Acute macular neuroretinopathy (AMN) commonly affects young to middle-aged females and is considered a relatively rare retinal disease, and the etiology is complex. Advances in multimodal imaging provide a better characterization of retinal disorders and have helped identify that one of the etiologies of AMN is microvascular in nature. This case is clinically relevant as it adds to the literature that the pathophysiology of AMN is vascular-driven. Our case is a 24-year-old Black female with no past medical history, the only medication she was taking was an oral contraceptive pill, who presented to the emergency room with a 24-hour history of left central field vision loss and endorsed a recent upper respiratory tract infection preceding the acute vision loss. It was subsequently found on admission that the patient tested positive for and had a SARS-CoV-2 infection. A retina specialist performed optical coherence tomography (OCT), which showed disruption in the outer segment junction, including the ellipsoid zone and outer plexiform. The use of multimodal imaging like OCT helped confirm AMN; therefore, prompt examination by ophthalmology is critical to confirm a correct diagnosis. This patient’s vision improved and remained stable five months later. This case demonstrates that, like other viruses, SARS-CoV-2 has the potential to cause retinal disease complications such as AMN. These findings reinforce and add to the current literature that SARS-CoV-2 can cause multiple-organ system dysfunction at a vascular level through immune-mediated pathways. Acute macular neuroretinopathy (AMN) is a rare macular disorder that was discovered in the Netherlands in 1975 by Dr. Bos and Dr. Deutman. These physicians noted this neuroepitheliopathy affecting the retinal layers of the macula in four women, aged 24 to 35 years, who were all on oral contraceptives [The primary AMN symptoms are paracentral scotomas, or blind spots, in an otherwise normal visual field. Other symptoms that can arise include acute loss of vision, blurry vision, floaters, and metamorphopsia ,4. The eRecent literature has illustrated a rise in AMN since the start of the coronavirus disease 2019 (COVID-19) pandemic in 2020, caused by SARS-CoV-2. A disease that was known to be rare, where providers saw roughly less than one case of AMN per year, suddenly was seen more often; providers and researchers began observing a relationship between increased AMN incidence and SARS-CoV-2 infection and vaccination. A case series completed in 2022 included 14 cases of patients diagnosed with AMN following recent SARS-CoV-2 infection or vaccination, further supporting the theory of the possible inflammatory etiology of the virus or vaccines triggering a thromboembolic event or vascular cause, leading to ischemia to the deep retinal capillary plexus . This caA 24-year-old Black female with no significant past medical history arrived at the emergency room with a two-day history of left monocular painful vision loss. She reported running fevers of unknown temperature, malaise, and sore throat three days prior with a two-day history of a clear productive cough. The day before coming to the ER, she awoke from a nap and noted a frontal headache (no prior history of migraines) and left central vision loss (darkened vision in the center) along with retrobulbar pain, which progressed later that evening to decreased vision in both eyes, with left eye worse than right. That night she took over-the-counter Tylenol and Zicam without any relief of symptoms. The following day, her vision did not improve, and she still had pain with extraocular movements, so she went to the urgent care center that directed her to the ER for concern of potential optic neuritis. Her only home medication was an oral contraceptive pill, ethinyl estradiol-norethindrone (Tarina Fe 1/20), once a day for the last six years. She endorsed diarrhea (three to four bowel movements a day) that began on the day of admission and lasted roughly four days. Imodium was given as needed during her hospital stay. She denied redness, tearing, or discharge of the left eye. She denied any sensory deficits, previous vision loss, or a family history of multiple sclerosis. Visual acuity on admission in the left eye (OS) was 20/70 and 20/20 in the right eye (OD).A battery of tests was obtained on admission, and relevant findings included a comprehensive metabolic panel (CMP) , complete blood count (CBC) with differential (leukopenia at 3.3 x 103/μL with a low absolute neutrophil count of 1800 per microliter and with elevated monocytes at 13.5%), D-dimer within normal limits at <150 ng/dL, and a C-reactive protein (CRP) . Respiratory multiplex “BioFire” polymerase chain reaction (PCR) was positive for the SARS-CoV-2 virus without other concomitant infections . Intraocular pressure  was within the normal range of 10 to 21 millimeters of mercury (mmHg). On a fundoscopic exam, there was no optic disc edema or relative afferent pupillary defect (RAPD). Macula was flat and sharp with good reflex OD. There was, however, a petaloid appearance in the left macula with mild reflex suggesting a macular process. Extraocular muscles were intact in both eyes (OU), and admission pain with lateral gaze deviation of her left eye improved , pupils were equally round and reactive to light and accommodation, and the visual acuity exam with Snellen chart showed 20/20 vision in the right eye (OD) and 20/50 in the left eye (OS). Vision remained stable during the four-day hospital course.The patient was started on aspirin 81 mg once a day with famotidine 40 mg once a day for stomach protection, which was discontinued one month after discharge. On the day of discharge, the patient started a seven-day steroid taper . Diflucan 100 mg for three days was also given to start after steroid taper to prevent thrush. The patient was referred to a retina specialist for further evaluation with optical coherence tomography (OCT) to view the retina and optic nerve, which showed disorganization of the outer retina in the parafoveal region, consistent with her visual field defects and the wedge-shaped lesions seen on the exam, supporting a diagnosis of AMN in the left eye  receptor, which is found throughout the body, in every central organ system . ACE-2 rOur patient did have lymphocytopenia, a mildly elevated CRP, and elevated monocytes, all hallmark signs of an enhanced inflammatory cytokine storm. The pro-inflammatory mediators produced during a cytokine storm can cause a systemic activation of the coagulation pathways, which can lead to microthrombi, capillary obstruction, vascular leakage, cellular dysfunction, and subsequent tissue ischemia. The hypothesized mechanism of AMN includes a hyperinflammatory chain reaction leading to a microvascular thrombotic event and ischemia to the deep retinal capillary plexus. Thus, endothelial cell dysfunction and microvascular angiopathy after SARS-CoV-2 play a role in causing damage to the inner structures of the eye . One stuOCT is a non-invasive imaging tool that allows for precision diagnosis. It enables analysis and mapping of the retinal microvasculature by producing high-resolution cross-section images . CharactSex hormones are proven to affect the retina as there are estrogen and progesterone receptors located on the cornea, lens, retina, the central part of the retina known as the macula, and multiple other ocular tissues ,27. FurtOverall, this case demonstrates that AMN is associated with SARS-CoV-2 infections. The proposed pathophysiology is a result of an inflammatory reaction leading to ischemia in the deep retinal capillary plexus. Furthermore, the spike protein has the capability to attach to the ACE-2 receptors of the retinal ganglion cell layer, inner plexiform layer, inner nuclear layer, and photoreceptors coupled with mitochondrial dysfunction. This case highlights the fact that SARS-CoV-2 is a vascular illness that can cause multi-organ injury, including ocular damage. Lastly, research studies would be helpful to confirm the association between AMN and SARS-CoV-2 and to help better understand treatment options for this etiopathogenesis of AMN. This study demonstrates the importance of prompt ophthalmology evaluation and the use of OCT to obtain an accurate diagnosis.This case of a 24-year-old female with no prior medical history, other than long-term oral contraceptive use, focuses on a patient who was diagnosed with a rare, acquired retinal disorder known as AMN. AMN in this patient was characterized by a left paracentral visual field deficit and a petaloid or wedge-shaped lesion noted in the macula. Antecedent to this event, the patient had an upper-respiratory-like illness and was found to be positive for SARS-CoV-2 infection. This case adds to the literature because it demonstrates the vascular pathophysiology behind SARS-CoV-2 and its ability to cause retinal vascular disease. Furthermore, it notes the importance of having ophthalmology conduct a thorough exam, including the use of multi-modal imaging such as OCT, as this can confirm the exact diagnosis. This patient only has minor visual changes and overall had resolution of her scotoma. AMN currently has no gold standard treatment, but understanding that this might be a vascular and/or immune-driven process might help with future research for treatment options that can aid in reperfusion.


The rapid and extensive transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented global health emergency, affecting millions of people and causing an immense socioeconomic impact. The identification of SARS-CoV-2 phosphorylation sites plays an important role in unraveling the complex molecular mechanisms behind infection and the resulting alterations in host cell pathways. However, currently available prediction tools for identifying these sites lack accuracy and efficiency.In this study, we presented a comprehensive biological function analysis of SARS-CoV-2 infection in a clonal human lung epithelial A549 cell, revealing dramatic changes in protein phosphorylation pathways in host cells. Moreover, a novel deep learning predictor called PSPred-ALE is specifically designed to identify phosphorylation sites in human host cells that are infected with SARS-CoV-2. The key idea of PSPred-ALE lies in the use of a self-adaptive learning embedding algorithm, which enables the automatic extraction of context sequential features from protein sequences. In addition, the tool uses multihead attention module that enables the capturing of global information, further improving the accuracy of predictions. Comparative analysis of features demonstrated that the self-adaptive learning embedding features are superior to hand-crafted statistical features in capturing discriminative sequence information. Benchmarking comparison shows that PSPred-ALE outperforms the state-of-the-art prediction tools and achieves robust performance. Therefore, the proposed model can effectively identify phosphorylation sites assistant the biomedical scientists in understanding the mechanism of phosphorylation in SARS-CoV-2 infection.https://github.com/jiaoshihu/PSPred-ALE and Zenodo (https://doi.org/10.5281/zenodo.8330277).PSPred-ALE is available at  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped positive-sense RNA virus that is closely related to SARS-CoV and several SARS-related coronaviruses . PhosphoAlthough wet experiments such as mass spectrometry can identify phosphorylation modification sites in high throughput, most laboratories do not have the necessary instruments and knowledge to use this technique  SARS-CoV-2 phosphorylation modification site predictors and handcrafted feature-based methods. This reveals that the features learned by the adaptive learning embedding mechanism are more effective and potentially than that of handcrafted feature engineering. Moreover, we also provide a 2D visualization comparison between different feature representation spaces to illustrate their efficacy in separating positive and negative samples. These experiments mentioned above also demonstrate the robustness and generalization of PSPred-ALE. We anticipate that this model will promote the exploration of new phosphorylation modification sites in SARS-CoV-2 infection and the understanding of the related pathogenesis and therapeutic strategies.https://www.ncbi.nlm.nih.gov/geo). The dataset contains independent biological triplicates of transformed lung alveolar (human A549) cells infected with SARS-CoV-2  for 2/6/12/24 h. Differentially expressed genes (DEGs) were analyzed by the R/limma package. To obtain significant DEGs, |LogFC > 0.1| and P-value of .01 were set as the thresholds. Pathway enrichment and analysis of biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed by the R/clusterProfiler package based on the two databases of the KEGG and Gene Ontology (GO). P < .05 and enriched gene numbers (count) ≥2 were considered for the edges. Finally, the heatmap was used to show the results of the enrichment analysis. According to the results of GO analysis, experiments are differentiated into two groups (the high expression group and the low expression group). Then the gene set enrichment analysis (GSEA)  for bioinformation analysis were downloaded from the GEO databases , sensitivity (SE), specificity (SP), area under the receiver operating characteristic curve (AUC), and Matthew's correlation coefficient (MCC). Detailed descriptions and calculation formulas for these metrics are presented in the We performed principal component analysis (PCA) on the mRNA dataset to reduce the dimensionality of the data and visualize sample differences between infected and uninfected groups. The PCA showed that the eigenvalues of the two first principal components represented 92.49% of the total variance  of the observations . Figure et al. by rebuilding the models. Thus, all compared models are compared fairly based on the same dataset with a sequence length of 33. The performance results of these compared predictors are summarized in To evaluate the proposed PSPred-ALE, we compared its performance with four SOTA prediction tools, including DeepPSP, MusiteDeep2017, MusiteDeep2020, and DeepIPs. The performance metrics of MusiteDeep2017, MusiteDeep2020 and DeepPSP were obtained by Lv As evidenced by To accurately identify phosphorylation sites, it is important to consider the bias of amino acids specific to their positions relative to the phosphorylation site. This requires determining the optimal window for flanking sequences around phosphorylation sites. On the other hand, the performance of the predictive model is strongly related to the input sequence length. We analyzed the impact of window size ψ on the predictive performance using the training dataset. The scope of w ranged from 5 to 33, with an increment of 2 amino acids. All compared models were performed and evaluated on the training dataset, with a 5-fold cross validation approach. As we can see from To gain a more intuitive understanding of the effectiveness of the adaptive learning embedding features, we further utilized them to train traditional machine learning models. We output the learned representation matrix before the fully connected layer and flatten for each sample. Then, these features were input to the classifiers to obtain corresponding models. The results metrics are also presented in To provide an intuitive demonstration of the effectiveness of PSPred-ALE, we reduced the feature space to a 2D space using principal component analysis (PCA)  and unifThe identification of SARS-CoV-2 phosphorylation modification sites is a significant endeavor that can facilitate the development of related new drugs and treatment strategies, which indirectly contribute to global health care. According to the results of the bioinformatics analysis, it is clear that protein phosphorylation events are significantly altered upon cellular infection with SARS-CoV-2. However, the current lack of machine learning tools specifically designed for identifying these modification sites poses a challenge in this field. In this work, we developed a novel deep learning predictor named PSPred-ALE for identifying SARS-CoV-2 phosphorylation modification sites. The framework utilizes only the protein primary sequence for prediction. In particular, we use an adaptive learning embedding algorithm to generate better protein sequence representations, which can overcome the inefficiencies of traditional computational methods that rely on handcrafted feature engineering. The experimental results demonstrate that our model is capable of adaptively extracting high-quality and discriminative features from different class examples, resulting in a significant improvement in prediction performance. The comparative experiments show that PSPred-ALE achieves superior performance on most evaluation metrics when compared to existing methods, thereby providing further evidence that protein sequences themselves contain sufficient information to predict SARS-CoV-2 phosphorylation modification sites. To facilitate use by the relevant research community, we have made the source code for implementing PSPred-ALE publicly available. Due to the current lack of accurate models for predicting phosphorylation modification sites of SARS-CoV-2, our study presents a comprehensive methodology that can serve as a foundation for future research in this field. We expect that PSPred-ALE will be a valuable tool to complement wet lab experiments in identifying phosphorylation modification sites of SARS-CoV-2 infection, and its application can help reveal relevant biological functional mechanisms and perform numerous sequence-based analyses.btad627_Supplementary_DataClick here for additional data file.


Vaccines have reduced severe disease and death from Coronavirus Disease 2019 (COVID-19). However, with evidence of waning efficacy coupled with continued evolution of the virus, health programmes need to evaluate the requirement for regular booster doses, considering their impact and cost-effectiveness in the face of ongoing transmission and substantial infection-induced immunity.We developed a combined immunological-transmission model parameterised with data on transmissibility, severity, and vaccine effectiveness. We simulated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission and vaccine rollout in characteristic global settings with different population age-structures, contact patterns, health system capacities, prior transmission, and vaccine uptake. We quantified the impact of future vaccine booster dose strategies with both ancestral and variant-adapted vaccine products, while considering the potential future emergence of new variants with modified transmission, immune escape, and severity properties. We found that regular boosting of the oldest age group (75+) is an efficient strategy, although large numbers of hospitalisations and deaths could be averted by extending vaccination to younger age groups. In countries with low vaccine coverage and high infection-derived immunity, boosting older at-risk groups was more effective than continuing primary vaccination into younger ages in our model. Our study is limited by uncertainty in key parameters, including the long-term durability of vaccine and infection-induced immunity as well as uncertainty in the future evolution of the virus.Our modelling suggests that regular boosting of the high-risk population remains an important tool to reduce morbidity and mortality from current and future SARS-CoV-2 variants. Our results suggest that focusing vaccination in the highest-risk cohorts will be the most efficient (and hence cost-effective) strategy to reduce morbidity and mortality. In a modelling study, Alexandra Hogan and colleagues investigate long term vaccination strategies to mitigate the impact of SARS-CoV-2 transmission. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus causing Coronavirus Disease 2019 (COVID-19), is now endemic globally.Vaccination remains important to reduce hospitalisations and deaths.Health authorities need to consider how frequently booster doses will be required and in which age groups.They also need to know the additional value of switching to vaccines that have been adapted to match more recently circulating variants of concern.We developed a mathematical model that captures the continued circulation and evolution of the SARS-CoV-2 virus in the presence of widespread infection-induced immunity from past exposure as well as vaccine-induced immunity from primary vaccination campaigns in 2021/2022.We used the model to explore different strategies for continued vaccination including the age group targeted, the frequency of boosting, and whether the vaccine was adapted to match more recent variants.In both high-income and low-middle-income settings, regardless of whether there was a high level of transmission in 2020/21 or a zero-COVID policy, we found that the most cost-effective vaccination strategy was to boost those at highest risk.We found that the current variant-adapted vaccines could avert nearly twice as many hospitalisations and deaths compared to the ancestral vaccines, and that updating these vaccines each year—as is done for seasonal influenza—could avert a further 30% of hospitalisations and deaths.Continued booster vaccinations will remain important to reduce both hospitalisations and deaths but should be targeted towards the highest risk groups.The estimates provided here can help to inform discussions around value for money by comparing the cost-effectiveness of COVID-19 vaccination to other health programmes.The precise values are limited by uncertainty as to whether the virus will continue to evolve, whether any new variants may emerge, and the additional protection provided by further booster doses given the widespread exposure of the population to infection. The rapid development and delivery of vaccines to protect against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and Coronavirus Disease 2019 (COVID-19) dramatically altered the course of the pandemic, saving an estimated 19.8 million lives in the first year of vaccination alone –12.Many countries are continuing to evaluate how best to schedule regular boosting to protect against ongoing endemic circulation of the virus as well as against future epidemic waves with new variants. This is reflected in the World Health Organization (WHO) roadmap which, in the most recent update (March 2023), recommended different vaccination schedules for high, medium, and low priority use groups, with boosting restricted to the highest risk group  . The benThroughout the COVID-19 pandemic, mathematical and computational modelling has been a key component of longer-term planning and has been widely used to inform decisions on future vaccine strategies . A numbeThe aim of our study was to estimate the infections, hospitalisations, and deaths averted at the population level of a range of future COVID-19 vaccination strategies compared to a baseline of no further boosting. In contrast to other transmission modelling studies, we developed a transmission model that explicitly incorporates hybrid immunity (immunity induced by both infection and vaccines), in order to capture the interactions between past exposure and vaccination. We did this by embedding an existing within-host model of underlying immunity dynamics and protection against infection and severe disease (similar to that presented in Khoury and colleagues ), which The immunological model is as described in Hogan and colleagues . BrieflyWe use the same approach to capture infection-induced immunity and its interaction with vaccine-induced immunity, where each infection is assumed to generate a boost to IL of 1, i.e., equivalent to that measured in convalescents . In our We assume that following the emergence of a variant, the infection-induced IL developed through exposure to previous variants is reduced by the VFR in the same way that vaccine-induced protection is reduced. However, subsequent infections with the new variant are assumed to match and therefore are not reduced by the VFR. The degree of matched protection is set to capture strain-specific protection against infection without explicitly modelling each variant see .We capture the additional benefit of variant-adapted vaccines by increasing the immunogenicity generated upon vaccination (so as to reduce the impact of the VFR once variant-adapted vaccines are introduced). Khoury and colleagues estimated a 1.61-fold  relative neutralization titre for variant-adapted compared to ancestral vaccines based on the vaccines available at the end of 2022 . To captWe further explore the benefits of introducing a vaccine that is updated each year. To do so, we assume that the vaccine is matched to the variant that is circulating 1 year earlier. In the model, at the time point that a new dose is scheduled to be rolled out to the eligible population, we obtain the level of immune escape  at exactly 1 year earlier. We then multiply the vaccine-induced IL by this prior VFR to obtain an increase in the level of vaccine protection, and apply this process from dose 5 onwards, for the applicable scenarios. We refer to this schedule as “yearly updated” vaccination.https://mrc-ide.github.io/safir/) [To explore the population impact of vaccines, we developed a stochastic, individual-based model of SARS-CoV-2 transmission and vaccination (open-source at /safir/) . The maiVaccine-derived and infection-induced immune dynamics follow the immunological model described above. The model structure and epidemiology broadly mirror a previously published compartmental model, but these processes are instead implemented at the individual level . This alThe model structure also allows for a high degree of flexibility in dose and age-based vaccine prioritisation strategies. However, only 1 vaccine type can be modelled across the population; the results presented here are generated using the parameters from Hogan and colleagues  for the We consider 2 representative income settings—high-income countries (HICs) and lower-middle-income countries (LMICs)—and characterise each setting by contact patterns and demography ,37. In LWe further stratify the current epidemiological state of countries into 3 categories. “Category 1” represents countries that have experienced substantial past transmission  alongside a high level of access to vaccines. Many high- and upper-middle-income countries fall into this category—including countries in North America, Central/South America, the Middle East, and Europe. We created a representative epidemic profile for such countries, with a first wave occurring between March and May 2020, a second wave during the northern hemisphere winter of 2020/21, and transmission gradually increasing (interventions being relaxed) from mid-2021 Fig B in . This brIn all settings, we assume that the Omicron variant (BA.1 and BA.2 subtypes) gradually replaces Delta over 1 month from end-November 2021. This replacement impacts infection- and vaccine-induced immunity, transmissibility, and severity see . FollowiThe maximum population-level coverage for each income setting is based on the current WHO-reported coverage by income setting, which on 20 June 2023 reported 75% and 48% for the primary series and booster doses, respectively, in HIC settings, and 61% and 19%, respectively, in LMIC settings . For ourVaccine distribution strategies are implemented as follows. For Categories 1 and 3 (HICs), vaccines are administered at a constant rate of 5% of the population receiving 1 dose per week, starting 1 January 2021, assuming the mRNA-1273 vaccine for the primary 2-dose series and booster to those 10+. After the primary doses and first booster dose, we then either cease to administer any additional doses, or administer at the same pace, one of the following strategies with a variant-adapted vaccine: annual or 6-monthly booster doses to the 75+ population; annual or 6-monthly booster doses to the 60+ population; or annual booster doses to the 10+ population. We additionally consider the outcome if all doses from dose 4 onwards are the ancestral mRNA-1273 vaccine instead of a variant-adapted product.For Category 2 (LMICs), vaccines are administered at a maximum constant rate of 2% of the population immunised per week starting 1 April 2021. We assume the first 2 doses are the AZD1222 vaccine, the first booster (third dose) is with the mRNA-1273 vaccine, and subsequent doses are either with a variant-adapted vaccine (default) or the ancestral mRNA-1273 vaccine. We assume the primary series and first booster is administered to those aged 10+ according to the levels of uptake in Table D in For Category 2 (LMICs), we additionally model a separate scenario where we consider the relative impact of administering doses to vaccinate the younger working-age population with their primary series, versus diverting those doses to vaccinate the older population with a booster dose. We commence vaccination with the AZD1222 vaccine from April 2021, delivering the primary 2-dose series to the 40+ population. Once the target coverage is achieved, vaccination is paused until the delay between the second and booster doses (12 months) is complete. We then construct the following scenarios. For the first, we vaccinate the 40+ population with booster doses, beginning with the oldest (80+) age group. For the second, we take the same number of doses that would be required to give boosters to 40+ years, and instead deliver these doses to individuals younger than 40 years (2 doses per person). We construct these rollout scenarios such that the daily doses delivered is equivalent between scenarios. We compare these outputs with the scenario where no additional doses are delivered beyond 2 doses to the 40+ population.Setting characteristics and vaccine rollout assumptions are summarised in Table E in In addition to our baseline scenario in which we mimic the continued gradual antigenic drift within the Omicron clade that is captured in the main scenarios, we explored the impact of the emergence of a more antigenically distant dominant variant. This was chosen to reflect a “worst-case scenario” given the ongoing uncertainty in the future evolution of the virus. We assume that this new variant emerges and replaces the Omicron variant between 1 and 31 October 2023 and that thereafter this new variant continues to gradually drift (as for the Omicron variant) for the remainder of the simulation time period . We consider 3 possible new variants with the following characteristics: (1) severity increased to that of Delta (“increased severity”); (2) VFR relative to Delta increased to 10  and hence an additional 2-fold reduction relative to Omicron (an antigenic shift away from Omicron of a similar magnitude to the shift from Delta to Omicron); and (3) both severity increased to Delta and VFR increased to 10 (“increased severity and immune escape”). These 3 scenarios represent a range of plausible scenarios (since they are based on what has been observed with previous variants) and also generate a reasonable worst-case scenario.For each scenario, we repeat the model simulation across 50 random seeds, with a simulation population size of 1 million, and summarise the outputs by the median over these stochastic realisations. As the runs are based on a single model, we were unable to capture uncertainty in model structure. Furthermore, given the high degree of uncertainty in the future evolution of the virus and hence epidemic trajectories, we did not sample parameter uncertainty as these would give a sense of precision that is misleading. Instead, we evaluate the value of different vaccination strategies against a range of epidemic scenarios and address parameter uncertainty through sensitivity analyses. This is in line with the longer-term scenario methods used to support policy in situations of high uncertainty .We use these outputs to calculate the daily infections and hospitalisations from 1 February 2020 to 31 December 2024, as well as the total infections, hospitalisations, and deaths from 1 July 2022 to the end of the simulation window. Given the high degree of uncertainty in the future course of the pandemic, these numerical values should be interpreted as indicative guides rather than predicted estimates.The model outputs include infections, hospitalisations, and deaths over time alongside the number of vaccine doses that have been delivered. These outputs are used to estimate the number of vaccine doses required to avert X hospitalisations and deaths (where X is specified). We further estimate the incremental cost per hospitalisation and death averted of the vaccine strategies by calculating the total number of additional vaccine doses delivered, relative to the “3 doses only” (HIC) or “no additional doses” (LMIC) scenarios. These values are divided by the additional hospitalisations or deaths averted compared to the baseline scenario and multiplied by the assumed cost of each dose to obtain the incremental cost-effectiveness. We use 3 illustrative costs for the vaccine unit price  as this price is known to vary between countries and it not available in the public domain. While vaccine prices may differ between products, as this information is not publicly available, we assume no difference in price between the different vaccine types . These iAcross all scenarios, provided Omicron remains the dominant variant, our model simulations show a pattern of low-level continued circulation of SARS-CoV-2 from early-2023 onwards Figs . The preIn LMIC populations that have experienced substantial prior transmission and have low vaccine coverage, we project a similar pattern of endemic prevalence to HIC that have experienced substantial prior transmission due to the high levels of infection-induced immunity . HoweverWe additionally find that in LMIC settings with high prior transmission, prioritising booster vaccinations in the highest-risk population has a slightly greater public health impact, reducing hospitalisations and deaths by approximately 5% to 10%, compared to using these same doses to immunise younger age groups in an effort to reduce transmission Fig G in . We obseA completely new variant—simulated here as emerging in October 2023—that replaces the Omicron variant and its subtypes could rapidly result in a new epidemic wave, with the magnitude of this wave dependent on the properties of the variant . Under aOur results are sensitive to the assumed future level of virus drift Fig L in . In our Assuming continued circulation of the Omicron variant with a degree of virus drift, our simulations mimic continuation of the pattern of low levels of SARS-CoV-2 circulation from late 2022 onwards, with waves of infection, hospitalisation, and deaths driven by the continued evolution of the virus. Our results indicate that the greatest impact on this endemic prevalence can be achieved through regular boosting of the 10+ years population. However, the efficiency and cost-effectiveness of a boosting programme depends on the outcome measure; a strategy targeting only 75+ years averts the largest number of deaths and hospitalisations per dose, whereas a strategy targeting 10+ has the largest reduction in infections but is relatively inefficient in reducing severe outcomes. Similar patterns were obtained regardless of whether the country has previously experienced large waves of infection (and therefore has considerable infection-induced immunity) or whether the country had previously pursued a zero-COVID policy. However, in the zero-COVID policy setting we generally estimate higher numbers of hospitalisations and deaths compared to settings with both high prior transmission and vaccine coverage. The health burden is higher because vaccine-induced immunity alone is estimated to be less protective than the combination of vaccine- and infection-induced immunity (or hybrid immunity) ,50,51.Cost-effectiveness will likely be the metric driving future vaccine strategies. Our results suggest that across all settings considered, targeting the highest risk group is likely to be the most cost-effective strategy as judged by the cost of preventing either a hospitalisation or a death. With variant-adapted vaccines now routine in high-income settings and also being used in some lower-income settings, we estimate that switching to such a variant-adapted vaccine could reduce the cost of preventing a hospitalisation or a death by around half. Switching to a yearly updated variant-adapted vaccine—as indicated by recently released United States Food and Drug Administration (FDA) guidance for manufacturers —is projeIt should be noted that our estimates of variant-adapted vaccine effectiveness are based on immunogenicity studies and will therefore be sensitive to our fitted relationship between the underlying immunological mechanism and protection. The results will also be sensitive to our assumed continued level of antigenic drift. Furthermore, to capture the full cost-effectiveness further information is needed on variant-adapted and yearly updated vaccine effectiveness and the comparative unit price of new products. Importantly, we found that even continuing administration of the ancestral vaccine products (or existing variant-adapted vaccines where they have been introduced) is likely to reduce infections and severe outcomes in all settings. Furthermore, while estimating cost-effectiveness based on reductions in hospitalisations and deaths is relatively straightforward, such analyses do not account for the impact of high infection levels on long COVID incidence. COVID-19 hospitalisations and deaths in HICs have been concentrated in elderly populations; in contrast, long COVID is reported across a wider age range ,54. CompOur analysis is caveated by the uncertainty in the timing and impact of any new variant. By definition, any variant that can replace the currently circulating Omicron variant will either need to be more transmissible or exhibit significant immune escape. Given that antigenic mapping studies suggest that, to date, there is no clear pattern of antigenic drift –40, our Our study has several limitations. First, the timing and magnitude of waves of SARS-CoV-2, the dominant circulating variant during these waves (particularly over the past 12 months), the timing and stringency of non-pharmaceutical interventions, and the vaccination response, has varied widely between countries. Our results are therefore illustrative and more detailed country-specific modelling will likely be required. Second, our immunological model is necessarily a simplification of the complex underlying immune response. The quality and durability of this response will likely vary by age; however, there are currently insufficient data to explore the impact of age on waning efficacy or immune escape from booster doses due to the shorter follow-up in younger populations. Furthermore, the degree to which prior immunity protects against future variants  remaOur analyses illustrate the importance of continued booster doses as part of the wider public health response to ongoing endemic transmission of SARS-CoV-2 ,60. PrioS1 Textt over time. Fig C. Exemplar demographic patterns for each of the 2 income settings. Fig D. Impact of vaccination in a high-income country setting with substantial prior transmission and high vaccine access, assuming no additional variant emergence beyond Omicron . Fig E. Impact of vaccination in a lower-middle-income country setting with substantial prior transmission and moderate vaccine access, assuming no additional variant emergence beyond Omicron . Fig F. Impact of vaccination in a high-income country setting with minimal prior transmission and high vaccine access (Category 3). We assume mRNA-1273 is implemented for the first 2 doses and the first booster (dose 3) and a variant-adapted vaccine for subsequent booster doses. Fig G. Impact of vaccination in a low-middle-income country setting with substantial prior transmission and low vaccine access, where individuals 40+ years are initially targeted. Fig H. Impact of vaccination in a lower-middle-income country setting with substantial prior transmission and moderate vaccine access (Category 2), assuming WHO coverage targets. Fig I. Comparison of vaccine impact for different ancestral and variant-adapted vaccine scenarios for the lower-middle-income country setting with substantial prior transmission (Category 2). Fig J. Comparison of vaccine impact for different ancestral and variant-adapted vaccine scenarios for the high-income country setting with minimal prior transmission (Category 3). Fig K. Impact of vaccination in future scenarios where an additional variant of concern emerges from 1 October 2022, in a high-income setting with minimal prior transmission and high vaccine access (Category 3). We assume a variant-adapted vaccine is implemented from dose 4. Fig L. Sensitivity of the model output to the level of “drift” in a high-income setting with substantial prior transmission (Category 1). Fig M. Sensitivity of model results to assumptions regarding the level of protection afforded by infection in a high-income setting with substantial prior transmission (Category 1). Fig N. Sensitivity of model results to the decay rate of protection following recovery from SARS-CoV-2 infection in a high-income setting with substantial prior transmission (Category 1). Table A. Prior and posterior parameter estimates for the immunological model. Table B. Transmission model state transitions. Table C. Transmission parameter description and values. Table D. Default scenarios and assumptions for vaccine uptake within targeted age groups for each of the 2 income settings. Table E. Default scenarios and assumptions for the 3 broad modelled categories of country and epidemiological state. Table F. Total doses delivered, infections, hospitalisations, and deaths for each of the Category 1 and 3 settings, for a range of vaccine dose strategies and variant scenarios. We assume mRNA-1273 is implemented for the first 2 doses and the first booster (dose 3), and a variant-adapted vaccine for subsequent booster doses. Table G. Total doses delivered, infections, hospitalisations, and deaths for each of the Category 1 and 3 settings, for a range of vaccine dose strategies and variant scenarios. We assume no additional variant emergence beyond Omicron . Table H. Total doses delivered, infections, hospitalisations, and deaths for the Category 2 setting, for a range of vaccine dose strategies and variant scenarios. We assume AZD1222 is implemented for the first 2 doses, mRNA-1273 for the first booster (dose 3), and a variant-adapted vaccine for subsequent booster doses (doses 4 and 5). Table I. Total doses delivered, infections, hospitalisations, and deaths for the Category 2 setting, for a range of vaccine dose strategies and variant scenarios. We assume no additional variant emergence beyond Omicron . Table J. Total doses delivered, infections, hospitalisations, and deaths for the Category 2 setting, for a range of vaccine dose strategies and variant scenarios, assuming the WHO coverage target assumption. We assume AZD1222 is implemented for the first 2 doses, mRNA-1273 for the first booster (dose 3), and a variant-adapted vaccine for subsequent booster doses (doses 4 and 5). Table K. Total additional infections, hospitalisations, and deaths averted, and total additional vaccine doses delivered for the Category 1 and 3 settings. We assume no additional variant emergence beyond Omicron . Table L. Total additional infections, hospitalisations, and deaths averted, and total additional vaccine doses delivered for the Category 2 setting. We assume no additional variant emergence beyond Omicron . Table M. Total doses delivered, infections, hospitalisations, and deaths for the Category 2 setting, for a range of vaccine dose strategies, for the scenario where individuals 40+ years are initially targeted. We assume AZD1222 is administered for all doses. Table N. Total doses delivered, infections, hospitalisations, and deaths for different ancestral, variant-adapted, and yearly updated vaccine scenarios. Table O. Impact of vaccination in future scenarios where an additional variant of concern emerges from 1 October 2023.Fig A. Schematic diagram illustrating the COVID-19 vaccine allocation algorithm. Fig B. Modelled trajectories of the reproduction number R(DOCX)Click here for additional data file.


Background: The association between tobacco use and COVID-19 is controversial. During the early course of the pandemic, limited testing prevented studying a wide spectrum of clinical manifestations.Objective: To examine the potential causal association between tobacco use and COVID-19 during the second wave (1 October 2020–30 June 2021) of the pandemic in Stockholm, Sweden.Methods: A population-based cohort study was conducted in the Stockholm region of Sweden, with information on tobacco use collected prior to the pandemic. Adjusted relative risks (RR) of COVID-19 and 95% confidence intervals (CI) were calculated, contrasting current smokers and snus users to non-users of tobacco.Results: Compared with non-users of tobacco, current smokers had a lower risk of COVID-19  and of hospitalisation for the disease. Current snus users had a higher risk of COVID-19. Heavy smokers and snus users had longer hospital stays than non-users of tobacco.Conclusion: Tobacco use may have a different impact on the risk of being infected with SARS-CoV-2 and the risk of developing severe clinical manifestations. Further research is needed to determine the underlying mechanisms. COVID-19, caused by SARS-CoV-2  and the In fact, the reported reduced risk of COVID-19 among smokers may arise from information bias; confounding; and selection bias . FurtherA source of bias that has not received enough attention so far is the non-differential misclassification of exposure, which usually entails a bias towards the null . This masnus [A recent population-based cohort in Sweden based on cases occurring during the first wave of the pandemic found smokers to be at reduced risk of being diagnosed with COVID-19 after adjustment for several potential confounders, while the reverse was true concerning the use of the moist oral tobacco snus . The chasnus , 22. Alssnus , allowinsnus . Therefosnus .The temporal concentration of studies examining the association between tobacco use and COVID-19 during the initial wave represents a limitation given the potential bias due to testing opportunities, as a consequence of the prevailing testing policies. Moreover, analyses of adverse disease outcomes during the first wave may have been hampered by insufficient data. Therefore, this study aims to examine the association between tobacco use and COVID-19 and its clinical outcomes during the second wave of the pandemic in Sweden (1 October 2020–30 June 2021).snus use is regularly collected and classified into no or current use, the latter including also information on the amount habitually used. Using the national personal numbers assigned to each resident in Sweden, we linked this information to the regional inpatient and outpatient healthcare (VAL) database to obtain information on COVID-19 diagnoses among the study population. Demographic information was obtained through record-linkage with the register of the total population of the Stockholm region held by Statistics Sweden. Only individuals with complete information on tobacco use who could be linked to the regional records were considered for the analysis. Subjects with a confirmed diagnosis of COVID-19 up to 30 September 2020, and those residing in assisted elderly living facilities were excluded. The latter include individuals with high levels of disabilities, elevated mortality rates due to COVID-19 and other factors, and a likely low prevalence of tobacco use. After these exclusions, there were 418,975 individuals in the cohort. We used medical records of adult clients aged 23 or older who sought care at public dental clinics in the Stockholm region from October 2015 to January 2020. In Sweden, region-based public dental clinics, known as Folktandvården (FTV), provide preventive oral check-ups to all residents who choose to receive care at these facilities. Detailed information regarding the public dental care system in Stockholm region has been given in a prior publication . During snus use. Both current cigarette smoking and snus use were reported as dichotomous variables (yes/no) with additional categorical variables giving the average daily consumption (for current cigarette smoking: 10 cigarettes per day or less (CPD); more than 10 CPD; for snus use: less than 1/2 can per day; ½ can per day or more). Only individuals who reported the amount of tobacco use were included in the analyses. This meant that 2,108 individuals who reported current use but not its amount were excluded. Different categorisations of tobacco use into mutually exclusive categories, including dual users, were also used in the analysis.Current tobacco use was assessed separately for cigarette smoking and Information about past tobacco use was found to be incomplete due to inconsistent assessment. Therefore, former users were included in the category of current non-users.Information on COVID-19 diagnoses was accrued from healthcare registers from 1 October 2020 to 30 June 2021. Five outcome variables were considered: 1. any diagnosis of COVID-19, confirmed by a positive polymerase chain reaction (PCR) test reported to the regional surveillance unit; 2. hospital admission with a diagnosis of COVID-19, as recorded in the International Classification of Diseases 10th Revision (ICD-10) codes U071 and U072, either as the primary or a secondary cause of admission; 3. admission to an intensive care unit (ICU) due to a COVID-19 diagnosis, recorded with the ICD-10 codes mentioned above; 4. death by COVID-19, registered in the Swedish Cause of Death Registry based on the death certificate filled out by physicians. All deaths during the follow-up period with COVID-19 as the primary cause were included in the analysis; 5. the number of days of hospital stay among individuals admitted to a hospital with a diagnosis of COVID-19.Other variables included in the analysis as potential confounders were: sex; age (as continuous variable); country of birth ; achieved education ; occupational risk categorised as high, moderate, or low risk of SARS-CoV-2 infection based on the probability of disease transmission connected to a specific job title. For instance, healthcare workers were considered at high risk; teachers were considered at moderate risk; while clerks enabled to remote work were considered at low risk; household disposable income expressed in Swedish crowns per year; and cohabitation .snus) as mutually exclusive categories with current non-users of any tobacco. It should be noted that among these latter, some individuals may have been former tobacco users. Adjustments were made for putative confounders, namely, age, sex, country of birth, occupational risk, education, income, and cohabitation, selected using a direct acyclic graph as shown in a previous study [snus use.Relative risks (RR) and their corresponding 95% confidence intervals (CI) of the study outcomes according to tobacco use were estimated using generalised linear models (GLMs). We used a modified Poisson regression with robust standard errors . The stuus study . Adjustesnus use ascertained in different periods before the pandemic  in order to understand whether information bias due to non-differential exposure misclassification could have affected the results; b) by mutually adjusting the estimates for either tobacco product instead of excluding dual users; c) through analyses of mutually exclusive outcome events to assess whether the prognosis of COVID-19 was affected by tobacco use; d) through stratified analyses by time period with reference the roll out of the vaccination program .We conducted sensitivity analyses as follows: a) by using information on smoking and A negative binomial regression count model  was usedAll analyses were conducted using Stata version 17  and R version 4.1.2.snus users was 12.5%, and that of dual users was 1.2%. The cumulative incidence of COVID-19 diagnoses in the study period was 12.0% of hospital admissions 0.6%, of ICU 0.06%, and of death 0.05%. A total of 418,975 participants were included in the study. snus use  . Currentsnus use ; and wersnus users had a higher risk of being diagnosed with COVID-19, both among females  and males  compared to non-users of tobacco   . The sam04–1.60) .snus users   was revealed in the pre-vaccination period but not after the rollout of the vaccination program .Using mutually exclusive outcome events, we found that the risk of being diagnosed with COVID-19 that did not result in hospital admission, admission to ICU, or death was lower among current exclusive smokers  and dual tobacco users  compared to non-tobacco users . The opp10–1.16) . The est10–1.16) . The assinations . HoweverN = 229,838) in the Stockholm region during the corresponding study period. The cumulative incidence of COVID-19-related diagnoses, inpatient care, ICU admissions, and deaths in our cohort, 12.0%, 0.6%, 0.06%, 0.05%, respectively, closely mirrors that of the entire Stockholm region during the same study period, at 13.5%, 0.5%, 0.06%, and 0.04%, respectively. Current exclusive smoking was associated with a lower risk of COVID-19 infection and hospital admission after controlling for potential confounders, while snus use was associated with an increased risk of COVID-19 infection, in line with what was previously reported for the first wave of the pandemic in the same cohort [snus use is potentially causally associated to the risk of infection rather than to the risk of disease progression. Also, when admitted to a hospital, current smokers, particularly heavy smokers, had prolonged hospital stays compared to non-users of tobacco. This finding indicates that smoking, a known cause of impairment of the respiratory system, could lead to more severe clinical course of COVID-19 in patients requiring hospital admission.This large population-based cohort examined the association between tobacco use and COVID-19 risk and its clinical outcomes during the second wave of the pandemic in Sweden (1 October 2020–30 June 2021). The cumulative incidence of COVID-19 diagnoses in this study (12.05%) was higher than the incidence reported during the first wave of the pandemic (1.5%), but mortality was similar in the two periods (0.05%) [The association between cigarette smoking and the risk of COVID-19 has been assessed in several studies with mixed findings. Most studies that reported lower proportions of smokers among COVID-19 patients suffered from selection bias or bias introduced by limited testing opportunities during the first wave of the pandemic . AlthougSnus use was associated with a higher risk of COVID-19 infection in this study, as it was in an earlier study based on the same population [snus is primarily used in Sweden, and to a lesser extent in Finland and Norway, but banned by law across the rest of the European Union [snus in this study aligns with a parallel population-based study in Finland [snus users in our study was no longer present following the implementation of the COVID-19 vaccination campaign in Sweden. This finding underscores the crucial role of COVID-19 vaccination in mitigating the risk of severe outcomes among tobacco users.pulation . This sman Union  gives th Finland . In addisnus users, thus enabling further insights into the potential role of nicotine in the occurrence and prognosis of the COVID-19 disease.The main limitation of this study is the lack of information on the incidence of testing among tobacco users. In fact, a lower incidence of PCR tests among smokers tests could at least partly explain the negative association found in this and other studies. However, consistent findings during the two waves of the pandemic in Sweden, despite different testing strategies, reduce the likelihood of a potential bias due to testing opportunities. The inclusion of former tobacco users among the current non-users may have biased downward the association introducing the potential for misclassification bias. Also, data in our study comes from individuals who underwent health checks at public dental clinics, who may not provide a representative sample of the source population. Notwithstanding, this study has several strengths. First, unlike other studies enrolling clinical samples, this study is based on a population-based cohort with the assessment of tobacco use completely prospective regarding the individual outcomes. Therefore, this study is less likely to be affected by selection or collider bias. Second, confounding was minimised by adjusting for several potential confounders that were unavailable in previous studies, such as occupational risk. Third, the study included several sensitivity analyses to test the stability of the results. Finally, to the best of our knowledge, this study included the largest analysis of COVID-19 among snus users does not support the hypothesised protective effect of nicotine on the disease. While the smoker’s paradox sparks interest, it is crucial to contextualize such findings within the broader scope of individual health. Smoking has long been established as a leading cause of numerous serious health conditions. From a public health perspective, the overwhelming adverse health consequences of tobacco use can far outweigh any potential reduction of SARS-CoV-2 infection risk.Smokers may be at lower risk of infection with SARS-CoV-2 but at higher risk of severe clinical course of COVID-19. The higher risk for both infection and severe clinical course among


We show that by sweeping the voltage bias in a normal-hybrid-normal double junction, the pattern of electric currents in the normal leads spans three main regimes. From single-mode edge-current quantization at low bias, to double-mode edge-current oscillations at intermediate voltages and up to diffusive bulk currents at larger voltages. Observing such patterns by resolving the spatial distribution of the local current in the thin slab could provide additional evidence, besides the global conductance, on the physics of chiral topological superconductors.The chiral topological superconductor, which supports propagating nontrivial edge modes while maintaining a gapped bulk, can be realized hybridizing a quantum-anomalous-Hall thin slab with an ordinary  A recent proposal7 for the realization of this exotic phase suggests exploiting hybridized quantum-anomalous-Hall (QAH) insulator heterostructures, inducing superconductivity in the QAH chiral edge modes through proximity coupling with an s-wave superconductor. 3D topological insulators (TIs) like 10, which is larger than the typical energy scale of the room temperature11. In a thick slab geometry, these topological boundary modes are well-defined for top and bottom surfaces. However, when placed in an effective 2D thin film, quantum tunnelling couples the Dirac cones localized on opposite surfaces, opening a mass gap in the energy spectrum13. Magnetic ordering induced by doping with transition metals (like V or Cr) can give rise to a QAH state with quantized Hall conductance16.The chiral topological superconductor (TSC) is a topologically-nontrivial superconducting state which supports 1D chiral Majorana edge modes (CMEM) while maintaining a full pairing gap in the 2D bulkIn this work, we discuss the electric conductance and the current spatial distribution for the specific case of a QAH thin slab containing a central proximity-hybridised sector in the chiral TSC phase. The system is, in practice, a normal-hybrid-normal double junction as sketched in Fig. 1719. Magnetic doping breaks time-reversal symmetry, coupling the electrons to the magnetization through an exchange interaction 20. The topological state of a 2D system with broken time-reversal symmetry is characterized by the Chern invariant2, which for 21. The 22.The 2D minimal model for a full translational invariant TI thin film, which captures the low-energy physics dominated by the Dirac-cone shaped topological surface states (TSSs) around s-wave superconductor induces finite pairing amplitudes 7. The effective description of the superconducting system can be carried out through the Bogoliubov de Gennes (BdG) Hamiltonian, which in the basis 242. In presence of a finite pairing amplitude, the 6, where the doubling of the edge modes is due to the electron-hole degeneracy introduced by the choice of the wavefunction in Nambu space. Asymmetric pairing amplitudes on top and bottom surfaces are required to lift the degeneracy7, leading to a chiral TSC with unpaired CMEMs propagating over the boundaries. For this reason, our numerical results were obtained for fixed 25, interlayer pairing terms in Eq.  junction between normal (N) and proximitized (S) magnetic TIs, with the central sector grounded. The normal leads are held into a QAH phase31b in lead j to a quasiparticle of type a in lead i. Given a voltage drop i-th terminal and the grounded superconductor, the electric conductance in the normal sectors can be defined as 32. In terms of scattering amplitudes, the conductance can thus be written asWithin the Blonder-Tinkham-Klapwijk formalism, the electric current G computed in the normal-hybrid-normal double junction is shown in Fig. V. Here, the three different bias-dependent regimes can be clearly distinguished: a low-bias conductance plateau an intermediate-bias regime with large conductance oscillations a metallic-like behaviour at larger biases, with quasiparticle diffusive transport.In the low-bias regime, a single CMEM can be found within the surface gap of the 33. Oscillations around the plateau are due to finite-size coupling between edge states on opposite y sides34. With a higher bias, but still within the surface energy gap, the normal leads remain in the QAH phase, while a pair of chiral edge states with different wavenumbers can be found in the superconducting sector. The quasiparticle propagation through the proximitized TI is affected by the spatial interference produced by the phase difference acquired along the propagation length 29, resulting in an oscillatory conductance between The electric conductance 38. Experimentally, the local probing of currents is in principle possible with magnetic imaging techniques using miniaturized squids39.The above different regimes can be further characterized in terms of the current densities along the transverse section of the junction. Resolving the spatial distribution of currents in proximitized TI thin slabs can provide detailed information on the quasiparticle transport processes occurring in the junction. Conversely, conductance measurements alone have proven unable to provide an unambiguous signature of chiral TSCs in proximitized QAH film40eV.The longitudinal component of electric-current density isnormal leads of the NSN junction is displayed in Fig. y at x at which the measurement is conducted.The current distribution along the transverse section in the two 12, the current is well-localized along the y boundaries: the peaks in the current density profile correspond to the injected quasiparticles, localized on opposite sides and propagating in opposite directions. Apart from small finite-size (33, as evidenced by Figure A different situation is shown in Fig. Finally, Fig. 42, allowing the manipulation of the Dirac surface states without altering the chemical potential of the bulk crystals.A similar analysis of the transverse current density can also be carried out in the proximitized section of the TI thin film, computing the average value In conclusion, we characterized the electric quasiparticle transport through a NSN junction made by magnetic TI thin slabs, where the normal leads are kept into a QAH state while the proximitized sector realizes a


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, has been reported to infect multiple animal species besides humans. In this study, SARS-CoV-2 infection with two viral variants; alpha and delta in two separate infection waves among the large cats housed in the Pittsburgh Zoo and Aquarium during the 2021–2022 pandemic is described. In March 2021, all but one of the lions exhibited clinical signs consistent with SARS-CoV-2 infection coinciding with the infection of an animal keeper. Viral shedding was detected during the infection phase. In December 2022, during the second phase, SARS-CoV-2 infection occurred in tigers and lynx along with a likely reinfection of lions. In the infected animals exhibiting clinical signs, the signs lasted up to 6 weeks and viral shedding in feces was variable. Virus genome sequencing indicated that the alpha variant and the delta variant were responsible for the first and second waves of infection in the zoo animals, respectively, and the viruses were closely related to variants circulating in human populations at the time of infection. Panthera leo krugeri) housed together exhibited respiratory clinical signs with viral shedding in their feces in March of 2021 coinciding with infection of an animal keeper. During the second infection wave in December 2021, four Amur tigers  and a Canadian lynx (Lynx canadensis) showed clinical signs and tested positive for viral RNA in feces. In infected animals, viral shedding in feces was variable lasting up to 5 weeks and clinical signs were observed for up to 4 weeks. Despite mounting an antibody response to initial exposure, lions exhibited respiratory clinical signs during the second infection wave, but none shed the virus in their feces. The lions were positive for alpha variant (B.1.1.7 lineage) during the first wave and the tiger and lynx were positive for delta variant (AY.25.1. lineage) during the second wave. The viruses recovered from felids were closely related to variants circulating in human populations at the time of the infection. Cheetahs (Acinonyx jubatus) in the park did not show either the clinical signs or the antibody response.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in multiple animal species besides humans. The goal of this study was to report clinical signs, infection progression, virus detection and antibody response in a group of wild felids housed in adjacent but neighboring areas at the Pittsburgh Zoo. Initially, five African lions ( Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of the coronavirus disease 2019 (COVID-19), infection was first identified in late 2019 and is largely a disease of concern affecting human populations worldwide . SARS-CoWhile the predominance of infections are in humans, SARS-CoV-2 infections have been shown to affect several animal species ,9. FarmePanthera tigris jacksoni) at the Bronx Zoo, New York City, USA tested positive along with co-housed animals, but with low reported transmissibility [Panthera leo krugeri), leopards (Panthera uncia) and pumas (Puma concolor) [In zoological park settings, several studies have shown that members of the Felidae family, particularly lions, tigers and snow leopards, can become infected. In April 2020, a Malayan tiger (sibility . Lions aoncolor) ,20,21,22oncolor) . In this report we describe the infection of lions, tigers and lynx at the Pittsburgh Zoo and Aquarium, USA during two different waves of human infection with animals showing signs consistent with SARS-CoV-2 infection. Infected animals were monitored for clinical signs and viral shedding in feces over the course of infection and reinfection of lions with suspected transmission of virus from animal keepers. The goal of the study was to understand infection exposure, disease progression, and viral shedding in a group of exposed and re-exposed animals showing clinical signs consistent with SARS-CoV-2 infection at the zoo.Panthera leo krugeri) at the zoo were housed in an exhibit less than ~100 feet away, across the public walkway. Four Amur tigers  and 5 Canadian lynx (Lynx canadensis) are housed in immediate proximity to each other. The only access point for lynx is to walk through the tiger area. The same keepers care for the lions, lynx, and tigers. Cheetahs (Acinonyx jubatus) are also located in same vicinity . Two new cheetahs were added in June 2022. The leopards were housed indoors next to lions separated by a walkway.Six African lions  exhibiting clinical signs and illness from 31 March to 21 May 2021 on at least weekly basis. Four other lions were not sampled or tested except for a one-time collection on 4 April 2021. Fecal samples were collected from the ground after animals had defecated. Caregivers used personal protective equipment including glove changes while collecting feces. To ascribe feces to a particular animal, caregivers only collected samples when they observed animal defecating. During subsequent illness in the second infection phase, 53 fecal samples were collected from 6 lions in the cohort from 21 December 2021, until 25 January 2022, at least once weekly. Fecal samples were also collected from 4 tigers (58 specimens) and 5 lynxes (55 specimens) from 1 December 2021, until 23 January 2022, and from 12 December 2021, until 23 January 2022, respectively, at least once weekly . Sera coInitial testing was performed at the University of Illinois Veterinary Diagnostic Laboratory. After the initial positive result, testing was performed at the Pennsylvania Veterinary Laboratory (PVL) from additional collection time points. The RRT-PCR test results for each animal initially found to be positive were confirmed by the National Veterinary Services Laboratory (NVSL).RNA extraction and RRT-PCR were performed as previously described for animal samples ,17. BrieWhole-genome sequencing was performed at the NVSL as previously described ,23. Virahttps://gxy.io/GTN:T00168 (accessed on 3 August 2022)). Partial sequences of the spike protein genes from lynx samples were aligned to those from lion and tiger samples using the European Bioinformatics Institute (EBI) Clustal Omega platform ).For comparison, two human host COVID-19 viral samples from Pennsylvania were selected from GISAID . These human references were selected because collection dates (4 April and 6 December) were close to the dates of felid infections. Using the NextClade platform, phylogenetic trees of the human and big cat samples were generated to determine the relatedness of the viruses. Portions the SARS-CoV-2 spike protein gene from lynx samples were sequenced and Prokka was used to annotate partial sequences of the spike protein gene  was used to demonstrate presence of neutralizing antibodies. The assay was performed according to the manufacturer’s protocol and as previously described . BrieflyLions were the first group of animals to exhibit clinical signs including coughing and sneezing after a zookeeper tested positive for SARS-CoV-2 in March 2021. Feces from Lion 1 were tested after coughing was noticed, and the animal was positive for SARS-CoV-2 by RRT-PCR. Following confirmation of SARS-CoV-2, all lions living in the same enclosure were monitored for clinical signs and fecal viral shedding by PCR testing a. Lion 1In December 2021, tigers were the first Felidae group that showed clinical signs and were also SARS-CoV-2 positive upon testing of the feces with the RRT-PCR. Tigers showed clinical signs starting in December 2021 through January 2022 b. The fiIn the neighboring enclosure, coinciding with the sickness in tigers, the lions again became sick between December 2021 to January 2022 c. The liSARS-CoV-2 viral genomes recovered from Lion 5 (GISAID EPI_ISL_ 2928452) and Tiger 4 (GISAID EPI_ISL 8145733) were compared to SARS-CoV-2 variants circulating in human population in the region at the time of infection in the zoo animals using the NextClade resource. The virus recovered from lions in April 2021 belonged to PANGO lineage B.1.1.7, while the virus detected from human population at that time in the region was from a neighboring clade-B.1.429. Similarly, the virus detected from tiger belonged to the PANGO lineage AY.25.1, while the virus detected from the human population at that time in the region was identified as lineage AY.3.1 . The virWe attempted to sequence the SARS-CoV-2 genome from the fecal sample collected from a lynx sample (Lynx 1) that tested positive for SARS-CoV-2 virus by PCR. While we were unable to construct a consensus full viral genome sequence, we were able to sequence portions of the viral genome from the sample. Sequence alignment indicated a high similarity of the SARS-CoV-2 spike protein gene from the lynx sample with the spike protein gene of SARS-CoV-2 recovered from the lion and tiger in the zoological park .Serology to detect exposure to SARS-CoV-2 was conducted using C-pass neutralization assay. Sera available from two of the lions (Lions 1 and 5) collected in June 2019, prior to the COVID-19 pandemic, showed no reactivity to SARS-CoV-2. After the infection, all lions  showed strong antibody response, as measured by interpolated serum titers and with competitive inhibition titers using the surrogate virus neutralization assay . Lion 6 The SARS-CoV-2 pandemic has had an enormous impact on the human population, but infections in other mammals have also been reported including companion, farm, zoo, and wild animals. As of 7 July 2023, at least 32 animal species from 17 animal families belonging to 6 animal orders were reported positive for SARS-CoV-2 . While mLions at the Pittsburgh Zoo were the first species that showed clinical signs after an animal keeper was found infected with SARS-CoV-2. Strict biosecurity protocols including but not limited to caregiver isolation, and personal protective equipment use by the keepers were soon implemented to avoid infection of other susceptible animal species in nearby enclosures or living areas. Once the lions exhibited signs of a respiratory infection, and tested positive for SARS-CoV-2, other animals living in the same enclosure and neighboring enclosures were subsequently monitored for SARS-CoV-2 infections for several months. Viral RNA shedding was detected for a considerable period and clinical signs in some animals were apparent for at least a month after infection was initially diagnosed. The PCR detection and subsequent sequencing of viral RNA from the feces of infected animals also confirmed that the animals had contracted the virus. Viral sequences suggest that the viral variants detected from zoo animals were contemporaneous to variants circulating in humans during the two infection waves and likely indicates humans as the source of infection despite the clade differences. Interestingly, the zoological park was closed to the public during the first wave infection wave (March-May) but was open to the public during the second wave in December 2021. An Alpha variant of SARS-CoV-2 was recovered from the lions during the first wave infection (March to May 2021) in the park. During the second wave of infection starting in December 2021, the tigers, lynxes, and lions all showed signs of infection, and fecal samples from these animals tested by fecal PCR assay over the observed time. The viral shedding was detected in several tigers and one lynx but none of the lions were positive for fecal viral shedding during this second round of infection at the zoo. Also, during the second phase of infection, as animals started getting sick, none of the keepers showed signs of illness with SARS-CoV-2 infection. It is highly likely the source of infection during the second phase was from asymptomatic shedding from humans. During the second infection wave, the tigers were found to be infected first followed with lynx. The lions appeared to have been concurrently infected as they started exhibiting similar signs as during first wave but did not show any detectable viral shedding . HoweverIn the present study, it appeared that the cheetahs either did not get exposed to SARS CoV-2 or resisted infection. Similarly, although Amur leopards were closer to the lion enclosure, they also did not show any clinical signs. Lack of detectable neutralizing antibodies to SARS-CoV-2 in serum samples from cheetahs also corroborated absence of infection. Cheetahs are interesting animal group showing genetic monomorphism . CheetahIn most studies of SARS-CoV-2 infection in captive animals, evidence has pointed toward the caretakers as their primary source of transmission ,16,31 anIn the present study, infections were cleared in all felids without any observed mortality, and the two variants resulted in similar clinical signs. The lions, tigers, and lynx cleared the infection and recovered within 4 weeks of illness. The infected animals showed strong antibody response as determined by a surrogate virus neutralization assay. These findings were similar to other studies in tiger and lions ,16, wherIn summary, we report SARS-CoV-2 infection dynamics in the large felids from the Pittsburgh Zoo. The animals were monitored for clinical signs and fecal shedding of virus and viral variants and antibody response. The viral variants belonging to Alpha and Delta lineages were confirmed, contemporaneous to those variants circulating in the humans at the time of infection.


The bandpass response is achieved by combining the high-pass characteristic of the GGW and the low-pass behavior of the metallic pins, which act as impedance inverters. This simple structure together with the rigorous design technique allows for a reduction in the manufacturing complexity for the realization of high-performance filters. These capabilities are verified by designing a fifth-order GGW Chebyshev bandpass filter with a bandwidth BW = 3.7 GHz and return loss RL = 20 dB in the frequency range of the WR-75 standard, and by implementing it using computer numerical control (CNC) machining and three-dimensional (3D) printing techniques. Three prototypes have been manufactured: one using a computer numerical control (CNC) milling machine and two others by means of a stereolithography-based 3D printer and a photopolymer resin. One of the two resin-based prototypes has been metallized from a silver vacuum thermal evaporation deposition technique, while for the other a spray coating system has been used. The three prototypes have shown a good agreement between the measured and simulated S-parameters, with insertion losses better than IL = 1.2 dB. Reduced size and high-performance frequency responses with respect to other GGW bandpass filters were obtained. These wideband GGW filter prototypes could have a great potential for future emerging satellite communications systems.This paper presents for the first time a compact wideband bandpass filter in groove gap waveguide (GGW) technology. The structure is obtained by including metallic pins along the central part of the GGW bottom plate according to an  ILs), due to the dielectric substrate inserted in the structure; the small thickness of the substrate; and the dimensions and lower conductivity of the conductor type employed.Microwave filters are key devices in the communications payload of satellites . Among dFBWs) have been successfully implemented in ESIW technology in recent years to benefit from RW-like properties. The designs with FBW lower than 4% are based on coupled cavities, resonators, and inductive posts [FBWs higher than 10% are obtained by means of stepped impedances [Recently, many modified SIW technologies have been proposed to improve insertion losses by partially or fully removing the dielectric substrate. The structures with the fully removed substrate are named empty and dielectricless SIWs (ESIW and DSIW) ,9, whileve posts ,17,18,19pedances . NeverthQ) values and dispersive behaviors [Q-factor in low- and high-frequency applications . Recently, glide-symmetric holey electromagnetic bandgap (EBG) structures have also been proposed instead of periodic structures of metallic pins to perform artificial PMC sidewalls for cost-effective gap waveguide technology [Gap waveguide (GW) technology was proposed in  to enhanehaviors ,27. GGW chnology ,29.FBW lower than 4%. A wideband bandpass filter with FBW = 22.2% has also been proposed, introducing quasi-periodic transverse corrugations inside the GGW [Several bandpass filters have been successfully implemented in GGW technology ,43,44,45FBW > 10%) using a robust technique against manufacturing tolerance, thus allowing their low-cost implementation with an emerging three-dimensional (3D) printing technique. To achieve compactness and large FBWs, simple metallic pins have been employed, and a rigorous synthesis method based on stepped impedances has been applied to obtain the desired frequency response. The synthesis technique uses Chebyshev transfer functions and impedance inverters [10 mode) of the GGW. The proposed design technique and the behavior of the pins inserted in this wideband GGW filter differ from the pin-based bandpass filter solutions proposed in [FBWs). However, the technique proposed in this work [RL) and the bandwidth (BW) of the GGW bandpass filter. In [FBW > 10%). The slow wave solution presented in [Q-factors resonant elements. The structures that result from this design method are suitable not only for prototype manufacturing using a computer numerical control (CNC) machining technique, but they can also be fabricated with an emerging 3D printing technique [The aim of this paper is to design compact bandpass filters in GGW technology with large fractional bandwidths  and return loss RL = 20 dB is described in In this work, a compact fifth-order wideband Chebyshev bandpass filter in GGW technology is proposed for the first time. The design of this filter with a bandwidth W) of the GGW, which act as impedance inverters. The design steps of this bandpass filter according to the design specifications given in FBW = 36.4% and RL = 20 dB was selected.The structure of the proposed wideband Chebyshev bandpass filter based on GGW technology is depicted in p, which are separated from each other by a groove width W. Both periodic structures act as artificial perfect magnetic conductor (PMC) sidewalls in a certain frequency band and do not allow wave propagation along the x and y transverse directions between the gap h. The upper plate is situated at a height W of the groove area, it is possible to propagate a quasi-z-axis, inside the stopband of the periodic structure, thus avoiding leakage in the transverse plane between 8.3 GHz and 15.5 GHz. The dimensions W and b of the GGW given in As shown in ith-section , which meets the design specifications initially defined in eθ) that work as impedance inverters. In this way, the lower cut-off frequency ,LCf = 8.3 GHz of this filter is consequence of the high-pass behavior of the GGW, while the higher cut-off frequency ,HCf = 12 GHz is due to the low-pass characteristics of the metallic pins and GGW sections of electrical length (eθ). Return loss in the passband is less than RL = 20 dB, except at frequencies near to ,LCf, where it is better than 10 dB. This deterioration is due to the high dispersion of the quasi-TE10 mode close to the GGW cut-off frequency  and to the strong frequency dependence of the impedance inverters in this region [RLSB = 77 dB. Outside the frequency range (8 GHz–15 GHz), the two periodic structures of the GGW no longer behave as PMC sidewalls machining technique is typically used to manufacture waveguide components at mm/microwave-wave frequencies. This technique requires an operator to carry out the machining of the device . The 3D printing technique is an emerging technology that is easier to use than the traditional machining method, since it does not require monitoring of any manufacturing process once the printing has started. Furthermore, 3D printing has recently been applied to GGW and RW technologies to produce low cost and weight plastic components ,41,50. T2 area of the bottom part of the filter.Three GGW Chebyshev bandpass filter prototypes have been manufactured to make a comparison between both manufacturing techniques. One was made in an aluminum material  using a aR = 0.15 μm was measured.The CNC machining technique is a subtractive manufacturing method. This technique removes parts of a material bulk from rotary tools to achieve the desired device shape. The bulk of material can be plastic, wood, metal, etc. The two parts of the proposed GGW bandpass filter were CNC machined from a bulk of 6082 aluminum with a tolerance of ± 100 μm. The conductivity of 6082 aluminum given by the manufacturer is y-axis) of 50 μm and a resolution in the  plane of 25 μm from this resin. In the same way as for the previously CNC machined filter, sidewalls, and rectangular transitions (WR-75) have been added to the structure for the measurements. Two resin-based prototypes were made. The manufacturing process of the resin-based GGW bandpass filter finishes by coating their surfaces with a conductive layer. The surfaces of one resin-based prototype were metallized using a high-vacuum thermal evaporation deposition technique, while those of the second resin-based prototype were coated by means of a conductive paint spray system.The 3D printing technique is an additive method that consists of making the desired 3D device layer by layer by means of resins, plastic filaments, metallic powders, etc. This technology is more ethical than previous CNC machining, since it generates less material waste to produce devices. The two parts of the proposed GGW bandpass filter a were ret = 5 μm was deposited on the surfaces of the two parts of the resin-based GGW bandpass filter prototype  allows single-mode operation (TE10) in the WR-75 rectangular waveguide and GGW , the other filters developed are narrowband (FBW < 4%), since they were obtained from resonant cavities [RL = 15 dB and IL = 1.2 dB, the other two wideband GGW filters (RL and IL than most of the filters reported in RLSB) is similar to the highest values obtained with the narrowband filters. The three fabricated prototypes did not require any post-manufacturing tuning, since the sensitivity to the mechanical tolerance is lower than bandpass filters based on high-Q resonators. It should also be noted that the metallic pins along the groove area of the GGW, which are properly centered, distributed, and sized according to a stepped impedance technique, allow the implementing of compact wideband Chebyshev GGW filters. The designed fifth-order wideband GGW filter has a first-order normalized area of  filters ,43,44,45 filters ,41 that cavities ,34,35,36cavities ,40,41,42nt spray  that has filters , based oQ resonators. The three prototypes have exhibited high-performance responses and a reduced size compared to other GGW bandpass filters. These wideband GGW filter prototypes are expected to be useful in future emerging communications systems.A fifth-order wideband Chebyshev bandpass filter in groove gap waveguide (GGW) technology is proposed for the first time in this paper. This filter is conceived from metallic pins, acting as impedance inverters. The metallic pins are adequately centered, distributed, and sized along the groove area of the GGW, according to a Chebyshev stepped impedance technique. The bandpass response of this filter is obtained by combining the high-pass behavior of the GGW with the low-pass characteristics of the metallic pins. This design technique is simple and allows suitable implementations of high-performance wideband filters using a computer numerical control (CNC) machining or an emerging three-dimensional (3D) printing technique, thus providing low-cost and low-weight prototypes. Three prototypes of the proposed filter have been fabricated: one using a CNC milling machine and the other two by means of a stereolithography-based 3D printer and a photopolymer resin. One of the two resin-based prototypes has been metallized using an expensive high-vacuum silver evaporation technique, while the other has been coated by means of a cheap conductive paint spray system. The measured frequency responses of these prototypes have shown good agreement with EM simulations. The proposed filter is less sensitive to mechanical tolerance since it is not based on high-