individual exposure histories to endemic human coronaviruses on age-dependence in severity of COVID-19

Cross-reactivity to SARS-CoV-2 from previous exposure to endemic coronaviruses (eHCoV) is gaining increasing attention as a possible driver of both protection against infection and severity of COVID-19 disease. Here, we use a stochastic individual-based model to show that heterogeneities in individual exposure histories to endemic coronaviruses are able to explain observed age patterns of hospitalisation due to COVID-19 in EU/EEA countries and the UK, provided there is (i) a decrease in cross-protection to SARS-CoV-2 with the number of eHCoV exposures and (ii) an increase in potential disease severity with number of eHCoV exposures or as a result of immune senescence. We also show that variation in health care capacity and testing efforts is compatible with country-specific differences in hospitalisation rates. Our findings call for further research on the role of cross-reactivity to endemic coronaviruses and highlight potential challenges arising from heterogeneous health care capacity and testing.

The impact of host resistance on cumulative mortality and the threshold of herd immunity for SARS-CoV-2

It is widely believed that the herd immunity threshold (HIT) required to prevent a resurgence of SARS-CoV-2 is in excess of 50% for any epidemiological setting. Here, we demonstrate that HIT may be greatly reduced if a fraction of the population is unable to transmit the virus due to innate resistance or cross-protection from exposure to seasonal coronaviruses. The drop in HIT is proportional to the fraction of the population resistant only when that fraction is effectively segregated from the general population; however, when mixing is random, the drop in HIT is more precipitous. Significant reductions in expected mortality can also be observed in settings where a fraction of the population is resistant to infection. These results help to explain the large degree of regional variation observed in seroprevalence and cumulative deaths and suggest that sufficient herd-immunity may already be in place to substantially mitigate a potential second wave.