A Quick Summary of the COVID-19 Literature So Far
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What your doctor is reading on Medscape.com:
MAY 18, 2020 — Since March 25, two HIV clinical fellows, Eric Meyerowitz, MD, and Aaron Richterman, MD, MPH, have recorded a biweekly deep dive into the most compelling COVID-19 data. Their presentations have become “must-see” TV (or rather, YouTube) for those trying to make sense of all the pandemic-related literature.
Medscape asked them to summarize what they’ve learned so far, ahead of their next update, scheduled for May 19.
Below are key takeaways from our fourth update, covering April 23 to May 5, during which more than 3000 COVID-related papers were published on PubMed and another 766 were released in preprint form:
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Remdesivir: A small, underpowered study in China found no difference in 28-day clinical improvement or mortality, in contrast to as-yet unpublished data from a larger NIAID study.
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The benefit of IL-6 inhibitor therapy is unknown; multiple randomized controlled trials (RCTs) are ongoing.
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Early studies suggested that viral RNA was rarely found in the blood. Now viremia/RNAemia with extrapulmonary infection is becoming more characterized, but it’s still not clear whether it represents systemic infection with infectious virus.
-
It’s currently unknown what proportion of patients have a viremic phase of illness.
-
The association between thrombosis and COVID-19 is becoming clearer, but the benefit of changing evidence-based anticoagulation strategies is unknown.
-
Structural inequities around racism and impoverishment are associated with differential outcomes, and more data are urgently needed.
-
Nonpharmaceutical interventions are important for epidemic control and economic recovery.
COVID-19 Therapy Randomized Trials
We summarized the major RCTs on COVID-19 therapeutics for which we have full papers (some in preprint form) (Table 1).
Table 1. Major COVID-19 Randomized Treatment Trials to Date
|
Ref
|
Drug Tested
|
Total N
|
Outcome
|
Notes/Limitations
|
|
|
Lopinavir/ritonavir
|
199
|
No difference
|
Clinical improvement, mortality, and percentage of patients with detectable viral RNA similar; median of 13 days from illness onset to randomization
|
|
|
Favipiravir versus umifenovir
|
240
|
For patients with moderate COVID, favipravir led to faster day 7 clinical recovery and resolution of fevers but no difference in need for mechanical ventilation
|
Preprint report
|
|
|
Hydroxychloroquine
|
150
|
No difference
|
Primary outcome of viral clearance at 28 days may not be a good endpoint; randomized late in illness course
|
|
|
Lopinavir/ritonavir versus umifenovir versus control
|
86
|
No difference for primary or secondary outcomes
|
Randomized 2:2:1; open-label trial with relatively small N; primary endpoint was time to negative RT-PCR, which may not be meaningful
|
|
|
Remdesivir
|
237
|
No difference in primary outcome; trend toward mortality improvement for those started within 10 days of symptom onset
|
Outbreak controlled in Wuhan before prespecified enrollment goal could be met: underpowered; majority of patients received steroids in this cohort
|
Continued
We also discussed additional therapeutic data from press releases (Table 2).
Table 2. Preliminary Data on COVID-19 Randomized Treatment Trials
|
Ref
|
Drug Tested
|
Total N
|
Outcome
|
Notes/Limitations
|
|
|
Remdesivir
|
1063
|
Remdesivir group: 31% faster recovery compared with placebo; trend toward improved mortality
|
Preliminary report of findings based on press release; formal report pending peer review
|
|
|
Remdesivir
|
397
|
Similar improvement in severe-disease patients who received 5 or 10 days of remdesivir
|
Industry-sponsored trial (Gilead); no placebo arm
|
|
|
Tocilizumab
|
129
|
Primary outcome was need for mechanical ventilation or death; “A significantly lower proportion of patients reached the primary outcome in the tocilizumab arm.“
|
Open-label study (no placebo); preliminary report of findings based on press release; formal report pending peer review
|
|
|
Sarilumab
|
457
|
“Negative trends” in severe-disease group in phase 2, with “positive trends” in critical group
|
Industry-sponsored trial (Regeneron/Sanofi); phase 3 trial continuing with sarilumab 400 mg versus placebo in critical group only
|
SARS-CoV-2 Transmission
The table below summarizes the key transmission findings.
Table 3. Key Findings in Mode of Transmission
|
Source
|
RNA Detected?
|
Live Virus?
|
Mode of Transmission and Evidence
|
|
|
Nasopharynx (1)
|
Yes
|
Yes
|
Droplet confirmed
|
Direct contact suspected
|
|
|
Yes
|
Yes
|
Airborne likely in some circumstances
|
|
|
Saliva (3)
|
Yes
|
Yes
|
Direct contact suspected as above
|
|
|
|
Yes
|
Yes
|
No evidence fecal-oral to date: Macaques challenged with intragastric SARS-CoV-2 were not infected (however, direct inoculation in oral mucosa suspected)
|
|
|
|
Yes
|
No
|
No confirmed bloodborne transmissions to date
|
|
|
|
Yes
|
Yes
|
Macaques with corneal inoculation develop infection
|
|
|
Vertical
|
Yes
|
N/A
|
Several cases of fetal IgM, 1 case of neonate with RNA at 16 hours (10) (11); additionally, multiple reports of placental infection (12)
|
|
|
Semen/vaginal fluids
|
Yes
|
|
SARS-CoV-2 RNA has been detected in semen, including after recovery (13); most reports have not found virus in vaginal fluids, but there is a signal report with positive vaginal swabs (14)
|
|
|
Urine (15)
|
Yes
|
Yes
|
|
|
|
Cats (16)
|
Yes
|
Yes
|
Cats can transmit SARS-CoV-2 between each other
|
|
The Figure below illustrates what we know about the clinical course of the disease
Continued
Here are some key points from our first three presentations that are still valid.
Viral Shedding: Key Points
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Nasopharyngeal viral load peaks around 1 day prior to symptom onset, correlating to peak time of infectiousness.
-
Saliva may become an important sampling site for diagnosis.
-
SARS-CoV-2 is a descending infection; in later disease, viral loads are higher in the lower respiratory tract (especially in severe/critical illness).
-
In mild cases, live virus is isolated up to day 8 after symptom onset.
-
There can be prolonged shedding of viral RNA lasting many weeks, particularly after critical illness. Correlation with infectiousness is unknown.
-
Studies differ on whether severity of illness correlates with viral load.
-
In some cases, viral RNA has also been identified in the stool, blood, conjunctiva, urine, cerebrospinal fluid, and pleural fluid.
SARS-CoV-2 Seroprevalence
-
Studies with (near) universal screening of various populations are increasingly available, finding a wide range of asymptomatic people with positive RT-PCR tests.
-
Varying rates relate to local stage of epidemic, population and sampling, and mitigation strategies in place.
-
Some asymptomatic people are likely to be presymptomatic given the variable and sometimes lengthy incubation period.
Viral Entry: Key Points
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ACE2 is an important receptor for viral cellular entry.
-
TMPRSS2 primes the S protein and allows for efficient cellular entry.
-
An interaction between SARS-CoV-2 and CD147 may facilitate invasion.
-
Many unresolved questions remain regarding the exact role of CD147 in viral entry. Does it directly interact with the S protein or is the interaction mediated by CypA and the N protein, as was found for SARS-CoV?
What Else Have We Learned?
Key observations from our first three updates that are still relevant:
-
Peak infectiousness is probably 1 day prior to symptom onset.
-
In the absence of therapy/vaccine, intermittent social distancing is likely to be needed for years to avoid overwhelming critical care capacity.
-
Emerging pathologic correlates of clinical presentations:
-
Multiple mechanisms of cardiac injury
-
Virus can cause systemic infection
-
Viral endotheliitis and possible complement activation as cause of micro/macro thromboses
-
-
Obesity is a risk factor for severity of disease. -
Hypercoagulability is a key feature of the disease.
-
Age-based sheltering is unlikely to be effective without social distancing.
-
Epidemic control is feasible with contact tracing if minimal delay is achieved.
-
Asymptomatic/presymptomatic transmission is substantial.
-
The incubation period is highly variable (median, 5 days).
Continued
For full details, please see our original presentations—part 1, part 2, and part 3—and be sure to tune in for part 5 on May 19.
Follow Drs Meyerowitz and Richterman on Twitter: @EricMeyerowitz and @AaronRichterman
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Fox Corp.: MyNetworkTV. Maidenberg, Micah; Schwartzel, Erich (March 4, 2019).
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Stability sheet In complete, the two groups have met 97 instances in official competition since 1979.
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However worse was to come.
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Speeches of Dally d’Agier and Barnave.
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A complete of 561 Classical Harappan (2600-1900 BCE) and Sorath Harappan (2600-1700 BCE) sites are reported in Gujarat.
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Freeport Indonesia Copper and Valuable Metals Mine – Irian Jaya, Indonesia presented to the Overseas Non-public Investment Corporation (PDF) (Report).
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Gujarat has numerous archaeological sites related to the Indus Valley civilization.
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National Institute for Implementation Research on Non-Communicable Diseases is one of the 33 permanent institutes of Indian Council of Medical Research, which is an autonomous body for the formulation, coordination, and promotion of biomedical analysis within the country.
The sites of the submit-Urban interval include Lothal B, Rangpur IIC and III, Rojdi C, Kuntasi, Vagad I B, Surkotada 1C, Dholavira VI &VII.
Many games enable one individual within the group to act as a frontrunner.
When lightning strikes a steel tower or strikes near a constructing containing electrical equipment, a big, quickly altering magnetic area is generated.
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Among these research, Avdjiev, Hardy, McGuire, and von Peter (2020) take a cross-country perspective, utilizing the Financial institution for International Settlements’ worldwide banking statistics, to distinguish the position of dwelling and host elements in assessing prudential and monetary coverage spillovers.
Indeed, this is almost a type of fastened level arithmetic for the reason that position of the radix point is implied.
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Appointed interim prefect by way of Supreme Decree 25734 on the same day a state of siege was declared by President Hugo Banzer.
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The city’s culture of anti-black police violence might be mitigated some by its economic alternatives, which ranked among the best within the country for black individuals.
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They gather as souls, standing together in acknowledgment of our mutual passage via life.
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Retrieved 15 July 2021.
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What we wish,’ replied one, `is to speak to you the desire of his highness.
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Gordon Flemyng. It was written by Robert Sabaroff, based upon the Parker novel The Seventh by Richard Stark (a pseudonym of Donald E. Westlake).
Canadians eat more of this product than some other nation.
An artist may combine strategies by means of masking or silkscreening.
The Signature of America by Charles Hamilton, Harper & Row, 1979, 279 pages.
As the types of acids used on this process are extremely hazardous (see hydrofluoric acid for security), abrasive strategies have gained popularity.
Weblog articles offer suggestions and practical recommendation for spiritual progress, and methods through which a site customer can assist the ministry are put forth.
Burt’s Bees is an American multinational personal care product company.
Infants are born with some pure antibodies from their mother, however they solely final from one month to a yr.
The loss eventually noticed Kawasaki Frontale failed to win the league and finished the season as runners-up despite the membership winning the remaining two matches.
In January 2010, Arsène Wenger stated that Łukasz Fabiański could turn into among the best goalkeepers in the Premier League.
World Conflict II: Time-Life Worldwide.
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Additionally the stained glass in the east window of the Parish Church of St Mary Magdalene, Gillingham.
294. A lady in a simple turquoise gown with massive matching bows; her buddy in a white costume with crimson trim.
In the semi-finals towards Colombia, he scored Switzerland’s last goal of their 4-zero win to reach their first ultimate of a FIFA competition since a 3-0 loss to Uruguay within the 1924 Olympics.
Readers can expect to study varied frequent issues comparable to paper jamming, typing errors, and issues with the power supply.
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He wrote, “For concentrated loveliness, I know nothing that may quite compare with the lakes and mountains of Westmorland, Cumberland and Lancashire”.
In his painting, Clarke developed a strictly abstract Constructivist language of geometric signs; often his work had an underlying grid structure made from repetitions and variations on the cross.
Thread the ribbon: Information the ribbon by means of the guides and over the ribbon vibrator (the part that moves up and hits the paper once you press a key).
It comes from a particular cherry in Germany’s Black Forest, and German law says that any cake within the nation labeled as Black Forest cake must use the actual cherry liqueur.
Their church windows were executed in a Classical style usually based on well-known religious paintings, resembling those by Raphael, and had pictures or scenes painted on nonopalescent glass.
Rakshit, Abhisek; Dey, Soham (10 June 2021).
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He played his first official match for Milan and managed to score his first purpose, a free kick, to win the first leg of Milan’s Europa League qualification match against CS U Craiova on 27 July.
Konya may be a lesser-recognized metropolis, but you have most likely heard of Istanbul or Ankara.
In his youth, Warrington first educated along with his father as a painter of armorial shields.
Which means the blonde in the yoga pants can be far less more likely to hit her husband’s golf clubs when she pulls into the garage, because the automotive will no longer block her view of the ground directly in front of her.
Smith-Corona typewriters are also highly regarded for their durability and smooth typing expertise.
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Archaeological finds from this period embody colored glass ingots, vessels (usually colored and formed in imitation of extremely prized hardstone carvings in semi-treasured stones) and the ubiquitous beads.
173. A pair of ladies are seen of their effective night gowns, complete with gloves and fans.
A townhouse in Greenwich Village designed for a composer, an artist, and their son honors each the household’s Japanese heritage and its hectic journey-heavy way of life with a serenely fashionable bathroom design.
Cudicini was capped at underneath-18 and under-21 stage, but never represented his country of beginning at senior level.
Stained glass: historical past, expertise and follow.
St Hilda’s Oratory Bethnal Green 1909 Davis designed two single mild windows for St Hilda’s, this by way of James Powell and Sons.
In 1893, he emigrated to Kokomo, Indiana, within the US, where he established the first American manufacturing facility to produce sheet glass for stained glass home windows.
The Signature of America by Charles Hamilton, Harper & Row, 1979, 279 pages.
A lot early glass manufacturing relied on grinding techniques borrowed from stoneworking, akin to grinding and carving glass in a chilly state.
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Journey is a good teaching software, especially for kids and young adults.
We will trace the roots of Southern delicacies back to 2 issues — out there sources and African influence.
By the point he left Kawasaki Frontale, Kawashima went on to make 17 appearances for the side in all competitions.
Hills, Ann (April 1987).
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After IMG scored 23 factors in the first quarter, organizers for the occasion spoke to Johnson about calling the game by way of mercy rule, but he refused.
Nonetheless, the Dutch troops in Zeeland and the colonies continued the battle whereas Queen Wilhelmina established a government-in-exile in Britain.
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He performed all three matches for Switzerland on the 2012 Olympics, during which they have been eliminated within the group stage.
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The British Middle East Command, with troops from the United Kingdom, South Africa, British India, Uganda Protectorate, Kenya, Somaliland, West Africa, Northern and Southern Rhodesia, Sudan, and Nyasaland participated within the campaign.
It can’t hit 200 mph, but it could possibly accelerate zero – 60 in lower than three seconds.
Noise from automobile maintenance and restore at your residence could be unreasonable.
Deep down she felt so helpless and I would typically hear her crying to herself.
Now in high school, Website positioning-Wha continues to be attached to Sa-Eun.
After the season ended, Chhetri had scored four targets in eight league matches as he helped Churchill Brothers to their second ever I-League title.
Korean Cultural Service New York.
Despite the failure of numerous rapidly planned counterattacks to collapse the German bridgehead, the French Army was profitable in re-establishing a steady defensive position additional south; on the west flank of the bridgehead, nevertheless, French resistance began to crumble.
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For the 2021-22 season, Kotal was appointed as one of many captains of the club.
Typing on a desktop typewriter appears like taking part in a grand piano.
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France formally surrendered to the Germans on June 22 in the same railroad automobile at Compiègne through which Germany had been forced to surrender in 1918.
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Kinsey, Joe (August 30, 2021).
In a digital age dominated by computer systems and smartphones, the resurgence of interest in electric typewriters could seem surprising to some.
He was also the second high scorer for Bengaluru in the league and won the Hero of the League.
At the top of the 2013-14 season, Kawashima had made forty seven appearances in all competitions.
In the direction of the tip of the sequence he and Cheng Yanan arrange for his or her dad and mom to satisfy and after the year hole they marry each other making Solar Hao and Yanan brother and sister and their parents giving start to their baby half brother.
Michael and All Angels in Bude Haven which was built between 1834 and 1835 and consecrated in 1835 and was the present of Sir Thomas Dyke Acland.
Franklin, Cory (6 October 2016).
For example, groups can attempt area goals, which have a high charge of success.
Following World War II, the GCMA French airborne commandos, serving within the Indochina Struggle, were created on the model of the gaurs (CLI) who had been themselves modelled on the British Chindit special forces.
Britain lent warships to the Free French Naval Forces.
The keys are gentle and sprightly; each taps a playful notice within the melody of my storytelling.
Hohmann, George (December 13, 2012).
Additionally, it’s an ideal concept to have a “Monthly Cost Date” in your planner to ensure you by no means miss debt payments.
31 March 1979: Arsenal beat Wolverhampton Wanderers 2-0 at Villa Park to succeed in the FA Cup closing.
The decoration is essentially made up of heraldry and variations of the fleur-de-lis design.
The European Union is concentrating on 60 million heat pumps put in by 2030, which would imply an annual progress price of almost 15.
Duran is also excellent at adapting pure shade patterns and textures into her makeup seems.
The keys usually require extra power to press, offering a distinct really feel that some customers choose for its nostalgic and bodily feedback.
The Basilique Saint-Urbain de Troyes constructed by City IV starting in 1262 at his birthplace, was a superb example of the new type.
Australia beat Namibia 142-zero within the 2003 Rugby World Cup.
All CED’s have a number printed on the raised center section of the disc that corresponds to both the number under the UPC (bar code) located on the rear of the caddy or to the inventory number printed on the sting label of the caddy.
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At Marseille, the French took over 1,800 casualties and acquired roughly 11,000 extra prisoners.
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