Covid19-Sources

Scientists, unions and teachers concerned after data cut from Public Health England report ahead of shift on face masks

The Moderna booster shots appear to be effective at neutralizing at least two of the new variants. But their new study also revealed the current vaccines don't protect against variants for as long as we initially hoped.

New study by PHE shows for the first time that 2 doses of the COVID-19 vaccines are highly effective against the B.1.617.2 variant first identified in India.

Berufe in der Betreuung und Erziehung von Kindern waren von März bis Oktober 2020 am stärksten von Krankschreibungen im Zusammenhang mit Covid-19 betroffen. Eine Analyse der Arbeitsunfähigkeitsdaten der AOK-Mitglieder durch das Wissenschaftliche Institut der AOK (WIdO) zeigt, dass in diesem Zeitraum 2.672 je 100.000 Beschäftigte in dieser Berufs-gruppe krankheitsbedingt im Zusammenhang mit Covid-19 an ihrem Arbeitsplatz gefehlt ha-ben. Damit liegt deren Betroffenheit mehr als das 2,2-fache über dem Durchschnittswert von 1.183 Betroffenen je 100.000 AOK-versicherte Beschäftigte. Auch Gesundheitsberufe waren überdurchschnittlich oft im Zusammenhang mit Covid-19 arbeitsunfähig, stehen aber nicht mehr an der Spitze des Rankings. In einer früheren WIdO-Auswertung für die erste Phase der Pandemie von März bis Mai 2020 belegten Berufe in der Alten- und Krankenpflege die Spitzen-plätze, jetzt finden sie sich im Ranking auf Platz 7 und 8. Medizinische Fachangestellte sind nach der aktuellen Auswertung bezogen auf den Zeitraum von März bis Oktober 2020 noch stärker betroffen und stehen mit 2.469 Erkrankten je 100.000 Beschäftigten auf Platz 2 der Liste. „Beschäftigtengruppen, die in der Pandemie weiter am Arbeitsplatz präsent sein muss-ten und nicht ins Homeoffice gehen konnten, sind im bisherigen Verlauf der Pandemie stärker von Covid-19 betroffen. Dies sind insbesondere Berufe mit direktem Kontakt zu anderen Men-schen“, sagt Helmut Schröder, stellvertretender Geschäftsführer des WIdO.

Severe respiratory disease coronavirus-2 (SARS-CoV-2) causes the most devastating disease, COVID-19, of the recent century. One of the unsolved scientific questions around SARS-CoV-2 is the animal origin of this virus. Bats and pangolins are recognized as the most probable reservoir hosts that harbor the highly similar SARS-CoV-2 related viruses (SARSr-CoV-2). Here, we report the identification of a novel lineage of SARSr-CoVs, including RaTG15 and seven other viruses, from bats at the same location where we found RaTG13 in 2015. Although RaTG15 and the related viruses share 97.2% amino acid sequence identities to SARS-CoV-2 in the conserved ORF1b region, but only show less than 77.6% to all known SARSr-CoVs in genome level, thus forms a distinct lineage in the Sarbecovirus phylogenetic tree. We then found that RaTG15 receptor binding domain (RBD) can bind to and use Rhinolophus affinis bat ACE2 (RaACE2) but not human ACE2 as entry receptor, although which contains a short deletion and has different key residues responsible for ACE2 binding. In addition, we show that none of the known viruses in bat SARSr-CoV-2 lineage or the novel lineage discovered so far use human ACE2 efficiently compared to SARSr-CoV-2 from pangolin or some of the SARSr-CoV-1 lineage viruses. Collectively, we suggest more systematic and longitudinal work in bats to prevent future spillover events caused by SARSr-CoVs or to better understand the origin of SARS-CoV-2. ### Competing Interest Statement The authors have declared no competing interest.

The presentation of patients with COVID-19 and seasonal influenza requiring hospitalisation differs considerably. Severe acute respiratory syndrome coronavirus 2 is likely to have a higher potential for respiratory pathogenicity, leading to more respiratory complications and to higher mortality. In children, although the rate of hospitalisation for COVID-19 appears to be lower than for influenza, in-hospital mortality is higher; however, low patient numbers limit this finding. These findings highlight the importance of appropriate preventive measures for COVID-19, as well as the need for a specific vaccine and treatment.

Ist COVID-19 eine Gefäßerkrankung? Anfangs als reine Lungenkrankheit betrachtet, deuten immer mehr Studien darauf hin, dass eine COVID-19-Erkrankung die Blutgefäße schädigt und Gefäßerkrankungen wie Thrombosen, Lungenembolien oder Schlaganfälle begünstigt.

Mass vaccination offers a promising exit strategy for the COVID-19 pandemic. However, asvaccination progresses, demands to lift restrictions increase, despite most of the populationstill being susceptible. Using our age-stratified model and curated epidemiological andvaccination data, we quantified at which pace European countries can lift restrictions withoutoverwhelming their health-care systems. The analysed scenarios range from immediatelylifting restriction (accepting high mortality and morbidity) to reducing case numbers untiltest-trace-and-isolate programs facilitate control. In general, the age-dependent vaccinationroll-out implies a transient decrease in the average age of ICU patients and deaths by aboutseven years. The pace of vaccination determines the speed of lifting restrictions; all scenariosallow to steadily increase contacts starting in May 2021 and relax most restrictions byautumn 2021. Throughout summer, only moderate contact restrictions remain necessary.However, with the assumed vaccination protection, further waves among the unvaccinatedpopulation can only be avoided with high vaccine uptake (>90%).Strategies that maintainlow case numbers instead of high ones reduce infections and deaths by a factor eight andfour. Policies with low case numbers significantly benefit from vaccination, as the overallreduction in susceptibility will further diminish viral spread. Keeping case numbers low isthe safest long-term strategy because it i) considerably reduces mortality and morbidity,ii) offers better preparedness against escape virus variants, and iii) allows higher contactnumbers ("freedom") over the summer.

Washington – Das US-Biotech-Unternehmen Novavax hat den Zulassungsantrag für seinen Coronaimpfstoff verschoben. Geplant sei nun ein Antrag auf Zulassung bei... #COVID-19 #Coronaimpfstoff #Novavax

The on-going presence of either shortness of breath, anosmia, ageusia or fatigue as long-lasting symptoms even in non-hospitalised patients was observed at four and seven months post-infection and summarised as post-COVID syndrome (PCS). The continued assessment of patients with PCS will become a major task to define and mitigate the socioeconomic and medical long-term effects of COVID-19.

Man hat für nichts mehr Kraft. Kann kaum mehr aufstehen oder arbeiten gehen. Dazu: Muskelschmerzen, Nervenstörungen und Grippesymptome über Jahre und Jahrzehnte hinweg. All das können Hinweise auf ME/CFS sein.

Pre-pandemic issues such as severe budget cuts to local government and poor integration between the NHS and social care weakened England’s ability to respond to covid-19, the public spending watchdog has said.1 The National Audit Office (NAO) assessed the government’s response to the pandemic and also found many issues with transparency around personal protective equipment (PPE) contracts, provision of PPE for the social care sector when compared with the health sector, and inconsistencies between what providers and frontline staff were reporting in terms of having protective equipment. Responding to the findings, the NHS Confederation’s chief executive, Danny Mortimer, said, “This report re-emphasises the long term issues that severely weakened the foundations of health and care, which meant the country was not better prepared to deal with the pandemic and its fallout . . . “Importantly, this report also highlights the ever more pressing need to make sure reform of the social care sector is swift and far reaching. The two are sister services, and when one is hit hard, so is the …

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1–6. While pathological innate immune activation is well documented in severe disease1, the impact of autoantibodies on disease progression is less defined. Here, we used a high-throughput autoantibody (AAb) discovery technique called Rapid Extracellular Antigen Profiling (REAP)7 to screen a cohort of 194 SARS-CoV-2 infected COVID-19 patients and healthcare workers for autoantibodies against 2,770 extracellular and secreted proteins (the “exoproteome”). We found that COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition, and found that murine surrogates of these autoantibodies exacerbate disease severity in a mouse model of SARS-CoV-2 infection. Analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics and disease severity. In summary, these findings implicate a pathological role for exoproteome-directed autoantibodies in COVID-19 with diverse impacts on immune functionality and associations with clinical outcomes.

Die Covid-19-Pandemie und die damit einhergehenden Ausgangsbeschränkungen wirken sich deutlich auf die psychische Gesundheit aus. Das zeigt eine Studie der Donau-Universität Krems. Depressive Symptome und Schlafstörungen sind häufiger geworden.

In December 2020, two COVID-19 vaccines were granted Emergency Use Authorization(EUA)by FDA. Produced by Pfizer/BioNTech and Moderna, both vaccines use the same technology (mRNA) and are highly effective at preventing COVID-19infection. In February 2021, a COVID-19 vaccine developed by Janssen Biotech, Inc.was grantedanEUA by FDA.A comparison of key details for each vaccinecan be found below.This list is not exhaustive. For further details,see the FDA EUA document for Pfizer/BioNTech,Moderna,and Janssen. Note:head-to-head COVID-19 vaccine studieshave notbeenconducted. Therefore,directvaccine efficacycomparisonsarenot possibleat this time.

If the case that SARS2 originated in a lab is so substantial, why isn’t this more widely known? As is now obvious, there are many people who have reason not to talk about it.

Daten zu Corona nach Schlagworten finden

RELATED | Pfizer approves vaccine for 12-15 year old children. Early in the a. m. , most 12-year-olds like to hide under the covers. But for Wednesday, it's just different. “It’s very hard to wake her up in the morning and it’s hard to keep her awake,” said Melissa Lynch. She stated that her daughter, Wednesday, has struggled with COVID-19 for eight months, dealing with debilitating waves of symptoms that start like a cold, and then “...

COVID-19 treatment and research information from the US federal government.

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been approved for emergency use, but, despite elevated risk of severe disease, pregnant women were excluded from the clinical trials that led to their authorization.1 Placental findings can indicate potential clinical risk and could be an early signal for rare injury seen only after widespread use in the pregnant population.2–6 Maternal SARS-CoV-2 infection has been associated with decidual arteriopathy, fetal vascular malperfusion, and chronic histiocytic intervillositis.7–9 mRNA vaccines induce an immune response through activation of TLR3, which has been linked to decidual arteriopathy, growth restriction, preterm delivery, and fetal loss in mouse models.10–14 Our objective was to evaluate the frequency of these key placental lesions in patients who received SARS-CoV-2 vaccination in pregnancy.

This study assesses the immunogenicity of the current COVID-19 mRNA vaccines in pregnant and lactating women against both the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants of concern.

The shots may also have benefits for infants and do not seem to damage the placenta, according to the latest research.

In recent years, in vitro transcribed messenger RNA (mRNA) has emerged as a potential therapeutic platform. To fulfill its promise, effective delivery…

Estimates of the prevalence of self-reported “long COVID” and the duration of ongoing symptoms following confirmed coronavirus infection, using UK Coronavirus (COVID-19) Infection Survey data.

#LongCovid risk is 12% in 17-24 year olds and 8% in 12-16 yo yet the govt is removing the one layer of protection these unvaccinated age groups have against #SARSCoV2 infection: masks in secondary schools and colleges. I don’t understand how this is acceptable. I really don’t. https://t.co/KkrnyrUS2e

Many people are not recovering for months after being infected with SARS-CoV-2. Long Covid has emerged as a major public health concern that needs defining, quantifying, and describing. We aimed to explore the initial and ongoing symptoms of Long Covid following SARS-CoV-2 infection and describe its impact on daily life in people who were not admitted to hospital during the first two weeks of the illness. We co-produced a survey with people living with Long Covid. We collected the data through an online survey using convenience non-probability sampling, with the survey posted both specifically on Long Covid support groups and generally on social media. The criteria for inclusion were adults with lab-confirmed (PCR or antibody) or suspected COVID-19 managed in the community (non-hospitalised) in the first two weeks of illness. We used agglomerative hierarchical clustering to identify specific symptom clusters, and their demographic and functional correlates. We analysed data from 2550 participants with a median duration of illness of 7.7 months (interquartile range (IQR) 7.4-8.0). The mean age was 46.5 years (standard deviation 11 years) with 82.8% females and 79.9% of participants based in the UK. 89.5% described their health as good, very good or excellent before COVID-19. The most common initial symptoms that persisted were exhaustion, chest pressure/tightness, shortness of breath and headache. Cough, fever, and chills were common initial symptoms that became less prevalent later in the illness, whereas cognitive dysfunction and palpitations became more prevalent later in the illness. 26.5% reported lab-confirmation of infection. The biggest difference in ongoing symptoms between those who reported testing positive and those who did not was loss of smell/taste. Ongoing symptoms affected at least 3 organ systems in 83.5% of participants. Most participants described fluctuating (57.7%) or relapsing symptoms (17.6%). Physical activity, stress and sleep disturbance commonly triggered symptoms. A third (32%) reported they were unable to live alone without any assistance at six weeks from start of illness. 16.9% reported being unable to work solely due to COVID-19 illness. 66.4% reported taking time off sick (median of 60 days, IQR 20, 129). 37.0% reported loss of income due to illness, and 64.4% said they were unable to perform usual activities/duties. Acute systems clustered broadly into two groups: a majority cluster (n=2235, 88%) with cardiopulmonary predominant symptoms, and a minority cluster (n=305, 12%) with multisystem symptoms. Similarly, ongoing symptoms broadly clustered in two groups; a majority cluster (n=2243, 88.8%) exhibiting mainly cardiopulmonary, cognitive symptoms and exhaustion, and a minority cluster (n=283, 11.2%) exhibited more multisystem symptoms. Belonging to the more severe multisystem cluster was associated with more severe functional impact, lower income, younger age, being female, worse baseline health, and inadequate rest in the first two weeks of the illness, with no major differences in the cluster patterns when restricting analysis to the lab-confirmed subgroup. This is an exploratory survey of Long Covid characteristics. Whilst it is important to acknowledge that it is a non-representative population sample, it highlights the heterogeneity of persistent symptoms, and the significant functional impact of prolonged illness following confirmed or suspected SARS-CoV-2 infection. To study prevalence, predictors and prognosis, research is needed in a representative population sample using standardised case definitions (to include those not lab-confirmed in the first pandemic wave). ### Competing Interest Statement NAA, MEO and CH experience(d) Long Covid symptoms. ### Funding Statement The study received no specific funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of Southampton, Faculty of Medicine Ethics Committee (Reference 61434) All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The survey data is available on request provided ethics committee approval for sharing the anonymised data is granted.

1 Tag nach Injektion der Erstdosis Biontech/Pfizer; 30 mcg Spike mRNA verpackt in LipidNanoPartikel (LNP).Was ist passiert, wo ist das Zeugs?Nach Injektion in den Oberarm bleibt der Großteil im Muskel bzw in den Lymphknoten der Achselhöhle. Ein beträchtlicher Teil...1/n pic.twitter.com/YyIOGeP4xG— Johann Holzmann, PhD (@JohannHolzmann) May 15, 2021

Science is hard. This is not meant to dissuade anyone from going into the sciences. It’s just a statement of fact with which all scientists would probably agree, and it’s a sort of mantra we can repeat to ourselves to recalibrate our expectations once in a while. There is a paper that came out in the Proceedings of the National Academy of Sciences (or PNAS) that I fear will be weaponized by anti-vaccine activists. It is not a study that should be casually dismissed, nor can its results be embraced and spun into catastrophic conclusions. Again, science is hard. It has to do with the claim (and I must repeat, the claim) that the genetic material from the coronavirus could integrate itself inside our own genetic material, that the SARS-CoV-2 RNA could get turned into DNA and mingle with our own. Anti-vaxxers, who downplay the threat of COVID-19, don’t typically see this as a problem with the virus itself; rather, they use this claim (again, claim) to scare the bejesus out of people contemplating one of the COVID-19 vaccines. You see, the COVID-19 vaccines in use right now contain genetic instructions (either RNA or DNA) to tell our body to manufacture the coronavirus’ spike protein. What if, anti-vaccine activists will argue to stir up the flames of anxiety, the genetic material inside these vaccines shoves itself inside your DNA, disrupting the order of things and mutating you in unpredictable ways? Last December, they found a study they could use to bolster their claim. It had not been officially reviewed by other scientists, and it had not yet been accepted for publication in an academic journal. It was a pre-print. In it, scientists claimed to have discovered bits of the genetic material from the coronavirus fused to human DNA. This pre-print was met with thunderous rebuttals from many in the scientific community, and it was flown as a victory flag by the anti-vaccine movement. Now, this pre-print has been tweaked, peer-reviewed, and published in the journal PNAS. Its authors claim they “found that DNA copies of SARS-CoV-2 sequences can be integrated into the genome of infected human cells.” It sure sounds scary but, as always, the devil is in the details. And it begins with jumping genes. Whose LINE is it anyway? Our organs are made of tissues, and these tissues are made of cells. Inside the cell, there is a glob called the nucleus. It’s the command center of the cell and it contains our DNA. (There are powerhouses outside the nucleus called mitochondria, and they have a tiny ring of DNA, but we will put that aside for today.) This DNA is a very, very long spaghetti noodle that occasionally bunches up into discrete chromosomes, and that interminable noodle contains stretches that play different roles. There are genes—not as many as we once thought, about 20,000 in humans—and these genes get transcribed into RNA that is itself translated into a specific protein, the effector of the cell. But protein-coding genes only make up a tiny portion of the entirety of our DNA. If you keep roaming down that long spaghetti noodle, you are bound to see a LINE-1 element. In fact, you will see many. That is because they are estimated to make up about 17% of human DNA or almost one-fifth. They are long stretches of DNA with recognizable sequences and they technically have the ability to pack up their stuff and move elsewhere in the genome. They can jump around. Most of them, though, are molecular fossils. They used to be able to jump around in our DNA eons ago, but they lost this ability and have been silenced. I reached out to Professor Geoffrey J. Faulkner at the University of Queensland, who studies these jumping bits of DNA like LINE-1 elements. We are known to have about 500,000 of these LINE-1 sequences in our genome. “Of those, in each of us,” he told me, “there are about 100 copies that have the potential to jump. That’s a very small number out of half a million.” And these 100 are not typically seen jumping around in recent times; only about five or six of them do. It’s like our DNA is littered with the tired bodies of long jumpers, with only a handful still able to compete for Olympic gold. I bring up LINE-1 elements because the authors of that PNAS paper about bits of the coronavirus possibly integrating into our DNA have evidence that puts LINE-1 elements at the scene of the alleged crime. As with most police procedurals, we should not jump to conclusions. What the researchers are alleging based on their laboratory experiments and their scrutiny of the genetic material collected from people with severe COVID-19 is that our own LINE-1 elements—these stretches of DNA that have the machinery necessary to pluck themselves free from the DNA molecule and reintegrate elsewhere—can grab hold of the coronavirus’ RNA that is floating around, transform it back into DNA, and integrate it inside our own DNA as if it were a long jumper competing for the gold. To be fair, some viruses can do that. Famously, HIV, a retrovirus, comes with the necessary machinery to slide itself into our genome. Some viruses that are not retroviruses can even do that. Our genome and that of other animals bear the marks of many viruses that, over the course of millennia, have been swallowed up by our DNA. But, and this is a telltale “but,” as Professor Aris Katzourakis, who studies the integration of viruses into animal genomes at the University of Oxford and who was critical of this PNAS paper on Twitter, told me, “there are no known integrations of coronaviruses at all in any of the genomes that have been published.” At the start of the pandemic, he consulted databases out of professional curiosity to see if he could find traces of the genetic material from any of the many coronaviruses in existence integrated in any of the couple of thousands of animal genomes available. He did not find anything even remotely coronavirus-like. After hundreds of millions of years of evolution, despite LINE-1 elements existing and despite coronaviruses infecting animals left and right, there was no trace of coronaviruses having jumped inside animal genomes. What were the odds that this brand-new SARS-CoV-2 coronavirus managed to do just that in a matter of months? “That would be a really big surprise,” he said to me. When claims meet evidence The claim that bits of the SARS-CoV-2 virus might be integrated inside our DNA is thus an extraordinary claim given the context. Professor Faulkner reminded me of a famous saying popularized by Carl Sagan—that extraordinary claims require extraordinary evidence—especially when they have public health consequences. “When I think of this [paper], I think of that quote. The claims are extraordinary but the evidence is not.” One of the reality checks we need to bring up with regards to the paper is that most (but not all) of their data comes from an experimental system that does not reflect reality, but rather acts as a proof of principle. If you eat your first meal with cilantro and you can’t really tell if you like the herb or not, you can buy some cilantro and add a lot of it to your next meal. By increasing the signal (the amount of cilantro), you can detect it better and decide if it pleases you. The researchers here did something similar. They chose a line of human cells they could grow in the laboratory, a line of cells that already expresses a lot of LINE-1, and they gave them a bit of DNA that made even more LINE-1. They wanted to crank up the system—pour a lot of cilantro on top of it—in order to see if anything would happen. The experts I asked about this agree that doing this is a good first step, but it does not represent what happens when you or I get infected by the coronavirus. You can make something happen artificially that would not happen naturally, including integration. “LCMV, lymphocytic choriomeningitis virus, is a non-integrating virus,” Pr. Katzourakis told me, “but if you stick it in a cell line experiment expressing very, very high levels of LINE-1 and make the cell line permissive, you can make a virus that doesn’t normally integrate into a cell line.” Moreover, some of the bits of coronavirus genetic material stuck to human DNA that the researchers detected might not be evidence of integration; rather, they may just be artefacts. When copies of genetic material are made, the enzyme that carries the work sometimes behaves like a distracted seamstress, switching off of a piece of fabric and moving on to another, sewing the two together. The coronavirus itself does this, and these artefacts can also be generated by the laboratory technology used by the researchers. This was brought up when the pre-print was published. The researchers tried to take this into account, but it’s still not a slam dunk. Finally, the sequences they report—those hybrids of coronavirus and human genetic material allegedly created by LINE-1 elements—just don’t look right, according to both the experts I spoke to and the researchers themselves. Indeed, the authors report something strange in their paper. They expected those coronavirus bits would get plopped inside our DNA at random because this is how LINE-1 elements behave. Instead, the bits they saw were 26 times more likely to be found squeezed inside the useful part of our genes. This is very bizarre. Also, certain molecular signatures accompany LINE-1-mediated events, and these signatures are not always there in the sequences reported in this paper, experts tell me. They don’t look right. The authors speculate based on some of these strange results that other mechanisms besides LINE-1 might be involved. There is a fine LINE between implausible and impossible I am not worried about the possibility that pieces of the coronavirus might integrate inside my DNA. It has never been seen before with coronaviruses. The evidence presented here is very artificial and unconvincing to me, although I applaud the researchers for not only doing important work but for collaborating with one

Vitamin D: What's its role in fighting the #coronavirus? Thread I was initially reluctant to look into it. I'm very skeptical of the supplement industry given that most supplements don't really work, which is connected to the fact that they're not regulated. [1/ https://t.co/YnMLGQKU6X

Infections of the respiratory tract are more frequent in the winter months and especially in the northern latitudes than they are in summer [1]. This obviously also applies to the COVID-19 infectious disease that briefly spread all over the world in the winter months and became a pandemic [2,3]. A common feature of the winter months and the inhabitants of all countries north of the 42nd parallel is a hypovitaminosis D that frequently occurs during this period [4]. In addition during cold temperature the virus will be more easily transmitted. This raises the question of whether an inadequate vitamin D supply has an influence on the progression and severity of COVID-19 disease.