Woman Living Near Wuhan Lab May Have Been 'Patient Zero' - 3 Weeks Before China Claims First Case

 Three weeks before China admitted that a mysterious virus was circulating in the city of Wuhan, a 61-year-old woman who lived about a mile from several bat research facility was known as "Patient Su" at a local hospital, according to the Daily Mail.

Her identity was accidentally revealed after a leading Chinese official sent a screen-grab to a medical journal which partially revealed personal information, including the fact that she was admitted to the Rongjun Hospital in Wuhan, and "almost certainly lived in the Kaile Guiyan community on Zhuodaoquan Street, about 600 metres from the medical centre."

What's more, "Patient Su" became ill three weeks before China claimed anyone had been stricken with the novel virus.

The academic then detailed two more suspected cases reported to Wuhan doctors on November 14 and 21, along with several others before December 8 – the date that China gave to the World Health Organisation for the ‘earliest onset case’.

The Health Times article included a screenshot of the two November cases on the professor’s database. Although personal details were blurred out, some were visible, including the hospital name and home district.

They show Patient Su was treated at Rongjun Hospital in Wuhan and, given the building and street numbers, almost certainly lived in the Kaile Guiyan community on Zhuodaoquan Street, about 600 metres from the medical centre. -Daily Mail

Patient Su also lived close to a stop for the high-speed rail line believed to have played a key role in spreading the virus around the city of 11 million people, according to the report. 

Both the hospital and Su's presumed residence are in the Hongshan district, where both China's CDC and a downtown site run by the Wuhan Institute of Virology were located less than a mile away. According to former lead US State Department investigator David Asher, three researchers became ill with a mysterious respiratory condition in November 2019 - with the wife of one scientist dying.

One Washington source told The Mail on Sunday that US intelligence on the Wuhan researchers was collected in late 2019 in data-scraping from routine surveillance. It is thought to include tapped phone conversations, texts and emails.

He said it was not discovered until efforts were intensified last year to investigate the pandemic’s origins and any possible links with Wuhan laboratories – and that it is backed by testimony from a source with access to one of the units. -Daily Mail

The Wall Street Journal last week reported on the three ill lab workers who ended up in the hospital - claims which Beijing furiously disputes. Meanwhile, US President Joe Biden has ordered a 90-day intelligence review after it was revealed that US intelligence agencies have been sitting on a 'raft' of un-analyzed intelligence gathered during the course of their investigation - largely because establishment minions wrote it off as a partisan witch hunt.

"The time has come for China to open up all its files so the world can find the truth about the origins of this pandemic," said Tom Tugendhat MP, Chairman of UK's foreign affairs committee. "We cannot protect against future risks if there is not recognition that we all need to share knowledge and learn from any mistakes."

Covering up the report

Professor Yu Chuanhua, professor of biostatistics at Wuhan University, was the one who revealed that Patient Su fell ill three weeks before the official disclosure date. According to the Daily Mail, however, China is hard at work performing yet more damage control.

Professor’s Yu’s interview with Health Times took place on the day China’s health authorities issued a silencing gag on the novel coronavirus as President Xi Jinping tried to regain control of the situation.

Yu rang the journalist within two days to retract this information, claiming the dates had been entered incorrectly and all the other suspected cases before December 8 needed verification.

The details were discovered by Gilles Demaneuf, a member of the ‘Drastic’ group of online digital activists who have uncovered many of the facts seen as contradicting the official Chinese narrative that Covid-19 was a disease that crossed over naturally from animals. -Daily Mail

"We were able to pinpoint the exact name, age and address of a very early suspected case nearly one month before the official first case," said Demaneuf, a French data scientist who works for a New Zealand bank. "That address is right next to the subway line No 2 and also not far from a People’s Liberation Army hospital that treated some of the other earliest cases."

Demaneuf argues that the new findings highlight how many more clues might be accessible if people continue to pursue the lab leak theory, rather than "wishful acceptance at face value of statements from China."

https://www.zerohedge.com/covid-19/61-year-old-woman-living-near-wuhan-lab-may-have-been-patient-zero-three-weeks-ccp-claims

Malaysia to allow many manufacturing sectors to run during lockdown

  Large parts of Malaysia’s manufacturing sector will be allowed to keep working, with reduced workforce capacity, during a strict coronavirus lockdown to be imposed from Tuesday, the defense and international trade ministries said on Sunday.

Relatively unscathed during much of last year, the country has seen a very steep increase in COVID-19 cases in recent weeks and recorded five straight days of record daily infection counts this week, prompting Prime Minister Muhyiddin Yassin to announce the lockdown from June 1-14.

However, many sectors will be allowed to keep working.

Among the manufacturing sectors allowed to operate with 60% of the workforce are those producing personal protective equipment including rubber gloves, electrical and electronics, oil and gas including petrochemicals, and chemical products, the International Trade and Industry Ministry said in a statement.

Other manufacturing sectors that can run are food and beverages, aerospace, packaging and printing, health and medical care, personal care and cleaning supplies, Defense Minister Ismail Sabri Yaakob told a news briefing.

“We hope that the sectors allowed to open will follow instructions given by the government because from the complaints I have received on social media, I was informed that there are employers who force their workers to (go to) work, more than the 60% allowed,” Ismail said.

Palm oil and rubber plantations, as well as agriculture, fishery and livestock are also allowed to operate during the two-week period, including the supply chains that support the industries, he said.

Malaysia reported 6,999 new coronavirus cases on Sunday, bringing the total infections in the country to 565,533, with a total of 2,729 deaths.

Nearly 6% of the country’s 32 million people have been vaccinated, according to the website of the governmental Special Committee for Ensuring Access to COVID-19 Vaccine Supply.

The government is planning to set up more large-scale vaccination centers and get private doctors to join immunization efforts, Science Minister Khairy Jamaluddin told an earlier news briefing.

“As the supply (of vaccines) increases, we want to facilitate private clinics, (general practitioner) clinics, private hospitals to roll out the vaccines via our program, for free,” he said.

The private vaccination centers could administer a total of 40,000 doses a day, he said, adding that the government aims to raise vaccinations to 150,000 doses a day. It reached 107,000 doses a day this week.

https://nationalpost.com/pmn/health-pmn/malaysia-to-allow-many-manufacturing-sectors-to-run-during-lockdown

Even After U.S. Shift, Opponents Resist COVID-19 Vaccine Patent Waiver

 A deal on an intellectual property waiver for COVID-19 vaccines at the World Trade Organization (WTO) was no closer to acceptance on Monday despite Washington's backing, due to expected scepticism about a new draft, sources close to the talks told Reuters.

Negotiations reopened at the WTO on Monday, focused on a highly anticipated revised draft submitted by India, South Africa and dozens of other developing countries last week.

A surprise U.S. shift earlier this month to support a patent waiver heaped pressure on remaining opponents like the European Union and Switzerland that are home to numerous drugmakers. But Monday's discussions - the 11th session since the initial waiver proposal in October - failed to achieve a breakthrough.

The waiver's main backers presented their new draft in Monday's private WTO meeting, allowing key players to give their first official feedback on its contents.

The meeting is critical because it will determine if the talks will advance to "text-based negotiations" as sought by director-general Ngozi Okonjo-Iweala.

A Geneva trade official said the proposal to start text-based discussions "gained traction" on Monday, including from the United States, which said it was open to discussion on any proposal that could boost vaccine production and delivery.

It did not openly support the revised text, but said it was analysing it.

Around 10 countries, including South Korea and Britain, continued to express doubts and asked for more time to study the new South Africa/India proposal.

Three sources close to the talks see problems with the text.

"There is an ocean between this waiver proposal and what was suggested by the U.S.," said a source involved in the talks who declined to be named. "There's definitely no quick resolution for this."

Two aspects of the waiver draft that may harden opposition are its scope and duration.

While U.S. Trade Representative Katherine Tai had previously said she is only focused on increasing vaccine access, the new draft also includes diagnostics, therapeutics and medical devices, among others.

"When you have a big bomb like the U.S. saying we will support the waiver, people were expecting the revised proposal would narrow the scope," said a Geneva-based trade source.

The draft also sets a time span for a waiver seen as temporary of "at least three years" and allows the WTO's 164 members to determine when it ends. Given they would need to do this by consensus, one country could repeatedly prolong it.

"If the proponents insist on it (the duration), there will almost certainly be no consensus agreement on the waiver," said Peter Ungphakorn, a former WTO staff member who now writes blogs on trade.

An EU diplomat told Reuters that the revised text would"likely call the U.S. bluff". The European Union is set to present an alternative plan for boosting production and availability of COVID-19 vaccines to the WTO in early June.

https://www.usnews.com/news/top-news/articles/2021-05-31/even-after-us-shift-opponents-resist-covid-19-vaccine-patent-waiver

FDA Statement on Leronlimab

 FDA recognizes the substantial public interest in medicines that are being studied for the prevention or treatment of COVID-19, especially those medicines that may provide a benefit to patients with the most severe forms of disease that can result in respiratory failure and death.  Leronlimab, a monoclonal antibody investigational drug under development by CytoDyn, Inc. (CytoDyn), is one of the potential medicines that has been studied to determine whether it is safe and effective in treating patients with COVID-19, including those with severe outcomes from COVID-19.

CytoDyn has conducted two separate clinical trials investigating leronlimab for the treatment of COVID-19.  A smaller trial, titled CD10, which included 86 patients, studied leronlimab’s effect on mild-to-moderate COVID-19 disease. A larger trial, titled CD12, which included 394 patients, studied leronlimab’s effect on severe symptoms of respiratory illness associated with COVID-19. CytoDyn has communicated information to the public about the results of these trials. Although FDA generally cannot disclose confidential information about unapproved products, we have concluded that given the significant public interest in leronlimab, it is important to provide summary information about the status of the CytoDyn development program.

First, we underscore the significance of a well-designed clinical trial when evaluating whether a medicine is safe and effective for a particular use. Well-designed trials have specific objectives, referred to as “endpoints”, that are documented (i.e., pre-specified) in the study protocol before the initiation of the investigation. Data obtained from the clinical trial are later analyzed using pre-specified statistical methodologies. If the analyses of the primary and secondary endpoints do not support conclusions of the medicine’s benefit, then FDA considers subgroup analyses to be exploratory, meaning they may inform the design of future trials, but do not support reliable conclusions about the medicine’s benefit. Focusing on only the most favorable of many subgroup analyses, even if the sub-groups are pre-specified, can lead to overestimating the evidence of benefit, because regardless of a drug’s true efficacy, some analyses are likely to appear favorable by chance when a large number of analyses are conducted.  

With the conclusion of both the CD10 and CD12 clinical trials, it has become clear that the data currently available do not support the clinical benefit of leronlimab for the treatment of COVID-19. In the smaller study that CytoDyn conducted in patients with mild-to-moderate COVID-19 disease (CD10), there was no observed effect of the drug on the study’s primary endpoint or on any of the secondary endpoints. The primary endpoint for the CD10 trial relied on a measure of participants’ COVID-19 symptoms called a “total clinical symptom score”, which was assigned based on the severity of each participant’s fever, muscle aches, shortness of breath, and cough. This score ranged from 0 (no symptoms) to 12 (all 4 symptoms present and severe). The CD10 trial results showed no clinically meaningful differences in average change in “total clinical symptom score” from baseline to Day 14 between study arms (-3.5 in the leronlimab group versus -3.4 in the placebo group). Additionally, none of the secondary endpoints were met in this study, including mortality, time to symptom resolution, and time to return to normal activity. Taken together, the CD10 results indicate that most study participants experienced resolution in COVID-19 symptoms regardless of whether they received leronlimab or placebo.

The larger trial that CytoDyn conducted in patients with severe COVID-19 disease (CD12) also failed to find any effect of the drug on the primary study endpoint, with no difference seen in mortality (20.5% in the leronlimab treatment group and 21.6% in the placebo treatment group); or on any of the secondary endpoints, for example, with no difference on the average length of hospitalization (21.4 days in both the leronlimab and the placebo treatment groups). 

CytoDyn has publicly communicated differences in small subgroups from the CD12 trial (e.g., a sub-group analysis of 62 of the 394 patients studied) suggesting that the data demonstrated a mortality benefit in certain patients who had received leronlimab. Subgroup analyses have well-established limitations, especially in the context of a clinical trial that has failed to show a benefit in the overall study population. For example, subgroups are often small, and therefore imbalances are common. Here, the data from CD12 illustrated imbalances in mortality among subgroups, some favoring leronlimab and some favoring placebo. None of these analyses met statistical significance when using established and reliable analytical methods that correct for multiple comparisons. However, as noted above, such analyses may inform the design of future clinical trials investigating leronlimab for the treatment of COVID-19.  

If CytoDyn plans further studies of leronlimab to determine whether the drug can provide clinical benefit to individuals with COVID-19, FDA will continue to provide advice to the company on their development program.

FDA recognizes the critical unmet medical need for new, effective treatments for COVID-19, especially for severe forms of the disease. We are committed to working with sponsors of novel therapies to facilitate development and approval of new treatments.

https://www.fda.gov/drugs/drug-safety-and-availability/statement-leronlimab

Persistent clotting protein pathology in Long COVID/ Post-Acute Sequelae accompanied by increased levels of antiplasmin

  

View ORCID ProfileEtheresia Pretorius, Mare Vlok, Chantelle Venter, Johannes A. Bezuidenhout, Gert Jacobus Laubscher, Janami Steenkamp,  View ORCID ProfileDouglas B. Kell

doi: https://doi.org/10.1101/2021.05.21.21257578

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2021.05.21.21257578v1.full.pdf

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation. Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression. Given that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma clots that are resistant to fibrinolysis. We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms. We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits. We also show that these anomalous deposits in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits. Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might therefore benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

N/A

Clinical Protocols

https://1drv.ms/u/s!AgoCOmY3bkKHi4M_1rPgXqXoq1XXSw?e=Uq0at7

Funding Statement

Funding DBK thanks the Novo Nordisk Foundation for financial support (grant NNF10CC1016517).

https://www.medrxiv.org/content/10.1101/2021.05.21.21257578v1

Persistent SARS-CoV-2 infection and the risk for cancer

 Miguel Alpalhão,a,b,c,⁎ João Augusto Ferreira,b,c and Paulo Filipea,b,c

doi: 10.1016/j.mehy.2020.109882

PDF: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831646/pdf/main.pdf

Abstract

The current SARS-CoV-2 has put significant strain on healthcare services worldwide due to acute COVID-19. However, the potential long-term effects of this infection haven’t been extensively discussed.

We hypothesize that SARS-CoV-2 may be able to cause persistent infection in some individuals, and should this be the case, that in a few years we may see a rise in cancer incidence due to carcinogenic effects of this coronavirus.

Non-retroviral RNA viruses such as Coronaviridae have been shown to cause persistent infection in hosts. Empirical evidence of viral genomic material shedding weeks after apparent clinical and laboratorial resolution of COVID-19 may be an indirect proof for persistent viral infection. Furthermore, tropism towards certain immune-privileged territories may facilitate immune evasion by this virus.

Structural homology with SARS-CoV-1 indicates that SARS-CoV-2 may be able to directly impair pRb and p53, which are key gatekeepers with tumor suppressor functions. Additionally, COVID-19 features preeminent inflammatory response with marked oxidative stress, which acts as both as initiator and promotor of carcinogenesis.

Should there be a carcinogenic risk associated with SARS-CoV-2, the implications for public health are plenty, as infected patients should be closely watched during long periods of follow-up.

Additional investigation to establish or exclude the possibility for persistent infection is paramount to identify and prevent possible complications in the future.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831646/

Complement control for COVID-19

 Markus Bosmann1,2,3,4,*

 See all authors and affiliations

Science Immunology  25 May 2021:
Vol. 6, Issue 59, eabj1014
DOI: 10.1126/sciimmunol.abj1014

PDF: https://immunology.sciencemag.org/content/6/59/eabj1014/tab-pdf

Abstract

Excessive complement activation contributes to lung disease and adverse patient outcomes in COVID-19 (see the related Research Articles by Yan et al. and Ma et al.).

The complement system is an integral part of innate immune defense. It consists of about 50 proteins in plasma, on cell surfaces and inside host cells. The traditional view is that complement proteins guard the local extracellular spaces and systemic bloodstream against invading pathogens. Loss-of-function mutations resulting in terminal complement pathway deficiencies are associated with a 10,000-fold higher risk for life-threatening meningococcal infections in humans. Surprisingly, the complement system is redundant for defense against most pathogens except encapsulated bacteria. Newer concepts embrace the view that complement factors mediate functions inside cells either directly or through surface receptors. Complement activity fine-tunes homeostasis, metabolism and biogenesis. On the other hand, uncontrolled complement activation causes disease and can even worsen the outcome of infections. Toxic complement effectors mediate tissue destruction and organ injury during inflammatory diseases. Acute respiratory distress syndrome (ARDS) and sepsis are frequent and severe complications of acute infections and notorious for excessive complement consumption. The three pathways of complement activation are designed for immune sensing of non-self surfaces and foreign antigens. The mannose-binding lectin (MBL)/ficolin pathway starts with soluble pathogen pattern recognition receptors as sensors for foreign carbohydrate motifs (Fig. 1). The alternative pathway is fueled by a spontaneous ‘smoldering’ hydrolysis of C3 targeting all surfaces, unless these surfaces present complement inhibitory proteins (CD46, CD55, CD59) as a protective self-signal. This C3 ‘tick-over’ is sustained by the high concentrations of C3 in plasma (1-2 g/L) – the highest level of all complement factors. The classical pathway is initiated by antigen-antibody complexes which are recognized by the multimeric C1 complex. As a safeguard, IgG antibodies bound in clusters or pentameric IgM are required to surpass the activation threshold. All complement pathways converge on C3 convertase complexes leading to C3 cleavage into the larger C3b and the smaller anaphylactic C3a peptides. C3b is essential for the formation of C5 convertase for cleavage of C5 into C5b and the anaphylatoxin C5a. C5b is the starting point of the pore-forming membrane attack complex (MAC) consisting of C5b-C9 with a channel diameter of ~100 Å. The C3/C5 hub represents a gigantic amplification loop. The alternative C3bBb convertase (half-life ~3 min) cleaves additional C3, resulting in more C3bBb and so on and so forth. This enzymatic chain reaction can deposit millions of C3b molecules on target surfaces in a few seconds. It is no surprise that such explosive events need to be tightly regulated to maintain the delicate balance of effective and justified pathogen attack, while avoiding damage of innocent bystander cells.

SARS-CoV-2 infection of alveolar epithelial cells (type II and type I) and subsequent interferon-dependent JAK1/2-STAT1–induced expression of C3 and Factor B culminates in nontraditional intracellular processing of complement proteins. In the extracellular spaces, SARS-CoV-2 activates complement via the mannose-binding lectin (MBL)/ficolin pathway which senses glycosylated S- and N-proteins. The C3 ‘tick-over’ of the alternative pathway is accelerated by a lack of complement inhibitors (CD46, CD55, CD59) on infected host cells and virions. The classical pathway is activated by antibodies against viral antigens and COVID-19–associated autoantibodies. All complement activation mechanisms converge on the C3/C5 hub to form the membrane-attack complex (MAC, C5b-C9) and generate anaphylatoxins (C3a, C5a). These effectors recruit myeloid cells and cause endothelial activation, endothelial injury, coagulopathy and hyperinflammation. The figure shows the molecular targets of several complement-inhibiting drugs proposed as COVID-19 treatments: eculizumab and ravulizumab block C5 conversion, AMY-101 and pegcetacoplan antagonize C3 activation, the IFX-1 monoclonal antibody inhibits C5a, and avdoralimab blocks the C5aR1 receptor. Abbreviations: vWF: von Willebrand Factor, Ang2: Angiopoietin-2, C3aR: C3a receptor, C5aR1: C5a receptor 1, C5aR2: C5a receptor 2, MASP1/2: Mannan-binding lectin serine proteases 1 and 2, ACE2: Angiotensin-converting enzyme 2, TMPRSS2: Transmembrane protease, serine 2.

https://immunology.sciencemag.org/content/6/59/eabj1014