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Correct. Friend had that option offered to him a few months ago when the lease had 6 months to go. Tesla delivered a new one for the new lease. Not sure what difference tax wise for a business owner that drives a lot.
HAIR - hits $2.5 today. That was a very costly financing round.
More about produced water in Permian. The bit about WS not knowing the issue is probably true and laughable. Laughable wrt to expecting analysts understanding the details and complexities upstream of final products and resulting P&L.
https://www.bloomberg.com/news/articles/2018-08-29/drowning-in-dirty-water-permian-seeks-a-22-billion-lifeline
How long for price discovery typically after collaboration news? Have some. TIA.
TSLA after the take private drama. Nov. 420 touch prob drops to 14%. Nov. 50/50 prob of touch drops to $360 from $375.
Toyota and Daimler both made big strategic mistakes. Their in house efforts if any must not be getting anywhere fast nor far. If you are a bunch of smart students in the Carnegie Mellon robotics program, why would you give away all your ideas to Uber, GM or TM?
https://insideevs.com/daimler-toyota-get-rich-tesla/
Some think it could be higher.
https://markets.businessinsider.com/news/stocks/google-stock-price-waymo-worth-100-billion-more-than-before-morgan-stanley-2018-8-1027439248
BNEF has updated global forecast for EV's and impacts.
https://about.bnef.com/electric-vehicle-outlook/#toc-download
All out would be the production rate when oil prices were well in excess of $100/Bbl. It isn't much different now. They could punch more holes and put in bigger and bigger submersible pumps. Most of that effort will go towards cycling ever more water.
A question remains from the failed IPO. Did they ever subject the reserves to an audit by D&M? If they did, are they afraid to reveal the numbers? If not, why?
As a country, IMO what will happen is an acceleration in renewables generation so that net oil exports can go up even as they struggle to cycle more water.
Not a big beer drinker myself but i have a lot left over from a party a few weeks ago. Had a lot of wine left over as well and gave those away. I ordered what the bartender suggested (approx 2-1 wine/beer in servings) and half of each was consumed. Beers used to be less than a glass of wine at restaurants but no more with the craft beers so perhaps there is substitution. Also, amongst younger friends, most prefer craft or small labels whereas the older folks still go with major brands like Bud or Coors. Foreign craft beers have spoiled me to the point that I rarely touch those big brand name beers. I would rather drink water or wine. So if I am representative, then there is something to the trend and the big companies need to up their game, or buy smaller craft breweries. The latter has been happening.
What do you think of the beverage space? Looking at bud and abev. ABEV has been hit being spread out through emerging markets. Both pay attractive dividends.
Seems like AMZN ought to be able to offer that fresh groceries service from your laptop sooner or later.
Waymo - RE Arizona beta testing and early signs of pricing. Interesting charts with no Tesla AP data. Waymo uses mechanical LIDAR in addition to other cheaper sensors and Tesla uses optics and radar with version 9.0 AP due to be released soon. Another article not linked about solid state LIDAR startup that is no doing well - not meeting specs.
https://www.bloomberg.com/hyperdrive
TSLA - option market probability of touch of $420, current price ~355
Sep expiration - 17.0%
Oct - 26.4
Nov - 34.9
Dec - 39.6
It would take a +$20 move to get the probability above 50/50 by Nov.
More details on SA interest in Tesla blog post this morning. IMO the chances of TSLA going private is higher than 50/50. The more interesting things to happen is what will be the BOD agenda items at Aramco founding sisters next board meetings. There have been spiteful discussions in the past between CEO's of oil and auto companies during stressful times. There will be more of those stresses.
Saudi Arabia is not quite finished yet wrt Tesla.
https://www.arabianbusiness.com/politics-economics/402699-saudis-pif-in-talks-to-become-significant-investor-in-tesla
HAIR - priced at 1.5 so MC will end up closer to 70M. Stock was around 3 and market cap around 100M (includes warrants and incentive stock). Will add some more at offering price.
Looking at the profiles of clinicians in Japan, all 4 handle botox as well as hair transplants.
Top five holders own >50% of shares not counting Saudi. It will take much less than half of EV to take it private. MS thinks the range is $15-20B. Not much in this world of multi billionaires.
T-1 Shorts on chopping blocks sweating buckets?
https://www.nasdaqtrader.com/trader.aspx?id=TradeHalts
TRXC - earnings CC. Preannounced 3 system sales for Q3. Down 10%.
http://ir.transenterix.com/events/event-details/transenterix-second-quarter-2018-financial-and-operating-results-conference
Here is the class action announcement from the main factory. People are angry about buying the IPO at $7 and sounds like a claim that they were hiding info. I haven't looked at the S-1 but I highly doubt the class actions will succeed in proving anything other than don't pay for high probability of success when a company doesn't deserve it until some time in the future.
https://www.rosenlegal.com/cases-1367.html
LNG, China and tariffs
China gas demand mostly belong to Russia, Kazakhstan, Qatar/ME and Australia in the long run. US producers need to develop more customers closer to home and EU. US consumers benefit for now.
https://www.bloomberg.com/view/articles/2018-08-06/china-s-lng-tariffs-could-slam-permian-oil-producers
https://eurasia-news-online.com/2018/03/25/the-battle-for-chinas-growing-gas-demand/
HAIR - Along the same thoughts, ie spending money to look good or just to maintain looks. HAIR is doing secondary and the stock tanks. I added some. MC was around 100M (including warrants and incentive stock) and it looks like it will remain around the same MC post offering. Too low IMO. Company is having a hard time with sales because of the upgrade of robot from harvest only to harvest + implant so system sales have been down trending for 2Qs. New system release is Sept so it should pick back up. Not sure what the upgrade package looks like for docs with the early version system. Reminds me of ALGN except that ALGN faced a different problem with ex-employee running off to Pakistan and infringing with exact copy (took a while to resolve). HAIR's competition will be manual for a while.
http://secfilings.nasdaq.com/filingFrameset.asp?FilingID=12895971&RcvdDate=8/6/2018&CoName=RESTORATION%20ROBOTICS%2C%20INC.&FormType=S-1&View=html
AD - BIIB etc
Further notes from Sherman after discussion with key opinion leaders
>>>>>>>>>
We recently hosted a Key Opinion Leader (KOL) dinner at AAIC 2018 focused on the current understanding of Alzheimer’s disease pathogenesis and updates in the clinical landscape. Our note below describes some of the most interesting parts of the discussion from the event. Our KOLs, Dr. George Bloom (University of Virginia) and Dr. John Hardy (University College London), are renowned research scientists in the Alzheimer’s field. Dr. Bloom’s laboratory focuses on deciphering the metabolic links that connect ß-amyloid and tau to damage neurons. Dr. Hardy has focused his research on molecular genetic analysis of these neurological diseases and discovered APP mutations as the first known cause of Alzheimer's disease in 1990. The following companies are mentioned in our note: Biogen (NasdaqGS: BIIB), AbbVie (NYSE: ABBV), Roche (SIX: ROG), Eisai (TYO: 4523), AC Immune (NasdaqGM: ACIU), and MorphoSys (NasdaqGS: MOR).
Analysts
David Sherman, Ph.D. (AC)
Dinner Summary
The key theme from the dinner was the uncertainty that remains in the field of Alzheimer’s disease (AD). Even things that may seem obvious, such as the functions of the amyloid beta and tau proteins, remain surrounded by controversy. The lack of clarity regarding the pathogenesis of AD has affected development of therapeutics for the disease. For example, even if an agent were to remove amyloid beta with a high success rate (as some agents do appear to effectively do), there may not be a cognitive or functional improvement for AD patients. This suggests that our fundamental understanding of AD, based on the amyloid hypothesis, remains up for debate. The two KOLs agreed that while amyloid is a key feature of the disease early on, by the time the plaques have built up, there are many downstream pathogenic mechanisms which are already in motion and cannot be stopped by reducing amyloid levels. Further research regarding disease pathogenesis, development of drugs with alternative targets for treating AD, studies evaluating combination therapy, and improved biomarkers will all be required in order to advance the field.
Discussion of BAN2401. The most anticipated news at this year’s AAIC was data from Eisai (TYO: 4523) and Biogen’s (NasdaqGS: BIIB) Phase II trial evaluating BAN2401. The highest dose achieved statistical significance on a number of endpoints (plaque reduction, ADCOMS, ADAS-cog) but failed to show significant difference over placebo on the CDR-SB. In addition, imbalances in the proportion of ApoE4 carriers across the different treatment groups (70% of total patients in the placebo group compared to ~30% in the 10 mg/kg biweekly group) and lack of a clear dose-response on the ADCOMS raises concerns. Despite concerns regarding the novel ADCOMS endpoint, one KOL did note that we still “don’t even know if we’re measuring dementia correctly” with currently used endpoints. The KOL stated that the work put into developing suggest that it is a “reasonable endpoint” for measuring dementia.
“If it just works a little bit, that’s a problem.” – As for many of the anti-Aß antibodies, BAN2401 has shown potential signs of efficacy. Had BAN2401 met all endpoints with statistical significance, the different treatment groups had similar baseline characteristics/demographics, and a clear dose-response been established, the path forward for BAN2401 would be clear. Similarly, had the drug failed to meet any of the endpoints, the path forward would also be clear (the path ends). However, the mixed results raise questions regarding whether BAN2401 will continue to be studied in a Phase III trial. Subgroup analyses may answer some of these questions, but it seems unlikely that BAN2401 will be the clear answer some were hoping for regarding the validity of the amyloid hypothesis for Alzheimer’s disease.
Importance of the CDR-SB for Read Through to Aducanumab – Going into the data readout, many considered the drug’s effect on the Clinical Dementia Rating – Sum of Boxes (DR-SB) to be the most critical metric. CDR-SB is a measure of both cognition and function in AD and is generally believed to be an appropriate endpoint in trials evaluating early AD patients. Notably, CDR-SB is the primary endpoint in Biogen’s Phase III trial evaluating aducanumab. Therefore, the effect of BAN2401 on CDR-SB was thought to have direct read through to aducanumab’s potential effect on this endpoint. However, this is the one endpoint where BAN2401 did not show an effect. While BAN2401 and aducanumab differ in notable ways (targeting different epitopes and different Aß species), this raises some concerns regarding aducanumab’s likelihood of success in the Phase III trial. Data from this trial is expected in 2020.
Other Targets for Treating Alzheimer’s Disease. While the amyloid hypothesis for the disease has dominated in the last few decades, the failures of anti-Aß antibodies has led researchers to evaluate other strategies for treating the disease. As one KOL noted, “if you had a drug that was 100% successful against amyloid, would dementia still exist? I think it would.” It is likely that once the “amyloid problem” is solved, the brain may be exposed to other pathogenic processes that result in dementia. Because of this, it seems that there is a need to study treatments for AD with alternative targets. Recently, there has been interest in targeting tau protein, motivated by the strong temporal and spatial correlation between tau protein and AD neuropathology over the course of the disease. Other potential interesting novel targets include glial cells and the mTOR pathway.
Growing Excitement over Anti-Tau Antibodies, Despite Much Remaining Unknown – Recently, companies have been developing anti-tau antibodies, including Biogen’s BIIB092, AbbVie’s (NYSE: ABBV) ABBV-8E12, and Genentech (division of Roche, SWX: ROG) and AC Immune’s RO 7105705. These candidates are earlier in development compared to anti-Aß antibodies, with the most advanced candidates currently in Phase II development. The KOLs, however, discussed the difficulties in targeting tau. Tau is a relatively large protein, consisting of roughly 400 amino acids, which is roughly 10 times the size of amyloid beta. The large size of tau makes it difficult to target. Additionally, it remains unclear exactly what area of tau would serve as the best target for antibodies. It is also important to consider that tau exists primarily intracellularly, which means that an anti-tau antibody would have to cross the cell’s plasma membrane in addition to the blood brain barrier. The anti-tau antibodies currently in development only target extracellular tau, which may be beneficial in preventing the prion-like spreading of pathological forms of tau after it is “dumped” into the extracellular space. Additionally, because the full range of functions for tau remains unknown, it is possible that knocking out tau may have deleterious effects. Several strains of knockout mice exhibit normal lifespans but show neurological deficits when the mice are older. Therefore, when targeting tau, it may be important to avoid knocking down tau past a certain threshold (Lei et al., 2014).
Renewed Attention Towards the Immune System with Modulation of Microglia – Because cells other than neurons are involved in AD pathogenesis, targeting other types of cells may be an interesting strategy for treating the disease. In recent years, the role of microglia has received attention in studying AD pathogenesis (Wes et al., 2016). Research has suggested that, in AD, microglia may enter a “primed” state following chronic activation. Once in this state, microglia may respond with greater sensitivity to any further insults. Therefore, the aim of microglia-targeted therapy for AD may be to change the phenotype of microglia back to that which is seen in cognitively normal individuals. However, the difficulty with this approach is that increased activation of microglia may be beneficial in certain brain regions while lower activation may be beneficial in other areas in a certain AD patient. Techniques for accomplishing this have not yet been developed. Interestingly, microglia may affect antibody treatments for AD because microglia are believed to be responsible for Fc receptor-mediated antibody effector activity, suggesting that combination therapy with an antibody and microglia-targeting agent may represent an attractive combination strategy.
Regulation of mTOR – The mammalian target of rapamycin (mTOR) pathway is involved in a number of pathways in the brain and may be specifically involved in mediating synaptotoxicity. One KOL stated that mTOR may be a “key player” in AD pathogenesis and mediate the toxicity caused by amyloid and tau. Research has shown that activation of mTOR increases production and deposition of Aß through changing the metabolism of APP and upregulating secretases involved in the APP processing pathway. Additionally, mTOR, as an inhibitor of autophagy, decreases the clearance of Aß (Wang et al., 2014). In studies looking at the relationship between tau and mTOR, an increase in mTOR signaling was shown to facilitate tau pathology (Caccamo et al., 2013). Rapamycin, an mTOR inhibitor, has been studied in AD animal models and was able to bring about improvement in AD symptoms. Other mTOR inhibitors with stronger safety profiles may represent an interesting therapeutic approach.
Developments in AD Biomarkers. With many recent failures in therapeutics for AD and concerns regarding which stage of patients may respond best in clinical trials, researchers have made advances in the development of AD biomarkers. Historically, CSF biomarkers (Aß 42, Aß 42/Aß 40, tau and pTau181) have been used primarily to assess AD (Lewczuk et al., 2018). While lumbar puncture (LP) is a routine procedure for clinicians, it is invasive and inconvenient for patients. Because of this, there has been an unmet need for blood-based biomarkers to allow for non-invasive screening. One of the KOLs noted that plasma neurofilament light may be one of the most promising biomarkers currently being developed.
Plasma Neurofilament Light as a “Game Changer” in AD Diagnosis – Recently, plasma neurofilament light (NFL) concentrations have been studied as a biomarker for AD. Research has shown that AD patients generally have increased plasma NFL concentrations (Mattsson et al., 2017). Increased NFL concentrations are also associated with cognitive decline, other AD biomarkers, and neurodegeneration. NFL levels may even indicate abnormalities at early stages of the disease, which could allow for its use in clinical trials or even in screening the general population.
Mechanisms of Toxicity in AD. The exact cause of cell death in Alzheimer’s disease remains unknown. There are multiple proposed mechanisms that were discussed by the KOLs and these are described below.
The Unknown Effects of Aß Receptor Binding – Generally, in order to characterize receptor-ligand interactions, one has to demonstrate saturation binding. However, this is not possible for amyloid beta given that the amyloid protein binds to itself as well as receptors. Despite this difficulty, biochemical research has shown that Aß interacts with a number of receptors on the cell surfaces of neurons, such as NMDA receptors, AMPA receptors, prion protein, APP, and others. However, exactly how Aß interacts with these receptors remains unknown. The downstream effects of Aß binding to cell surface receptors, such as activation of protein kinases, may be the most relevant to mechanisms of toxicity in AD.
Tau Protein May be the “Bullet” in AD Pathogenesis – The strong correlation between neurodegeneration and temporal and spatial deposition of tau protein supports the hypothesis that tau is critical for toxicity within AD pathogenesis. Research has shown that protein kinases, often activated by the Aß protein, catalyze site-specific phosphorylation on tau, which then allows for neuronal cell cycle re-entry. Re-entry into the cell cycle is a common apoptotic mechanism for neuronal cells, and this may therefore represent one mechanism for cell death in AD. Also, once hyperphosphorylated, tau dissociates from microtubules, after which it forms aggregates. These aggregates are believed to contribute to synapse dysfunction and mediating a number of downstream effects. As the KOL said, “once tau gets going, it has a life of its own.”
AD is Not a Cell Autonomous Process – The KOLs emphasized that AD is not a cell-autonomous process. In addition to neurons, microglia and astrocytes are also responding to Aß buildup. Once amyloid plaques have built up to a certain threshold, the brain’s immune system has likely initiated a number of inflammatory downstream processes to respond to the stress caused by amyloid buildup and these processes also contribute to the disease progression.
Amyloid Beta in Alzheimer’s Disease. Amyloid beta is a key defining feature of Alzheimer’s disease. It seems clear that some combination between overexpression and failure of clearance brings about decades of amyloid buildup, eventually triggering other pathogenic processes such as hyperphosphorylation of tau and an immune system response. However, despite the clear presence of amyloid buildup in Alzheimer’s disease, much remains unknown regarding the exact nature of amyloid beta’s role in the disease. Researchers are still studying the exact nature amyloid beta species, their mechanisms of toxicity and even what the endogenous function of amyloid beta is in cognitively normal individuals.
No Single Aß Oligomer Type – While we may think of oligomers as a single clear entity, in fact, as the KOLs discussed, amyloid oligomers may take a number of different forms. Monomers may organize into dimers, trimers, hexamers, etc. One could even arrange two identical Aß 42 molecules as dimers and get a number of different types of amyloid dimers, differing in terms of connections, folding, etc. Additionally, once oligomers form, they continue to grow, shorten, and rearrange. The KOLs noted that we currently do not have the tools necessary to properly study these dynamic molecules and all the different possibilities for their structure.
Are Oligomers Truly Toxic? – The KOL noted that while many assume Aß oligomers to be the predominantly toxic species in Alzheimer’s, the evidence for its toxicity has not been shown conclusively. In a review, researchers argued that the lack of correlation between neurodegeneration and location and timing of Aß oligomers deposition (Benilova et al., 2012). Additionally, some researchers posit that the toxicity of Aß is related to their lipophilic nature (Aß is considered a “sticky” molecule) and flexible structure, which allow the molecule to bind to a number of receptors. However, this would maybe mean that Aß’s toxicity is a result of its more generic properties (being lipophilic and having a flexible structure), rather than because of any innate toxic characteristics or pathways associated with the molecule. Further research is required to understand the variety of oligomers that exist in vivo and the respective toxicities of these oligomers. Another hypothesis proposes that, initially, amyloid plaques may in fact have neuroprotective features. Plaques can sequester the supposedly more toxic oligomeric species of amyloid beta. However, it is important to understand that the incorporation of oligomers into plaques is not an irreversible process. In later disease stages, plaques may in fact be sources of the toxic oligomers. This may explain why plaques are later surrounded by dystrophic neurites and microglia. At this stage of the disease, it is likely too late to attempt to target amyloid beta, as downstream toxic effects have already been initiated.
Failure of Aß Clearance – As one KOL mentioned, we are dealing with a “failing motor vehicle” in AD. At older ages, normal mechanisms in the brain start to work less or with lower efficiency. One of these mechanisms may be the normal clearance mechanisms in the brain, such as those related to the lymphatic system. Recent research has implicated the lymphatic system in the normal clearance of Aß. When individuals age, lymphatic clearance systems likely become less efficient, allowing for greater amyloid buildup.
Methods for Targeting Amyloid Beta. Despite the lack of a clear mechanistic role for amyloid in AD, the majority of drugs in development target Aß. Development of anti-Aß antibodies, however, has generally not been successful, with many antibodies failing to show an effect on cognitive/functional endpoints in Phase III clinical trials. Anti-Aß antibodies currently in Phase III of development include Biogen's aducanumab, Roche and MorphoSys' (Nasdaq: MOR) gantenerumab, and Genentech and AC Immune's crenezumab. In recent encouraging news for anti-Aß antibodies, Eisai and Biogen’s BAN2401 showed potential signs of efficacy in a Phase II trial. Despite this recent encouraging news, the validity of targeting Aß in the treatment of AD remains up for debate. One KOL stated that we have learned that “by the time the brain is full of amyloid, amyloid isn’t necessarily the right target.”
More Effective Approaches for Testing Anti-Aß Antibodies – The KOLs emphasized the importance of timing when it comes to effectively using anti-Aß antibodies in treating AD. With improved biomarkers and methods for early identification of high-risk individuals based on genetics, it may be possible to treat patients even before amyloid build-up reaches a significant level. Earlier is considered better in treating AD because, once Aß has built up in the brain past a certain (unknown) threshold, there are a number of downstream effects (activation of protein kinases, hyperphosphorylation of tau, changes to microglia phenotypes) that mediate the majority of the disease’s pathogenesis. Once these downstream effects have been initiated, clearing out amyloid will likely be unable to stop progressive neuronal death. One interesting approach for studying anti-Aß antibodies at a sufficiently early enough stage is targeting amyloid pathology in Down syndrome (DS). Because individuals with DS have a third copy of chromosome 21, which is where the APP gene is located, almost all individuals with DS exhibit Alzheimer’s-like neuropathology by the age of 40 (Head et al., 2012). These individuals have significant deposition of amyloid plaques and neurofibrillary tangles. Therefore, because these individuals almost certainly develop amyloid buildup over a certain age, these individuals may be good candidates for early treatment with anti-Aß antibodies to determine whether the antibodies are effective in delaying AD neuropathology and the associated dementia symptoms. Of note, AC Immune (Nasdaq: ACIU) is currently evaluating an anti-Aß vaccine, ACI-24, as a treatment for delaying cognitive decline in individuals with DS.
Other Methods for Targeting Aß – The KOLs discussed the “obvious attractiveness” of BACE inhibitors and the inherent difficulties associated with developing such drugs. Because BACE has a number of substrates throughout the body aside from APP, there is potential for deleterious off-target effects. Similarly, small molecules targeting amyloid beta, while potentially available at a significantly lower cost compared to antibody treatment, may have significant off-target effects due to their lower target specificity compared to that of antibodies. Following the approval of Biogen’s Spinraza, an antisense oligonucleotide (ASO) therapy, for the treatment of spinal muscular atrophy (SMA), interest has grown surrounding the use of ASO therapy in the treatment of other neurological disorders, such as AD. For ASO in AD, there are a number of potential targets such as APP, BACE1, PSEN1, tau, and ApoER2 (Chakravarthy et al., 2017).
After hours move in line with option pricing. Meanwhile, check out Tata's Jaquar Land Rover ugly results.
TRXC - Florida Hospital reporting first set of abdominal procedure after having the system since it was cleared last year. Shows the long time needed to get up and running and getting the support team trained. IDK why it takes so much longer in a large US hospital setting compared to EU where the systems get used much sooner after installation.
https://www.floridahospitalnews.com/florida-hospital-surgeon-performs-1st-nation-procedures-new-surgical-robot
Paper discussing learning curve for Da Vinci in small Florida community hospital for comparison purposes.
https://med.fsu.edu/userFiles/file/Jarrod%20Robertson's%20published%20paper.pdf
Florida Hospital reports on first set of surgeries. They have had the system since last year. Why did it take so long to get to clinical usage?
https://www.floridahospitalnews.com/florida-hospital-surgeon-performs-1st-nation-procedures-new-surgical-robot
BPMC - 16% bounce, I suppose CC served as therapy session.
https://edge.media-server.com/m6/p/fzrc89id
RDS - Missed the "shameful" sell side analyst q&a performance. What happened? Pls summarize.
Pump storage is the cheapest way to store excess electrical energy. MWD is lucky to have the choice.
That would be consistent with what I have seen in my small town. New model S and X are out selling Mercedes high end cars. The last Mercedes S class sedan I saw was 2013 vintage. The newest Mercedes I typically see are AMG convertibles or AMG GTs. Some C class. Tesla 3's are starting to invade that C class segment and they attract gawkers when parked. They were rare sightings 6 months ago. Now I see half a dozen a day just driving around town. They look great in red.
Do you think they are applying the same thinking in NASH? There is MDGL out there with a for sale sign.
AD - AAIC plenary session notes from D. Sherman of Lifesci capital.
Plenary Session: Multidomain interventions to prevent cognitive impairment and dementia
Dr. Miia Kivipelto
Treatment for AD is now largely preventative
Increasing evidence from experimental and epidemiological studies that AD is complex and multifactorial. There are multiple disease mechanisms and there are likely mixed pathologies.
There are several modifiable risk factors over the whole course.
Altogether, estimated that at least 30% of AD cases are related to 7 risk factors – diabetes, hypertension, obesity, depression, smoking, low education, physical inactivity
Both pharmacological and non-pharmacological interventions are starting earlier.
It may be that we need to target risk factors and mechanisms simultaneously to get optimal preventative effect
But also, one size does not fit all, need to tailor intervention to individual’s specific risk profile
WHO – highlighting prevention as one of the key elements for preventing global epidemic of AD
Very little evidence from low and middle-income countries. Quite little evidence from RCTs. May not be feasible to get evidence for several of these risk factors in trials. May want to add cognitive outcomes in other trials
How can we consider the evidence from multidomain interventions, which are coming from new studies?
Have some positive signals from trials looking at physical activity, cognitive training and certain dietary patterns
And then have multidomain trials where tried multiple things – FINGER, MAPT, pre-DIVA
FINGER – first large multidimension trial looking at diet, exercise, cognitive training and vascular risk monitoring compared to control people
Looked at at-risk people
2-year intervention and now in long-term follow up
Multidomain – used group and individual training
Summary of primary findings- Ngandu et al 2015
Intervention group had lower risk for cognitive and functional (IADL) decline, better health-related QoL
ApoE E4 carriers saw clear benefits of these interventions. ApoE E4 carriers may be more sensitive to harmful lifestyle factors.
New findings show that FINGER intervention seems to counteract shortening of telomeres among ApoE E4 carriers
Intervention group also had lower risk for multi-morbidities and lower rate of hospital days (20% lower)
MAPT Trial in France
Primary outcome was cognition. Not met.
However, in subgroups, saw some benefit for intervention group
preDIVA trial – all elderly persons were included, no risk-based selection
multi domain intervention – lifestyle and drug treatment over 6 years
primary endpoint was dementia incidence. This was not met.
people who had untreated hypertension exhibited lower dementia incidence
take together all 3 big trials, have over 6000 participants.
So far have learned 3 important things: timing is critical, focus on at-risk individuals, interventions must be “doing the right things and doing enough of them”
Initiated World-Wide FINGERS – trying to use similar methods but still adapting them to fit the needs of individual countries.
US POINTER – try to replicate FINGERs trial as much as possible. 60 – 79 yo, 2000 patients, normal cognition but increased risk, have self-guided lifestyle intervention (education and support, guideline-based health coaching) and structure lifestyle intervention (exercise, nutrition, cog stimulation)
MIND-CHINA – 60 – 79 yo, 3500 patients. Have 2 diff multidomain arms. One is multimodal intervention (focusing on lifestyle aspects in China, such as high salt diet and smoking) and one arm focusing on vascular risk factors.
SINGER in Singapore – first during a feasibility study to see what is most fitting for that culture and setting.
Great hope for blood-based biomarkers. If can start using it, would be helpful for FINGERS study.
GWAS may be helpful for clinical trials too. Want to start using big data in clinical trials.
Tools for combined prevention trials – lifestyle + Disease-modifying drugs together
Developing tools to get there now
MIND-AD pilot trial – combining multidomain lifestyle intervention with medical food. Have hypotheses to believe that there may be synergistic effects.
Do we have some good candidates for disease modifying drugs?
Target population has become more specific
Altogether, more than 200 drug failures in past 30 years, may in Phase 3. A lot of new Ph2 trials too.
In new trials, starting earlier, using adaptive design, more phenotyping
One example is EPAD in Europe – recorded more than 800 people in longitudinal cohort study.
From FINGER simulations – see that there may be cost savings and large societal effects with this type of intervention
Using E-health and M-health tools to support intervention
Take home “action points”:
Multi domain interventions seem effective and feasible
Need more tailored interventions for specific at-risk profiles. Hopefully can combine pharm and non-pharm interventions
Global collaboration is necessary – sharing data, joint projects.
I closed a 105/120 strangle on CLB on the compression of vol back to normal. Strangle was sold after my review of HAL and 10K and surmised that CLB will do fine because of completions on US wells that were being converted from DUC status. IDK if they bounce further from here but LNG exports to EU will help.
More like frustration of not being able to get the 3 out of LA traffic. Still the editor, last paragraph, summed up their anxiousness to put their hands on it again for a real test. "potential to be epic".
IMO this happens bouncing off every cycle lows in O&G services. Discounts given during tough times have stickiness that takes time to unstick. Particularly for field services, not so much lab services.
"The put premiums on TSLA are through the roof--and no wonder."
It is symmetric ie "no skew". What is the historic volatility around earnings? Options for earnings week pricing in an 8% move in either direction.
PS. Eyeballing the last 4 earnings reactions. Delta post announcement range from -15 to +30. So currently implied vol is about in line with prior earnings announcements.
CLB - business model and segments (they have bolted on a few small newer things but small relative to legacy segments) are essentially the same as what my prior understanding was. Given HAL's results CLB should have done well in the last Q.
https://www.sec.gov/Archives/edgar/data/1000229/000100022918000025/clb-20171231_10k.htm#s2DF4F6F8D42A5E5F91A93C95892F5408
PS. It is very expensive to core offshore and for that reason, usually not done until the development stage. Fluids do get collected as a matter of DST's but that is minor rev contribution.
The other CEO has stated that they try to avoid being used as leverage against ISRG. But there may be instances where lower abdominal capabilities do overlap (not urology, DV is clearly better for that) and you don't need all the bells and whistles of a DV.
I only know of one instance of remote "surgery" demonstrated in a clinical setting. Operator was in the US at a conference and clinic was in Italy. Not a selling point for any systems IMO for now. Haptics, atraumaticity and automation are more important IMO.
ISRG - Q2 report and CC. When momentum has inertia. Stock is down tho from strong opening.
http://phx.corporate-ir.net/phoenix.zhtml?c=122359&p=irol-newsArticle&ID=2359129
https://www.nasdaq.com/aspx/call-transcript.aspx?StoryId=4188571&Title=intuitive-surgical-inc-isrg-ceo-gary-guthart-on-q2-2018-results-earnings-call-transcript