A short post today, as the day job is keeping me busy.
(1) Today the results of the Phase 3 remdesivir trial were released. (I previously discussed its mechanism of action here: in brief, it’s a nucleoside analog that interferes with viral RNA copying by acting as an “imposter letter” in the RNA genetic code and causing further copying to break off.)
Again, as with prior trials, we see that it’s not a “magic bullet” drug, but clearly has a therapeutic advantage in patients with moderate disease (signs of pneumonia, but don’t yet need oxygen). The trial used almost 600 patients, divided into three roughly equal groups: (a) standard of care (SOC) + 5-day remdesivir; (b) SOC + 10-day remdesivir; (c) SOC only (control group). In the table below, percentages are given in parentheses:
The “ordinal scale” is an ad hoc 7-point scale ranging from hospital discharge on one end to death on the other end. In the 5-day regimen (which I read between the lines uses twice the dose for half the time), about 10% more patients see an improvement, and 8% fewer patients see a worsening from baseline than with SOC. No patients on the 5-day regime died (compared to four with SOC), but we are in “statistics of small numbers” territory.
As for drug side effects (“AE”), there are about 6% more than with standard care, but actually fewer serious side effects.
Additional Phase 3 trials in severe and moderate disease are in progress in various countries. The drug is currently approved in Japan and under FDA emergency authorization in the US.
(1) Dr. Seheult discusses remdesivir for different categories of patients, and suggests that the drug is most beneficial (in terms of quicker recovery) for patients sick enough to require oxygen, but not so sick as to require mechanical ventilation or ECMOs (“heart-lung machines”). In this latter group, the virus has already done so much damage that remdesivir amounts to “closing the barn door after the horses have fled”, while mild cases will resolve on their own.
The conventional division of patients is (averaged across age groups):
80% self-limiting, self-resolving disease
15% get more severely ill
5% critically ill
So it would be the 15% where the drug can make most of the difference, probably by keeping patients from moving into the 5% critical group.
(2) Dr. John Campbell’s video looks at the asymptomatic infection rate, which he frustratingly places “between 5% and 80%”, and briefly highlights different studies that arrive at wildly different rates. My working assumption all along has been “about 50%”.
(3) The Economist has a somewhat pessimistic take on the post-lockdown economy. Note that at least some of the economic effects of the pandemic are also felt in countries that never locked down, like Sweden.
Relatedly, Die Welt (in German) looks at how in reopened Germany, spending habits have changed to the extent that some retailers say they don’t see the point of reopening. The main shopping streets have seen foot traffic dwindle by 30 to 75% (Berlin’s famous Kurfürstendamm was hardest hit). Stores with an online presence, who kept in touch with customers during the crisis, have weathered the storm better, while some with a primarily online business model have seen revenue rise (including a new online grocery shopping chain).
(3) Miscellaneous updates:
Moderna’s COVID-19 vaccines now moves into Phase 2 clinical trials, reports the Jerusalem Post, who also note that the chief scientific officer of Moderna is an expat Israeli. (Like in information technology, tiny Israel punches well above its weight in biotech.)
Tangentially related, the Daily Telegraph looks at what awaits Hong Kong under full ChiCom rule. The UK has offered asylum to Hong Kongers who still hold BNO (British National Overseas) passports. (This unusual type of passport does not come with automatic “right of abode” in the UK.)
(0) Israel today celebrated its first day with zero new cases.
(1) Via Instapundit, SSRN (Social Science Research Network, a preprint server similar to arXiv.org, medrxiv.org, biorxiv.org and chemrxiv,org) has a article in press about the Swedish COVID19 epidemic.
Their per capita death rate is an order of magnitude larger than neighboring Scandinavian countries. It is tempting to attribute all this to Sweden’s Sonderweg (“road alone”) — but this article makes a case that at least part results from factors unrelated to Sweden’s decision not to go on lockdown.
Not only is half of Sweden’s mortality concentrated in just the capital city Stockholm, but over 70% of Sweden’s mortality is in nursing homes. As the article explains, in Sweden the elderly tend to stay at home for as long as possible, assisted by home helpers assigned by the public healthcare system. (Independent assisted living facilities do exist, apparently mostly in the private sector.) But normally a home for the elderly is a last-resort option, and those who move in there are generally so frail that their median stay there is under one year. (Such facilities in Sweden have doctors etc. on site.)
Now in a facility where everybody needs a lot of hands-on care, there is plenty of room for nosocomial (i.e., caregiver-transmitted) infections unless staff is (a) healthy and (b) has extensive training and/or experience in biosafety. Guess who does the most “hands-on” work at such care homes? First-generation immigrants from the Third World, often with at best high school education. And guess what else? Immigrants are the second most common group of COVID19 victims in Sweden, after the elderly.
Immigrants tend to live in crowded conditions, and many probably have major issues with vitamin D deficiency (and hence a weakened immune system) in winter. (Even light-skinned “Vikings” would be in trouble in a sub-arctic winter, were it not that Scandinavians tend to fortify their diet with vitamin D supplements — I was floored once to see cod liver oil at a hotel breakfast buffet!)
Intriguingly, overall year-over-year mortality is not as elevated as you might expect — COVID19 mortality was compensated in part by an unusually mild flu season.
Now Sweden is just an egregious example of a general trend: Steve “Vodkapundit” Green points out that 42% of Americans whose deaths have been attributed to COVID-19 were in nursing homes or assisted living centers.
On the 3rd of May there had been 7,844 deaths linked to COVID-19 in Belgium, of these, 4,164 people died in care homes (53%). The report also includes suspected cases and, of the total deaths, 83% of all care home deaths were suspected cases, and only 17% had been confirmed. The reported % of deaths in care homes has increased since the first date these data were published, from 42% on the 11th April to 53% on the 3rd May. The report also contains data on the numbers of care home staff and residents that have been tested since the 10th of April. As of May 3, 88,883 staff were tested, of these, 3% were positive, and of those who tested positive, 72% were asymptomatic. Of the 68,336 residents who had been tested, 7% were positive and of these, 74% were asymptomatic.
[…] In British Columbia[, Canada], counts published by the BC Centre for Disease Control11 on May 1 illustrate a total of 112 deaths as a result of COVID-19, of which 70 (63%) were patients/residents in care facilities, which includes acute care institutions, long-term care homes, assisted and independent living establishments. On that day, there were a total of 2,145 confirmed cases of COVID-19 in the province, of which 260 (12%) were patients/residents in these establishments.
[…] In Ontario[…] The official report included a total of 1,216 deaths as a result of COVID-19, of which 590 (49%) were residents in long-term care homes.
[…] Quebec is the province with the highest cases and the most deaths related to COVID-19 in Canada. According to the most up-to-date estimates from both governmental and media releases on April 29, a total of 1,859 deaths as a result of COVID-19 occurred in the province, of which 1,469 (79%) were residents in long-term care homes. Tabarnak!
[…] The total deaths in Germany on the 3rd May were 6,649, so deaths in communal settings represent 36% of all deaths (36.5% including mortality of staff in communal settings)24. […]
The first COVID-19 patient in Israel was diagnosed on February 27th and since then the number of confirmed cases has risen to 15,782 (as of April 29th), with 120 in serious condition and 202 deaths. Of the deaths, 65 were long-term care residents (32%).
[…] According to their data of the 3rd May41, the total number of deaths in nursing homes is 16,878, which, according to this source, adds up to 67% of all deaths by COVID-19 in Spain. The greatest number of deaths happened in Madrid (5,828) and Catalonia (3,044). […]
(2) Via the Jerusalem Post, here is a preprint from the Israel Institute for Biological Research
indicating that an analogue of Cerdelga (Eliglustat), a drug for the rare metabolic disorder named Gaucher’s Disease, might be a useful broad-spectrum antiviral. From the abstract:
Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target. We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection.
DIE WELT refers to Angela Merkel’s silence in the face of China’s repression of Hong Kong as “Merkel’s kow-tow”.
Elsewhere, the German paper reports on the “nightmarishly” empty beaches in St.-Tropez on the French Azure Coast. Now any tourist would be welcome — not just the rich and famous — but they aren’t coming. It would seem obvious that tourism is one sector of the economy that was going to get near-fatal blows with or without lockdowns.
According to the Daily Telegraph, remdesivir will be rolled out in the UK for treatment.
The NIH discontinued its double-blind remdesivir study. Mind you, not because the drug isn’t working, but because it is working substantially better than placebo controls, and they concluded that it was unethical to continue to feed patients placebos when they had a (somewhat) working drug on hand. Related.
Certain media outlets that cannot bring themselves to empathize with small business workers and owners who see their income dwindle to zero can somehow wax tearful about the plight of “sex workers” during the pandemic. Instapundit snarks:
“THE PRESS HAS SYMPATHY FOR SOME PEOPLE WHO ARE OUT OF WORK: The Fragile Existence of Sex Workers During the Pandemic. Sympathy for prostitutes, though, is probably just a species of professional courtesy.”
But as a sanity check, here is a list of countries in Europe and the Middle East that have started opening a while ago and still (click on the names for Worldometer links) have nicely trending-down active case numbers:
(1) OK, so you have an experimental coronavirus drug and suppose it actually works — what next? NATURE has an article on the challenges involved in scaling up production to massive quantities. For instance, Gilead, having donated its entire supply of drug on hand, has now licensed production to five generics manufacturers. And like with other manufactured products, the switch to “lean” “just in time” manufacturing and the outsourcing of critical components to cheap specialized suppliers abroad creates vulnerabilities. (The article gives a non-Chinese example: following the Fukushima earthquake and tsunami, the pharmaceutical industry faced a shortage of polyethylene glycol, as all major suppliers of this chemical were in Japan.)
(2) According to an analysis by the London School for Hygiene and Tropical Medicine, super-spreader events may be responsible for 80 percent of more of COVID19 cases, reports The Daily Telegraph.
“As most infected individuals do not contribute to the expansion of an epidemic, the effective reproduction number could be drastically reduced by preventing relatively rare superspreading events”[…] Hospitals, nursing homes, large dormitories, food processing plan[t]s and food markets have all been associated with major outbreaks of Covid-19.
Vigorous physical activity in an indoor space without adequate ventilation is one risk factor, as a South Korean analysis of outbreaks at intense workout classes at gyms found. Less strenuous classes, such as yoga, were not associated with such outbreaks, nor were outdoor sports.
Singing at high volume, and the attendant voice projection[*], is another factor associated with super-spreading events:
In Washington State on the west coast of America, a church choir went ahead with its weekly rehearsal in early March even as Covid-19 was sweeping through Seattle, an hour to the south. Dozens of its members went on to catch the virus and two died. [par] The Washington singers were not the only choristers to be hit. Fifty members of the Berlin Cathedral Choir contracted the virus after a March rehearsal, and in England many members of the Voices of Yorkshire choir came down with a Covid-like disease earlier this year. [par] A choir in Amsterdam also fell victim to the virus, with 102 of its 130 members becoming infected after a performance. One died, as did three of the chorister’s partners.
I’ve already mentioned carnival celebrations in Germany, with everybody kissing everybody and hollering at each other in packed beer halls to be understood over the loud ‘music’. (Outdoor beer gardens are probably safe, if you don’t share steins.) And then there are the apres-ski parties that have become a by-word:
Hundreds of infections in Germany, Iceland, Norway, Denmark and Britain have been traced back to the resort of Ischgl in the Tyrolean Alps. Many had visited the Kitzloch, a bar known for its après-ski parties. [par] The bar is tightly packed and famous for “beer pong” – a drinking game in which revellers take turns to spit the same ping-pong ball into a beer glass. [par] Earlier this year The Telegraph obtained a video from inside the Kitzloch. It may yet come to define the perfect superspreader event, with attendees all singing along to AC/DC’s Highway to Hell
Had I written the latter detail in a novel, an editor would consider it a particularly cheesy foreshadowing technique.
But here is the good news from all of the above: none of it is representative of how one goes about one’s normal daily business.
(3) Prayer without singing returns to synagogues in Germany and Israel (h/t: Mrs. Arbel). Church services in Germany actually reopened a couple of weeks ago: aside from social distancing similar to what is described below for synagogues, no singing. I had a look at the website of the Zentralrat der Juden in Deutschland (Central Council of Jews in Germany): they actually have a section with COVID19 guidelines. My abridged translation:
* public prayer and Torah reading are allowed again * people with even mild symptoms should stay away * maintain a distance of 1.5m (read: 5ft), preferably 2m (6.5ft) * it is recommended to keep attendance lists in case contacts need to be traced * if need be to maintain distance, use the largest hall or sanctuary available rather than a small chapel (as many congregations use for regular services) * no handshakes, hugs, kisses * worshipers are urged to wear masks (regular day-to-day nonsurgical masks OK) * recommended to bring your own siddur (prayer book) and, on the Sabbath, chumash (book with the Torah and commentaries) * using only one’s personal kippa/yarmulke/skullcap and tallit/prayer shawl (and, for weekday morning minyan, tefillin/phylacteries) * doorknobs etc. are to be disinfected frequently * disinfectant should be on hand * no kissing of religious objects (e.g., mezuzah, Torah scroll) — therefore, usual Torah scroll procession before the reading off the menu * no touching the Torah scroll when called up for a reading[NB: these behaviors are customs and not Jewish law]
(4) Matt Ridley Ph.D., veteran popular science writer and editor[**], lays out the evidence on vitamin D. As usual, his writing is a paragon of clarity.
[M]any people are deficient in vitamin D, especially at the end of winter. That is because, uniquely, vitamin D is a substance manufactured by ultraviolet light falling on your skin. You can get some from fish and other foods, but not usually enough. So most people’s vitamin D levels fall to a low point in February or March when the sun has been weak and its UV output especially so. Public health bodies have long advised people to supplement vitamin D in winter anyway. The level falls especially low in people who stay indoors a lot, including the elderly, and in those who have darker skin. Whereas the safe level of vitamin D is generally agreed to be above 10 nanograms per millilitre, one recent study of South Asians living in Manchester found average levels of 5.8 in winter and 9 in summer: too low at all times of the year. Darker skin reduces the impact of sunlight; so does the cultural habit of veiling; and so does a reluctance among some Muslims to take supplements that might have pork-derived gelatin in them.Vitamin D deficiency has long been known to coincide with a greater frequency or severity of upper-respiratory tract infections, or colds. That this is a causal effect is supported by some studies showing that vitamin D supplements do reduce the risk of such infections. These studies are not without their statistical flaws, so cannot yet be regarded as certain, but they are not quackery like a lot of the stuff coming out of the supplements industry: they come from reputable medical scientists.
What about vitamin D and Covid in particular? Results are coming in from various settings and the main message seems to be that vitamin D deficiency may or may not help to prevent you catching the virus, but it does affect whether you get very ill from it. One recent study in Chicago concluded that its result ‘argues strongly for a role of vitamin D deficiency in COVID-19 risk and for expanded population-level vitamin D treatment and testing and assessment of the effects of those interventions.’ The bottom line is that an elderly, overweight, dark-skinned person living in the north of England, in March, and sheltering indoors most of the time is almost certain to be significantly vitamin D deficient. If not taking supplements, he or she should be anyway, regardless of the protective effect against the Covid virus. Given that it might be helpful against the virus, should not this advice now be shouted from the rooftops? A new article by a long list of medical experts in the BMJ cautiously agrees, confirming that many people in northern latitudes have poor vitamin D status, especially in winter or if confined indoors, and that low vitamin D status ‘may be exacerbated during this COVID-19 crisis by indoor living and reduced sun exposure’.
Read the whole thing. I’ve been taking vitamin D and zinc supplements since the beginning of the crisis, even though I live in sunny Israel and have a very light skin type.
(5) This cartoon from Die Welt probably does not require translation:
[*] full disclosure: I am married to a classical soprano. She can easily fill a hall with sound without a microphone — and one does not achieve that feat without some serious air pressure.
[**] and member of the House of Lords, as the 5th Viscount Ridley
(1) The term “drug cocktail” is best known from AIDS, where the introduction of “cocktails” of (usually three from at least two different classes) antiretrovirals helped turn HIV from a death sentence into a long-term manageable disease. Now (h/t: Mrs. Arbel) a team from Hong Kong has achieved excellent results for COVID19 using a different cocktail, reports the Jerusalem Post. The full medical article in The Lancet can be read here: https://doi.org/10.1016/S0140-6736(20)31042-4
The cocktail in question has three components:
The HIV drug Kaletra, itself a mixture of two protease inhibitors, Lopinavir and Ritonavir.
The hepatitis drug Ribavirin, a nucleoside analog that can mimic both the letters A and G of the genetic code, and thus messes with copying of the viral RNA (cf. my earlier posts on Remdesivir)
The immunomodulator Interferon beta-1b, better known to multiple sclerosis patients as REBIF.
The control group was given just Kaletra. Otherwise, both groups received standard supportive care, including antibiotics for secondary bacterial infections.
What’s with the protease inhibitor? Many of these viruses (including SARS-NCoV-2 have their envelope etc. Proteins encoded as a single long “protein sausage” on their RNA. After protein synthesis in the ribosome (the cell organelle that assembles proteins from amino acids according to the ‘program tape’ on the RNA), a protease then splits the ‘sausage’ into individual ‘links’.
So we have two drugs that tamper with the ability of the virus to make its envelope, plus one that inserts junk ‘letters’ in the copied RNA. Even if each partially successful, they will slow down viral reproduction. So what is the role of the beta-interferon? To tell the body’s immune system: “don’t go berserk, take it easy!” and prevent cytokine storm.
If treatment was started less than 7 days after onset of symptoms, the “triple cocktail” group showed better clinical and virological outcomes than the control group across all meaningful measured variables. For the subgroups of patients where treatment was delayed longer, there was no statistically significant difference in outcomes between the cocktail and control group. So early intervention is worth a lot.
Median time to negative RT-PCR test was 7 days for the “cocktail” group, compared to 12 days for the control group.
It’s not a magic bullet drug: every doctor dreams of what Frederick Banting experiences when he first administered insulin to boys in diabetic coma, where the first boys were waking up before he’d finished injecting the last. But that kind of spectacular success is the rare exception in drug research.
What we can safely say we have here, I believe, is a ‘cocktail’ that is greater than the sum of the parts. And a nice thing about cocktails of existing drugs: each component already has undergone clinical trials and obtained FDA (or foreign equivalent) approval individually.
What about side-effects? Reading Table 4 in the paper, the difference with the control group for nausea, diarrhea,… is not statistically significant. No patients in the ‘cocktail’ group suffered severe adverse events, vs. one in the ‘Kaletra only’ control group.
(2) My friend “masgramondou” weighs in on the source code of the “Ferguson Model”: All models are wrong, and some are useless. Or worse than useless, in this case. He points to another model that might at least be somewhat more transparent than the others: https://covid19-scenarios.org, developed by the group of Prof. Richard Neher at U. of Basel, Switzerland.
(1) The top news item of the day is probably that Gilead Scientific’s antiviral drug remdesivir was given FDA Emergency Approval for use in COVID19 patients. Remdesivir is not a “magic bullet”, but it’s a start.
(2) Roger Seheult MD, pulmonologist and medical school instructor, gives a 1.5 hour recap video on what we know about COVID19.
(3) Miscellaneous updates:
the Ma`ayanei haYeshua [Wellsprings of Salvation] hospital in Bnei Brak, Israel (a COVID19 hotspot) has deployed an Israeli-developed UV-C room sterilization system. This is of broader relevance than COVID19, and if successful, will prove very helpful in the protracted and increasingly worrying struggle against hospital “superbugs” — bacteria resistant to every known antibiotic. (Such bacteria tend to develop in hospitals and long-term care settings through “Darwinian selection”, as both infections and treatment with aggressive antibiotics are frequent.)
worrisome reports about some peculiar COVID19-like pediatric syndrome noted in earlier updates: these now appear to have been identified as Kawasaki’s disease, which is of uncertain origin but some sort of autoimmune etiology is suspected. Coincidence or new cases triggered by COVID19 infection?
if you give people perverse incentives to cook the books, and don’t balance that out with a deterrent for the act of cooking — well, don’t be surprised if books get cooked. NYC funeral director on candid recording about people who obviously died from otehr causes being coded as COVID19. Mind you, I am sure the un-inflated COVID19 mortality in NYC would be quite bad enough (“thanks” to very high pollution density and the subway as “the mother of all superspreaders”) — but those numbers struck me as anomalously high from the start. (As discussed in previous updates, numbers from Italy and Belgium are inflated for different reasons.)
(4) In contrast, countries like South Korea and Germany have rather more scrupulous reporting standards. I’ve linked previously to the daily Korean CDC reports: here is the detailed daily update (in English) from the Robert Koch-Institute (Germany’s infectious diseases authority, named after the discoverer of the tuberculosis pathogen). A few highlights from the daily report:
Only 19% of all cases occurred in persons aged 70 years or older — but these account for 87% of deaths.
cases per 100,000 people in age cohorts are fairly homogenous across age cohorts 20-29 through 70-79, climb sharply in the highest age cohorts, and drop steeply for ages 10-19 and especially 0-9.
mortality in age cohorts 0-9 and 10-19 are ONE (1) patient each, while age cohorts 20-29 and 30-39 account for just 6 and 14 deceased out of a total of 6,472. Yes, Virginia, ages below forty account for just 0.3% of all dead, and all ages below fifty for just 1%. Fifty-somethings add another 3.2%, sixty-somethings another 9.0%.
Their technique of estimating the effective reproductive number R consists of dividing the 4-day moving average of new cases by the one 4 days earlier. At present it is R=0.79, with a 95% confidence interval of 0.66–0.90. Any R value below 1 implies that the epidemic will wither away, while any value over 1 implies slower or faster exponential growth.
Good morning, happy weekend, shabbat shalom. In today’s update, mostly videos, which I’m linking rather than embedding (as a workaround for a WordPress dot com editor bug).
(1) Mike Hansen MD reviews COVID19 drug trials. He’s bearish on HOcq (2/10) but surprisingly bullish on ARBs (angiotensin II receptor blockers, 7/10) and to a lesser extent ACE inhibitors (5/10), both types of drugs in established use as antihypertensives. For remdesivir: great results in Chicago leaked, less so in Mass (7/10). Favipiravir [sold in Japan as AVIGAN as an anti-influenza drug] targets RdRp (6/10). IL-6 inhibitors: tocilizumab (approved for managing cytokine storm, used in severe RA and in immunotherapy complications): expensive, potent immunosuppressants (5/10).
His top 5: Recombinant ACE2 (8/10); ARBs tied with remdesivir (7/10) and favipiravir/Avigan (7/10); Umifenovir/Arbidol (6/10)
(2) Via reader Dawn Miller, a two-part interview by a local ABC affiliate with Dr. Dan Erickson, operator and chief physician of Accelerated Urgent Care in Bakersfield, CA. Among many other things, he is saying that, at least at this point, the lockdown in CA is doing much more harm than the disease itself.
On a tangentially related note, a medical source in Belgium told me that, while they never did the “shut everything down to make room for COVID19 patients” thing, they notice a steep drop in patients coming in with suspected cardiovascular and cerebrovascular complaints, and like their German colleagues, they can’t believe “heart attacks and strokes are suddenly 30% less frequent”. They believe they’ll have huge “medical cleanup bills” on deferred care cases. He also told me that in the grey area of urgency, access to care can be problematic: he gave the concrete example of a tooth abscess in an elderly patient with a pacemaker. As pericarditis is a not-uncommon complication of dental surgery in such “risk patients”, he referred the octogenarian to an oral surgeon at the local hospital — but the department was closed due to COVID19. “Just take antibiotics.”
(h/t: Erik Wingren) fatal strokes showing up in young coronavirus patients?! (WaPo; archive) We know (see, e.g., Dr. Seheult’s video I’ve been linking) that blood clotting in the lungs is one phenomenon occurring during severe COVID19, hence prophylaxis regimes of some doctors include mild anticoagulants/antithrombotics like low(ish)-dose aspirin. Note that at least here, many doctors start prescribing the latter to patients for cardio- and cerebrovascular prophylaxis when the patients reach their fifties: these younger patients would not yet have been on them.
Marc Andreessen [of Mosaic/Netscape fame, and now Andreessen Horowitz]: It’s Time To Build
Belgium update: politicians accelerate the unlock time table, reports De Standaard (in Dutch): the 2nd phase has been moved from May 18 to May 11.
A community immunity testing effort by the University of Geneva Hospital is reported on here (in French). More later perhaps on this, but as of April 17, they found that 5.5% of testing subjects had antibodies for COVID19. Again we see a very substantial Dunkelziffer/”dark number”/stealth infection rate: on the same day, total known COVID19 cases accounted for just 0.3% of the Swiss population, though I don’t have numbers for Geneva specifically.
DIE WELT (in German) reports on the situation in the mostly-immigrant Paris suburbs of the 93rd Département, where workers in both the formal and “informal” economies have been pushed out of work. Even the Préfect (chief administrator of a Département, somwhere between a County Judge and a Governor in US parlance) takes seriously the possibility of food riots.
UPDATE: via David S. Bernstein, a profile of Stanford statistician John Ioannides (WSJ behind paywall, archive copy here).
(1) I saw a video by pulmonologist Mike Hansen MD that made me go “aha!”. He may be pitching its message a bit too strongly, but was delivered in a highly entertaining manner, and is easy to follow if you have some basic medical knowledge. See the video here. (Something is broken with the YouTube embedding widget that makes WordPress glacially slow to edit on my computer.)
It is almost like the disease has two faces. In the vast majority of patients, there is no involvement of the lower respiratory tract — just upper respiratory and some gastro-intestinal involvement (there are ACE2 receptors there), rarely some cerebral. This disease picture is the (generally) nonlethal one, ranging in severity from mild cold to severe flu without secondary infection. Such patients will get better on their own with nothing more than standard supportive treatment, like you would for a nasty flu at home.
It’s when the infection goes down to the lower part of your lungs that all hell can break loose. Effectively, the inflammation of the alveoli sets off a chain reaction (which he explains in great detail) that can easily blow up into ARDS (acute respiratory distress syndrome) and cytokine storm, and ends up with the patient getting killed by his own immune system. The key is to intervene before this happens.
In his picture, antiviral drugs would be most useful in the early stages — to stop the infection from spreading to the lower lungs — or even for prophylaxis. (However, I’d point out that, especially with remdesivir, there have been “saves” of severely ill patients.) In later stages of the disease, immunosuppressants actually would be more valuable, to rein in the immune system running amok.
The people who say “it’s just a flu” are actually right in 90+% of symptomatic cases. In the remainder it’s almost like what my brother would call the “autoimmune disease from Hell”.
Two other nuggets from the video:
(2) John Campbell keeps coming back to vitamin D and its vital role in the immune system. He points out that, while only 14% of Britons are nonwhite, they constitute nearly one-third of critical COVID19 cases. Socio-economic and cultural factors (e.g., multigenerational families under one roof, like is common in Italy) aside, vitamin D deficiency is much more common at northern latitudes if you have a dark skin type. (Anecdotally, I know that a family acquaintance of Yemenite-Jewish heritage [and hence with very dark skin] who moved to Sweden suffered all sorts of health problems, until UV lamps and vitamin D supplements entered the picture.[*] ) This aspect of the problem is very easy to solve…
Dr. Campbell is a bit dismissive of the estrogen-IL6 hypothesis “since why would there then be a gender difference at post-menopausal age?” Instead, he points out that many immunity-related genes are on the X chromosome, and if you have one defective copy and you’re male, that’s your only copy, while a female would have the 2nd X chromosome… (This is aside from the risk factor of smoking — in countries like China much more prevalent in men than in women.)
In another video (h/t Mrs. Arbel), he backtracks on earlier comments about Greece, and notes they have been more proactive than he thought (canceling school 9 days before the UK, in fact) and are now seeing the fruits thereof, as cases have dwindled. A similar decrease in deaths will lag by several weeks.
(3) Chemical and Engineering News, the house organ of the American Chemical Society, looks at the challenges for Gilead Sciences in scaling up production of remdesivir to the millions of doses range. In the earlier case of Tamiflu, Hoffmann-LaRoche licensed manufacturing from Gilead Sciences — and was able to provide 200 million courses’ worth of Tamiflu in comparatively short order.
(4) Via Instapundit: is there a correlation between universal BCG (Calmette-Guérin) tuberculosis vaccination policy and reduced COVID19 mortality?
I found this database of global BCG policies www.bcgatlas.org (documented here). Let me show a map:
A (ochre) refers to countries with mandatory BCG vaccination, B (purple) to countries who had it as mandatory in the past, and C (orange-red) to countries where it was never mandatory. The blatant difference in mortality between (culturally and ethnically very similar) Portugal and Spain has been ascribed to me by a Portuguese US immigrant to the existence of a parallel private medical system “that actually functions”, unlike the government-only option in Spain; but I wonder whether BCG couldn’t play a role. (TB used to be endemic in Portugal.) Belgium vs. Germany (again, ethnically and culturally quite similar) is another case. However, what about France then?
Israel used to have mandatory BCG until 1982—which implies the older generation (the most at-risk) would see some benefits. (As vaccines go, BCG is a pretty blunt instrument that “trains” the first responders of the immune system, which are not terribly selective.) And indeed, in combination with our young-ish population pyramid and our warm climate (today the mercury hit 90°F), this may go some way towards explaining the comparatively low mortality in Israel.
[…] Early on, as the epidemic loomed, many hospitals took the common-sense step of halting elective surgery. Knee replacements, face lifts and most hernias could wait. So could checkups and routine mammograms.
But some conditions fall into a gray zone of medical risk. While they may not be emergencies, many of these illnesses could become life threatening, or if not quickly treated, leave the patient with permanent disability. Doctors and patients alike are confronted with a worrisome future: How long is too long to postpone medical care or treatment?
Delaying treatment is especially disturbing for people with cancer, in no small part because it seems to contradict years of public health messages urging everyone to find the disease early and treat it as soon as possible. Doctors say they are trying to provide only the most urgently needed cancer care in clinics or hospitals, not just to conserve resources but also to protect cancer patients, who have high odds of becoming severely ill if they contract the coronavirus.
Nearly one in four cancer patients reported delays in their care because of the pandemic, including access to in-person appointments, imaging, surgery and other services, according to a recent survey by the American Cancer Society’s Cancer Action Network.
Tzvia Bader, who leads the company TrialJectory, which helps cancer patients find clinical trials, said frightened patients had been calling to ask her advice about postponements in their treatment.
One woman had undergone surgery for melanoma that had spread to her liver, and was due to begin immunotherapy, but was told it would be delayed for an unknown length of time.
“She says, ‘What’s going to happen to me?’” Ms. Bader said. “This is not improving her chances.”
And some clinical trials, where cancer patients can receive innovative therapies, have been suspended.
“The mortality of cancer has been declining over the last few years, and I’m so terrified we are going backwards,” Ms. Bader said.
[*] As for me, I can’t be outside for more than 30 minutes or so on an Israeli summer day without nasty sunburn 😉 There is a reason the term “redneck” exists in the American South, as does “rooinek” in Afrikaans…
(1) Today, Israel started Phase 1 of its “back to normality” plan. There appears to have been intense tug-of-war between economic and healthcare decision makers, which resulted in some tradeoffs. Masks were made mandatory, giving in to a strong demand from the Health Ministry, but in compensation, a large number of retail stores that were only supposed to reopen in Phase 2 are doing so right now.
I treated myself to a long walk around the Tel Aviv borough where I live. About 2 in every 3 stores was open for business, and of the remainder, some were setting up for reopening.
The numbers are shocking. Downstate has been so heavily impacted by the coronavirus that it skews the United States when you compare us to the rest of the world.
Downstate New York technically includes New York City, Long Island, and the Hudson Valley, but I am only including Kings, Queens, New York, Suffolk, Bronx, Nassau, Westchester and Richmond Counties. These counties have a population of 12,205,796, according to World Population Review’s numbers for 2020—bigger than many countries.
It’s currently claimed that the USA “leads the world in COVID19 cases and deaths”. In fact, as Matt points out, in confirmed cases per capita, the US is only #7 worldwide (Spain is #1). Bad enough, you say? But if we treated greater NYC/”downstate New York” as a separate country, it would have #1 worldwide by a longshot — with four times the per capita incidence of Spain at #2. “USA minus NYC” would only be #14 worldwide. In per capita fatality rates, the whole USA comes at #8 [I suspect actually as #9, since Sweden appears to be omitted in that list], but NYC treated as a country would again be the #1 by far, with double the mortality of the #2 (Belgium). “USA minus NYC” drops to #11.
(4) The Great Decoupling? Legal Insurrection reviews worldwide signs of countries “socially distancing” from the Chinese communist regime. Even Emmanuel Macron [!] now seems to get it.
(5) The German tabloid BILD reports on successful use of Remdesivir in Munich. With every new report, I’m getting more positive about that drug.
(6) Prof. Jonathan Gershoni of Tel-Aviv U. claims to be “2/3 of the way toward a vaccine”. The basic idea of most vaccine developers seems to be to target the “spikes” of the coronavirus, which are responsible for getting cells to let the virus in. If the virus were to lose those in a mutation-evolution process in an attempt to ‘get around the vaccine’, it would become a lot less dangerous anyhow.
(7) And it appears that some applied mathematicians who noticed a repeated empirical pattern in the progress of the epidemic in several countries may have rediscovered Farr’s Law.
The University of Chicago Medicine recruited 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir.
“The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish,” said Kathleen Mullane, the University of Chicago infectious disease specialist overseeing the remdesivir studies for the hospital.
Her comments were made this week during a video discussion about the trial results with other University of Chicago faculty members. The discussion was recorded and STAT obtained a copy of the video.
[…]
Mullane, while encouraged by the University of Chicago data, made clear her own hesitancy about drawing too many conclusions.
“It’s always hard,” she said, because the severe trial doesn’t include a placebo group for comparison. “But certainly when we start [the] drug, we see fever curves falling,” she said. “Fever is now not a requirement for people to go on trial, we do see when patients do come in with high fevers, they do [reduce] quite quickly. We have seen people come off ventilators a day after starting therapy. So, in that realm, overall our patients have done very well.”
She added: “Most of our patients are severe and most of them are leaving at six days, so that tells us duration of therapy doesn’t have to be 10 days. We have very few that went out to 10 days, maybe three,” she said.
There was anecdotal evidence from the start that remdesivir — originally developed for ebola, and previously shown to be active in vitro (i.e., in the test tube) against coronaviruses — was effective in at least some COVID19 patients. There were two early cures during the Washington state outbreak, and in Israel, “patient #16”, a tour bus driver who got severely ill after ferrying a group of infected pilgrims around for days, quickly recovered when given the drug as a last resort. Also, last week, a small trial was published in the prestigious New England Journal of Medicine.
Unlike the several mechanisms proposed for hydroxychloroquine, the mechanism by which remdesivir works is clearly understood and unambiguous. In plain English, the drug [*] pretends to be the letter A of the genetic alphabet, but when the enzyme RdRa (RNA-dependent RNA polymerase) starts making copies of the virus RNA and it grabs the “fake A” instead of a real A (adenosine), the next letter has nowhere to go, and copying breaks off. (This is not something I can see an easy way for the virus to quickly mutate-and-evolve its way into resistance for: making RdRa so clever it can tell the difference between real A and fake A? Developing an enzyme that selectively “eats” the fake A?)
The theory sounds good, and was confirmed in the test tube and in an “animal model” (in this case, rhesus monkeys): but many drug candidates that ticks all the boxes in the lab fall flat when administered to actual human patients. Fortunately, testing for safety and side effects in humans had already been completed years ago, when Gilead Sciences first tried to obtain FDA approval for its use in ebola. Thus, clinical trials could skip these steps and immediately proceed to actual clinical effectiveness tests.
I am looking forward to the final public release of data, but this looks quite promising.
Elsewhere on STATNEWS, I found another story reviewing the evidence (some of it covered here in earlier updates) about ventilators in a COVID19 setting, and how in many cases noninvasive respiration appears to be the preferred alternative. Read the whole thing.
In the US, President Trump has unveiled a staged “Opening Up America Again” plan (full text available at the link). The plan is attacked by some as being too timid and laying out unrealistic threshold conditions . Others say that it reflects a compromise between epidemiological and economic imperatives. We link, you decide.
Finally, Israeli PM Benjamin “Bibi” Netanyahu signed off in principle on a staged plan for reopening the Israeli economy, to be voted on in a cabinet meeting tomorrow night.
Unless important news breaks tomorrow, I will probably skip updates on the sabbath. Shabbat shalom, and to the Eastern Orthodox Christian readers, a meaningful Good Friday and a happy Easter. And to all: stay healthy and safe!
[*] technically, remdesivir is what pharmacologists call a prodrug, i.e., a molecule that within the body reacts to release the active drug component.
UPDATE: Dr. Seheult on remdesivir and on a novel approach to keeping hospital rooms and public spaces sterile: far UV-C lamps. UV-C light is the type of “hard” UV radiation that is blocked by the earth’s ozone layer. Far UV-C (207-222nm) is high enough energy to destroy bacteria and viruses, but too short-waved to penetrate further than the top layer of cells — therefore does not cause skin cancer or cataracts.
(1) Dutch scientists discovered that SARS-nCoV-2 can be detected in a city’s wastewater even before anybody realizes they are sick. “[Medema and coworkers] detected genetic material from the coronavirus at a wastewater treatment plant in Amersfoort on March 5, before any cases had been reported in the city, located about 50 kilometers (32 miles) southeast of Amsterdam. “
(2) Chemical and Engineering News, the house organ of the American Chemical Society, has more on remdesivir as well as on another antiviral discovered at Emory, EIDD-2081. While remdesivir needs to be administered intravenously, EIDD-2081 can be given orally. On the other hand, EIDD-2081 hasnever been tested in humans while remdesivir underwent safety testing back in 2015 (as a potential ebola drug.
(3) WIRED has a long story about masks. “Let’s face it: they work”. Most of the evidence concerns other respiratory viruses:
“A 2011 review of high-quality studies found that among all physical interventions used against respiratory viruses—including handwashing, gloves, and social distancing—masks performed best, although a combination of strategies was still optimal.”
Fortunately, the available evidence suggests that for most people in most situations, an N95 is not a necessary form of protection against Covid-19. If we eventually have a surplus of surgical masks, which are much more comfortable and affordable than respirators and still provide excellent protection, they would be an ideal choice for universal masking. In the meantime, homemade masks made from tightly woven yet breathable fabric are the best option and certainly better than nothing. A piece of cloth will never be as good as a manufactured filter, but it can still smother the brunt of a cough or sneeze and impede other people’s respiratory droplets.
Read the whole thing.
Seattle police during the 1918 “Spanish flu” pandemic
“Spain’s health ministry last Thursday said it had withdrawn around 58,000 Chinese-made test kits after it emerged that they had an detection accuracy of just 30 percent. The normal accuracy rate is more than 80 percent, local media reported.”
The story of a shipment of 600,000 mouth masks for healthcare workers being disapproved by the Dutch authorities as not meeting basic quality standards is all over the Dutch-language media, e.g., here in De Telegraaf.
(6) GenomeWeb reports that a genetic cancer testing company, that has seen demand slump as “non-urgent” medical tests are put off due to COVID-19, is now retooling for COVID-19 testing.
(7) Israel starts passive immune therapy experiment. This happened only today, as they needed a plasma donor who was not only cured, but had subsequently tested negative for the virus at least twice.
Normally, Phase I, II, and III clinical trials on a drug take a lot of time and effort. But if you are merely repurposing an existing drug for another disease, you can short-circuit a lot of that since you already know safe dosage range and side effects.
These are the three that jumped out at me.
(1) Remdesivir was originally developed by Gilead Science as an anti-ebola drug. It worked against that virus in vitro (i.e. in the lab “test tube”) but not in vivo (i.e. in actual patients). It also worked in vitro against MERS and against the original SARS, so trying it against COVID-19 was worth at least a try.
Which is what was tried as a desperation roll of the dice on an early patient patient in Washington state, with apparently impressive success . Since then, increasing confirmation has been seeping in. Controlled clinical trials are in progress, with results expected next month.
Remdesivir is a so-called “nucleotide analog”. In plain English, it pretends to be a nucleic acid (i.e., a letter in the genetic code), but when the “imposter” is being incorporated in a piece of RNA instead of the real nucleotide, it has no place to attach the next one, and copying stops. Thus, the virus cannot reproduce.
(2) Favipiravir (sold in Japan under the brand name AVIGAN by Toyama Chemicals, a subsidiary of FUJIfilm). This was developed as a broad-spectrum anti-RNA-viral drug. It is an RdRA (RNA-dependent RNA polymerase) inhibitor, i.e., it interferes with the enzyme responsible for copying the viral RNA.
Japanese doctors apparently are using the drug, and China is running clinical trials.
(3) Chloroquine (a 70-year old generic antimalarial), and its close relative hydroxychloroquine, are at first sight the odd duck among the three. It’s obvious why the two above drugs could work, and it appears that they do. But why do we hear a lot about chloroquine these days? Last time I checked, malaria was not even a viral disease?
There is a fairly lucid explanation here of what is going on:
Zn2+ and RdRA discussion about midway through the video
Like for AVIGAN, it’s again about RdRA. Turns out Zn2+ ions latch onto the enzyme and act as an inhibitor. [UPDATE: reference here.] The trouble is getting zinc into the cell. Now in a completely unrelated research project on metallophores as anticancer drugs, it was found that chloroquine is a very good zinc ionophore: https://doi.org/10.1371/journal.pone.0109180
I doubt it is the most effective of the three. On the other hand, chloroquine and its less toxic close relative hydroxychloroquine have been used extensively for decades in areas where malaria is endemic, both for treatment and prophylaxis, so their safety profile and side effects are very well understood. Besides they are very cheap as well. (Report of stocks running out in Western countries: well, these aren’t drugs you routinely stockpile unless you are dealing with malaria all the time… although they have been in some use for lupus and rheumatoid arthritis.) So it apparently has been part of treatment regimes in both Korea (hydroxchloroquine) and China, and it appears to at least some extent in Italy.
Speaking of Italy: yesterday the independent media circulated a report that only 1% of case fatalities in Italy were people without pre-existing conditions. Meanwhile, Bloomberg has picked up the story, and from there I located the original official report (in Italian) on the website of the Italian public health office. This graph is from the Bloomberg report:
and this table (screenshot) comes from the original report
Table 1 from the Italian March 17 report:pre-existing conditions in patients deceased from coronavirus
The Italian names mean, in order, coronary disease, atrial fibrillation, stroke, hypertension, diabetes, dementia, COPD (chronic obstructive pulmonary disease), active cancer in the past 5 years, chronic liver disease, and chronic kidney insufficiency. Needless to say, the statistical risk for ALL of these increases with age, so as patients get older, the percentage of them without any comorbidities will get smaller and smaller.
Stay well, stay safe, and above all, stay calm and rational.
One of the first countries to deal with the epidemic was South Korea. Unlike China, South Korea is a fairly transparent society and data published by the Korean CDC (Center for Disease Control) can be more or less taken at face value.
The most interesting part of the report is Table 5, which I am reproducing as a screenshot below:
Table 5 from the Korean CDC report, March 18, 2020
Let’s have a good look at this. Preliminary remark: Korea started a massive testing (according to Table 1 in the same report, nearly 300,000 people have been tested, at a current rate of 10,000 a day) and tracking program early, leveraging all available tech data — privacy concerns be darned.
Observation 1: overall mortality is 1 (one) percent. Still one percent too much, to be sure. But considerably lower than what has been reported from some other places — I suspect because of undertesting.
Observation 2: mortality in the 0-29 age bracket is nil — not one death out of 2,867 patients.
Observation 3: in the 30-49 age bracket, just two (2) deaths out of 2,044 patients, or about 0.1%. Only above 50 does mortality start rising, over 60 in a worrisome fashion. (Not coincidentally, so do comorbidities/pre-existing conditions. I would love to see the statistics broken down between otherwise healthy people and those with chronic cardiovascular/pulmonary/immunity/diabetes problems, or cancer patients. Hypertension is apparently another major risk factor.)
Observation 4: Note the interesting “gender gap”. Men (1.39%) have nearly twice the mortality of women (0.75%). I asked friends on Facebook familiar with South Korea, and they told me over half of men smoke, compared to fewer than five percent of women.
And then there is the uncertainty factor of how many people are asymptomatic virus carriers. This is impossible to ascertain without a much more massive testing program (and this isn’t a test you can quickly do with a strip!), but I have seen estimates from 5-7 carriers for each overt disease case.
But the Diamond Princess cruise ship offers an interesting insight. It had nearly 4,000 people on board—many of them in risk groups. (Somebody who used to perform aboard cruise ships quipped that passengers are mostly “the newlywed and the nearly dead” ;)) You’d expect these packed together on a ship in quarantine to be all infecting each others. And yet… 4,061 passengers and crew were examined, on board what effectively became an unintentional virus incubator. Only 712 contracted the virus (about 17.5%), of which 334 asymptomatic (8.2% of the total), leaving 378 (9.3% of the total) ill. Only 7 people died (1.85% of those ill, or 0.17% of all passengers and crew examined), all of them age 70 or older. (Remember, the passenger population is skewed toward the elderly.)
One might treat Diamond Princess stats as an upper limit (since spreading in even dense urban areas will never be as efficient as on a cruise ship) and South Korea as what can be achieved with agile and efficient tracking and containment measures.
Meanwhile, a frantic search for both vaccines and drugs continues. One track that may yield results earliest is the repurposing of existing drugs following off-label testing, since safety and “therapeutic interval” testing have already been done for their original approval. I have mentioned a promising remdesivir trial and I see increasing reports that chloroquine (which has been used for decades as an antimalarial) may interferewith the virus lifecycle. (See e.g., https://www.ncbi.nlm.nih.gov/pubmed/32171740)
Be well, stay healthy, be prepared, and remember:
[L]et me assert my firm belief that the only thing we have to fear is fear itself — nameless, unreasoning, unjustified terror which paralyzes needed efforts to convert retreat into advance.
UPDATE 2: computational biochemistry pioneer Michael Levitt (2013 Nobel Prize in Chemistry shared with Arieh Warshel and Martin Karplus) sounds an optimistic note based on what he knows. His comments start off with Israel (he divides his time between Weizmann and Stanford) but then go on to the rest of the world.
A guestblogger at Watts Up With That, who himself survived the infection, has a news-packed update. Read the whole thing, but perhaps the most important paragraphs are:
Transmission route is either contact or inhalation […] The significant inhalation route is now shown by both the Diamond Princess cruise ship experiment (more below) and by the fact that ordinary surgical masks proved ineffective in the Wuhan hospital setting (JAMA, previous post).
Incubation period is 7-10 days from initial infection. The good news is that the 14-day quarantine adopted pretty much universally last week should therefore be effective […] Wuhan then makes a now well-established clinical bifurcation. In 75-80% of cases, by symptom day 10 there is a normal ‘corona cold’ recovery lasting a few days. (In my own case last week, 3 recovery days in total, days 9-12 from symptom onset.) In 20-25% of cases, by symptom day 10 Wuhan progresses to lower respiratory tract pneumonia, where death may occur with or without ICU intervention. The percentage of these deep pneumonias that are viral as opposed to a secondary bacteria infection is not known, but the NEJM clinical case report from Washington State discussed in the following paragraph strongly suggests viral (like SARS), not secondary [opportunistic] bacterial [infection] treatable with antibiotics.
The bad news is that Wuhan IS transmissible during some later part of the symptomless incubation period. […]
And here is some good news:
The new NEJM [New England Journal of Medicine] case report is so important it is summarized here because it leads to a hopeful culminating section below. The Seattle Wuhan case evidenced x-ray diagnosed lower respiratory tract pneumonia from days 9-11 from symptom onset. Supplemental oxygen was started day 9. IV antibiotics were started day 10 to no effect, so discontinued after one day. Importantly (more below), experimental antiviral remdesivir started day 11 by IV under a compassionate use exception, and the deep viral pneumonia fully resolved (per x-ray diagnosis) within 24 hours!
Remdesivir was developed by Gilead Scientific as an antiviral for Ebola and Marburg viruses, but was subsequently found to be active against other single-stranded RNA viruses.
Based on this, China has announced a full-scale random double blind placebo controlled trial in 761 patients. As of this writing China reports successful synthesis of sufficient remdesivir active, so human testing begins today.
Spin, strangeness, and charm 