Our latest review on #CRISPR is now out in Bioessays. We discussed how Cas9 collateral damages (on- and off-target effects) occurs & how to predict, prevent & mitigate those. Base editing was not covered. Here is a short thread (shareable link end thread) onlinelibrary.wiley.com/doi/epdf/10.10…
We first discussed what are the various outcomes following Cas9 editing from correct editing to large chromosomal translocation. The common features between these outcomes is the double stranded break (wanted or unwanted).
An important point of discussion (unfortunately too brief) is Cas9 catalytic cycle and the mechanisms of target recognition or mis recognition (PAM recognition, target strand annealing, nuclease activation and cutting). Wish could discuss more on this but lacks space
This piece reports claims from the Health Minister -> "Australia has a 'golden opportunity' to become global medical research leader post-coronavirus" stating 1/ We led #COVID19 response 2/ strong medical research sector => global leader. Well not quite
This is true we are lucky in Australia to have successfully tackled #COVID19 & we haven't diverted considerable resources. True too that we have a strong medical research sector in Australia. However stating Australia has the potential to become a global leader is way overstated
In the global medical research landscape, Australia is small but we are doing pretty well in terms of output with little resources we have compare to others countries. But there are some serious issues in Australia theconversation.com/mckeon-review-…
Today #NHMRC Investigator grants results came out. As usual I crunched the numbers & made few graphs ! Congrats to the awardees & condolences for those that missed out.
If you wish to skip the thread => No major changes to last year: non clinical EMCRs screwed for this scheme
First success rate: Stable at ~ 13%. Funding hole for Mid career researchers with terrible success rate 10% for EL1 and 9.1% for L1 vs 49% for L3 which has slightly increased compared to last year. So I looked more into the details
An important question is seniority level vs success. I looked at academic level rather than years post PhD and well for 2020 L1 -> 74% are level E, for EL2 -> 65% are level D/E => shift from academic level (previous system) to post PhD level (actual). EMCRs highly disadvantaged
A cohort study & a small RCT came out yesterday in the @bmj_latest showing no efficacy of #HydroxyChloroquine (HCQ) for #COVID19. To date 187 trials on HCQ for #COVID19 are ongoing! How many more studies do we need to stop with HCQ, move on & test more promising drugs?
For details, the first study is a cohort study on 181 patients (HCQ+SOC =84, SOC = 89) with admission to ICU as a primary outcome. Comparable group, treatment French protocol. Outcome no difference at all between groups. 10% HCQ cardiac side effects bmj.com/content/369/bm…
The second study is a multi center open label randomized clinical trial (HCQ+SOC group 70 vs SOC group) Comparable groups. Primary outcome #SARSCoV2 PCR negative, no clinical data. French protocol. No differences in biological outcome and viral load. bmj.com/content/369/bm…
This is a cohort study on 132 patients (one center) HCQ ± AZ > 48 hrs versus standard of care (SOC) primary.
Incl criteria #SARSCoV2 pos (but 6 patients with neg PCR were included 😳) and/or CT scan pos (60% control group got a CT scan) 😳. So not all were #COVID19 infected
Treatment regimen follows the French protocol. Primary outcome: ICU admission. secondary outcome HCQ+AZ favorable treatment. So they divided in 2 groups (HCQ+AZ n=45, AZ alone n = 28, control group n= 59 (incl HCQ+AZ n=9, Lopi/ritonavir n=14). Not a control group & 3 groups !
Let's recap the main points of the study. First they evaluated the in-vitro effects of #Hydroxychloroquine (HCQ) on VeroE6 cells and found similar IC50 2.2 µM at 48 hrs consistent to previous reports but not in human airways epithelium unlike remdesivir -> not great result
What they did next they infected the macaques with French #SARSCoV2 clinical isolate and observe the clinical + biological outcome and viral load => Infection similar and directly comparable to human infection. This is important
This is a very much unconvincing evidence of a first #COVID19 case in December 2019 in France without having traveling to China from a retrospective observation for couple of reasons sciencedirect.com/science/articl…
1/ the patient never traveled to China or anywhere else seems really bizarre. 2/ the biological markers of inflammation were quite low, which is atypical for a #COVID19 patient. 3/ the rapid recovery (2 days) after antibiotics treatment looks more bacterial infection to me
But the most important point is the #SARSCoV2 RT PCR positive. Looking at the amplification curve, this doesn't look convincing at all (late amplification). Looks very much a false positive to me. Sequencing the virus would have allowed to compare to existing sequenced viruses
Wow !! This paper describes the reconstruction of #SARSCoV2 from 14 synthetic DNA fragments amplified, cloned and assembled using yeast in just a week !! => gives fully functional virus. They also did it with MHV or MERS-CoV ! Amazing !!! #COVID19#SynBionature.com/articles/s4158…
Importantly to give a context about this work. This work was undertaken 4 days after the first #SARSCoV2 genome was release the 14th January. The researchers didn't have access to the virus and decided to go for a reverse genetic approach
Another important point. While this work shows the power of reverse genetics to reconstruct a microbe and could be useful in specific context, it will fuel all sort of conspiracy theories on the fabrication of #SARSCoV2 virus in a lab in China, unfortunately.
1/ The US trial shows Remdesivir improves time to recovery from 14 days to 11 day & may reduce mortality whereas the Chinese trial (underpowered) shows no benefit. In my view Remdesivir may improve patients outcomes but clearly not the silver bullet or knockout effect as expected
2/ While we need more drugs to combat the infection, I really can't see a silver bullet drug coming through for #COVID19. It will be series of drugs with more or less effects on #SARS_CoV2 but expecting the miracle drug as AZT was for HIV is way overstated in my view.
Two results came out today on Remdesivir treatment for #COVID19 infection.
The first one is a double blind controlled multi center clinical trial on 237 patients in China
The second one 5 versus 10 days treatment in severe #COVID19 patients
Let's have a look -> thread
The first study is a double blind placebo controlled multi center clinical trial in China in 237 #COVID19 patients. We have now the published result of this trial. Please remember there was a leak on this trial a week ago
Also "Heparin-induced thrombocytopenia is associated with a high risk of mortality in critical #COVID19 patients receiving heparin-involved treatment" and without heparin in a cohort of 61 patients in ICU (critical state) medrxiv.org/content/10.110…
While according to this study shows that Heparin inhibits #SARSCoV2 cellular invasion & binds to the Spike protein S1 receptor binding domain (RBD) & change its conformation biorxiv.org/content/10.110…
Today I have been asked few times on the efficacy #hydroxychloroquine (HCQ) for #COVID19 (Australian based tweeps knows why). The question is: Is it ethical for clinical trials to go ahead given the lack of evidence on HCQ efficacy for #COVID19?
First: There are been an incredible & insane overhype on HCQ treatment for #COVID19 mainly based on the French open labeled clinical trials and series of non reported success stories in China or elsewhere. This was largely amplified from Donald Trump and this was incredible
After several weeks, what is the evidence for HCQ efficacy on #COVID19 infection? Well to date no clear evidence for efficacy but clear evidence for cardiac toxicity of HCQ, which in the risk/benefit balance, we are definitely more on the risk than benefit side.
A short update on #COVID19 in Australia. Well we well and truly #FlattenedTheCuve with today only 17 detected cases in Australia (6623), 4268 recovered and 71 death, & 555 community cases. This is a great news #SocialDistancing works ! However we still need to be vigilant.
States all #FlattenedtheCurve with no detected case today in QLD, SA, WA & NT. TAS is a worry due to the outbreak in the NW (+5 today & + 20 cases in 4 days) Hope this will slow down. Community cases stable and no real increase. Most cases are from known contacts -> traceable
Testing capability seriously increased last few days with > 10 K a day with a daily positive rate of 0.2% following recent relaxation testing criteria => no widespread community cases in australia, all in cluster => traceable & controllable
Let's talk about #COVID19 publications & #covardisation of the research. I have been following the literature last ~ 2 months & reviewed papers. I have a bit to say about it
Let's start first with 2 papers that came out today on #COVID19 and scholarly communication
First paper examines citations record, altmetric, social media... on early #COVID19 papers.
Out of 442 papers, only 26% primary studies => 21% -> basic science (too few) , rest clinical (case reports 42%)
Larger social media impact => high citations medrxiv.org/content/10.110…
The 2nd paper examines wether #COVID19 has speed up #peerreview process
Answer is yes & peer review length has decreased by 1/2 due to reduce time for review
However trade off is publication quality is lower (e.g NEJM or CELL..)
This brings me to my point biorxiv.org/content/10.110…
Another study on #Hydroxycloroquine efficacy in #COVID19 patients from a Brazilian team has been shared widely this evening. Unfortunately I have to comment it because well it might have some public health implication & this study is atrocious
This study is not a clinical trial but a cohort study on 721 patients, recruited by telemedicine. Incl criteria Flu symptoms, OK to be treated > 18 y/o. Probable diagnosis of #SARSCoV2 but RT-PCR or X ray not compulsory. We don't even know if those patients had #COVID19 😳 😡🤦♂️
Outcome -> hospitalisation at day 7, that's it.
721 patients unrolled. 85 not followed -> 636 left => 225 refused treatment -> control group 😳 & 412 patients Hydroxycholoquine + azithromycine (dose unknown)
All followed daily by telemedicine consultation => huge select biais
An update on #COVID19 situation in Australia. Few interesting development today. Detected cases 6449 (+38), recovered unreliable 3692 (+86), Death 63(+1). We still have #FlattenTheCuve & Still follow Korea path. Interesting first results of relaxation testing criteria coming out
State. all #FlattenTheCuve except TAS with +4 today => less than the last 3 days. Interestingly first results of relaxation criteria with + 10 community cases in VIC today 232 (10% cases). Curious to see relaxation criteria in other states will play out in the next few days.
Testing side, not a lot happening. Not real increase today in number of testing 370,000 tests performed in Australia ~ 5K tests today but 1st results post relaxation testing criteria are coming out. Positive rate 1%. I would expect an increase testing numbers in the next few days
This observational study consisting on a follow up of 181 patients hospitalized University hospitals at Paris for #COVID19 pneumonia shows no difference in efficacy of Hydroxychloroquine (HCQ) 600 mg/day versus non-HCQ group
This trial is part of a large trial in Brazil (n=440) with the CQ arm (n=80). This is a double blind randomized clinical trial. Incl criteria >18 y/o SaO2<90, FR>24, HR>125. Patients in ICU included. RT PCR for #SARS_CoV2 not confirmed during randomization. Excl patients <18 y/o
Group 1 n=40 high CQ dose 4x150mg x2/day for 10 days, total dose 12g.
Group 2 low CQ dose 3x150mg + 1 placebo x2/day Day 0, 3x150mg +1 placebo followed by 4 placebo tablets from D1 to D4
No group placebo alone (compassionate use of CQ, not allowed)
This is a result that many hoped. Today the @NEJM published a small cohort study on the compassionate use of Remdesivir for severe #COVID19 patients in ICU under mechanical ventilation showing 18% mortality (6/34). Let's have a look at the details
First the basics. What is Remdesivir? In short it is an antiviral drug, nucleic analog incorporating into the viral RNA, which leads to termination of transcription, which blocks virus replication
We have now a very good idea how does Remedesivir blocks #SARSCoV2 virus replication from a beautiful paper that came out yesterday detailing the mechanisms -> directly targeting RNA-dependent RNA polymerase (RdRp), critical for many virus to replicate biorxiv.org/content/10.110…
A question I often get. Why Lupus patients that have taken Hydroxychloroquine for years have no side effects whereas severe adverse cardiac side effects are described #COVID19 patients under hydroxychloroquine treatment? Let's have a closer look
Let's start with #COVID19. Does #COVID19 causes cardiac effects? The answer is yes from 2 published surveys from Wuhan hospitals. First one reports on 416 hospitalized patients -> 19.7% with myocardial injury + ⬆️cardiac troponin & high mortality rate 51% jamanetwork.com/journals/jamac…
The second paper shows similar observation on 187 hospitalized patients -> 27% had cardiac injury with again elevation of cardiac troponin and increase mortality rate at 59%. In short #COVID19 leads to significant cardiac injury but these are severe cases jamanetwork.com/journals/jamac…