Monthly Research Review – August 2019

 

At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during August 2019.

The post is divided into seven parts based on the type of research:

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials
  • Clinical trial news
  • Other news
  • Review articles/videos

 


So, what happened during August 2019?

In world news:

7th August – Scientists discovered that staring at seagulls can stop them from stealing food (Click here to read more about this – no, really, this is serious science).

14th August – Swedish climate activist, 16 year old Greta Thunberg set sail across the Atlantic ocean in a zero-carbon yacht – almost one year after she started her school strike for the climate protest on 20 August – to attend various meetings in the US (Click here to read more about this).

23rd August – At the G7 meeting, Western countries (who have utterly deforested themselves in the name of commerce) decried the burning of the Amazon rain forest (which does NOT contain 20% of the world’s oxygen – click here to read more about that), rather than simply proposing to re-foresting themselves (Click here to read more about this).

[Sorry to get political, but having returned from 12 days off the grid, I am shocked and saddened by the level of nonsensical noise upon reconnecting]

27th August – American rocket company SpaceX conducted a successful flight of their “Starhopper” craft. Starhopper is an early test prototype of SpaceX’s Mars-colonizing Starship spacecraft (Click here to read more about this)

28th August – Greta arrived in New York (Click here to read more about this).

In the world of Parkinson’s research, a great deal of new research and news was reported:

In August 2019, there were 924 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (5688 for all of 2019 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 5 pieces of Parkinson’s news

1. Enterin clinical trial results:

The results of the Enterin Phase 2a multicenter, dose-escalating RASMET study to evaluate the safety, tolerability & efficacy of orally administered ENT-01 for the treatment of constipation in Parkinson’s have been published, and they look promising. This was an open label trial, but 80%+ participants achieved the primary efficacy endpoint (with the mean number of complete spontaneous bowel movement per week increasing from 1.2 at baseline to 3.6 during fixed dosing. But systemic absorption was <0.3%, so effect is very local ( to read the results and click here for the press release).

2. Preclinical immunotherapy results:

The preclinical data of MEDI1341 (a α-syn-targetting monoclonal antibody developed by MedImmune, & being clinically tested for Parkinson’s by Astra Zeneca & Takeda Pharmaceuticals) have been published. It enters the brain, and binds monomeric & aggregated forms of α-syn. This therapy is currently in clinical testing ( to read more about this).

3. Parkinson’s – a “amyloidosis”

New microbeam X-ray diffraction research on mouse & human brain tissue supports the concept that Parkinson’s is a type of “amyloidosis” – a condition featuring the accumulation & propagation of amyloid fibrils of α-synuclein ( to read more about this).

4. Preclinical Prosavin

Preclinical results from the new & improved ‘Prosavin’ gene therapy viral vector (OXB-102/AXO-Lenti-PD) in non-uman primates has been published. Results ‘strongly support’ the ongoing clinical trial in Parkinson’s ( to read more about this).

 

5. The Linked Clinical Trials meeting

The 2019 Linked Clinical Trials (LCT) meeting was held in Grand Rapids (Michigan) this month. Chair of the LCT committee Prof Patrik Bundin (Van Andel Institute) has provided a video explaining how the LCT initiative (in partnership with the Cure Parkinson’s Trust) is trying to get new potentially disease modifying therapies for Parkinson’s:

Click here and here to read more about the Linked Clinical Trials process.

 

Basic biology news

  • In a manuscript on BioRxiv, researchers reports that cholesterol inhibits Parkinson’s-associated α-synuclein interactions with lipid bilayers, but significantly promotes α-synuclein fibrillation (>20x lag-time reduction before fibrillation – to read more about this).
  • Researchers report stress-induced phospho-ubiquitin formation causes Parkinson’s-associated PARKIN degradation (via the proteasome). Oxidative stress & metabolic dysfunction may contribute to loss of PARKIN. A broadly-generalizable mechanism? ( to read more about this).
  • Evidence that “non-invasive gene therapy” AAV-PHP.B virus administration results in a differential pattern of biodistribution in the brain in non-human primates compared to mice. May still be useful in humans using CSF routes of administration (Click here to read more about this).

  • New bioRxiv manuscript reports neurons missing Parkinson’s-asssociated PARKIN exhibit significantly enlarged lysosomes & decreased lysosomal enzyme activity. Curiously β-glucocerebrosidase (GBA) levels are significantly increased in these cells ( to read more about this).
  • Researchers have a mauscript reporting a buildup of lipid droplets in microglia with aging in mouse & human brains, which may contribute to age-related & genetic forms of neurodegeneration. Lipid droplet accumulating microglia are defective in phagocytosis, produce high levels of ROS, & secrete pro-inflammatory cytokines. CRISPR screening studies identifies genes linked to neurodegen. as genetic regulators of lipid droplet formation (including Parkinson’s-asssociated VPS35 –  to read more about this).
  • MISTERMINATE: Noun; a biological phenomenon; “MItochondrial-Stress-induced translational TERMINATion impairment and protein carboxyl terminal Extension”. May be involved in Parkinson’s (rescues PD models at least – to read more about this).
  • Long considered a waste product, Bilirubin is now found to have a unique redox activity & scavenges superoxide. Mice with no bilirubin are more vulnerable to oxidative stress. New therapeutic target for neurodegenerative conditions like Parkinson’s? ( to read more about this and click here for the press release).

  • Preventing α-synuclein aggregates is a plausible strategy against Parkinson’s. To this end, researchers have engineered the β-wrapin “AS69” to bind monomeric α-synuclein with high affinity. AS69 reduced α-synuclein aggregates & rescued locomotor deficit ( to read more about this).
  • Researchers report that E3 ubiquitin ligase Mul1 restrains Parkinson’s-associated PARKIN-mediated mitophagy in mature neurons via maintaining ER-mitochondrial contacts ( to read more about this).
  • One of the major mitochondrial protein import pathways – the presequence pathway – is facilitated by Parkinson’s-associated PINK1 & PARKIN activity (& antagonized by the ubiquitylase USP30). Mutations in PINK1 or PARKIN impair the system ( to read more about this).
  • Apolipoprotein E & α-synuclein cerebrospinal fluid concentrations appear to have an inverse correlation along the entire dopaminergic clinical spectrum (from Parkinson’s too little dopamine, through to schizophrenia – click here to read more about this and oooohh, a video abstract of the research:

  • New study suggests a novel process in which the modulation of calcium confers neuroprotection in model of Parkinson’s, via the autophagy-lysosome pathway ( to read more about this).
  • Simulating Parkinson’s – New paper probes the basis of α-synuclein aggregation by using simulations of single-molecule experiments. Identifies an ensemble of β-rich dimer structures from which dimer interfaces could be deduced (Click here to read more about this).
  • New manuscript on bioRxiv reports structural basis for Rab8a GTPase recruitment of RILPL2 via Parkinson’s-associated LRRK2 phosphorylation of switch 2 ( to read more about this).
  • N-terminal acetylation affects Parkinson’s-associated α-synuclein fibril polymorphism. Low-ThT Ac-αSyn fibrils seed both acetylated and non-acetylated αSyn. In contrast, the high-ThT NH3-αSyn seeds lose fidelity over subsequent generations (Click here to read more about this).

  • Study reports that the dopamine metabolite, 3,4‐dihydroxyphenyl‐acetaldehyde (DOPAL), enhance oligomerization of Parkinson’s-associated α‐synuclein, which inhibited mitochondrial function. Coenzyme Q10, Fenofibrate, Ginsenoside Re & Mdi‐1 rescue effect ( to read more about this).
  • New manuscript on bioRxiv suggests that the more exposed the N-terminus of monomeric Parkinson’s-associated alpha-synuclein, the more aggregation prone it is ( to read more about this).
  • Perturbations in RhoA signalling cause altered migration & impaired neuritogenesis in human iPSC-derived neural cells without Parkinson’s-associated PARKIN/PARK2 (Click here to read more about this).
  • RAB8, RAB10 & RILPL1 have been reported to contribute to Parkinson’s-associated LRRK2 kinase-mediated centrosomal cohesion & ciliogenesis deficits (Click here to read more about this).
  • Perturbations in RhoA signalling cause altered migration & impaired neuritogenesis in human iPSC-derived neural cells without Parkinson’s-associated PARKIN/PARK2 (Click here to read more about this).
  • New study uses longitudinal 18F-FDG PET brain imaging to determine a Parkinson’s-specific glucose metabolic brain pattern for a rat model of PD ( to read more about this).
  • Researchers present data demonstrating that genetic silencing of fatty acid desaturases modulates α-synuclein toxicity & neuronal loss in C. elegans models of Parkinson’s ( to read more about this).

  • Researchers report that “RNA, independent of its sequence, source & size, modulates recombinant prion protein aggregation in a bimodal fashion, affecting both the extent & the rate of rPrP aggregation in a concentration dependent manner”. Implications for Parkinson’s? ( to read more about this).
  • Researchers present data suggesting that ΔFosB elevation is responsible for the generation of Ldopa-induced dyskinesias in Parkinson’s & repressing its expression could have therapeutic value (Click here to read more about this).
  • Functional amyloid proteins stabilize biofilms & contribute to bacterial virulence. Curiously, reducing the amyloidogenicity of functional amyloid protein FapC increases its ability to inhibit Parkinson’s-associated α-synuclein fibrillation ( to read more about this).

 

Disease mechanism

  • Researchers have a bioRxiv manuscript using single cell gene expression analysis to reveal graft composition & differences between human stem cell- & fetal cell-derived grafts that correct model of Parkinson’s ( to read more about this – this is follow-on work to their previous research which was published earlier this year – click here to read that previous work).
  • New manuscript on bioRxiv reports N-ethylmaleimide sensitive factor aggregation in brain samples of animals & people with Parkinson’s-associated LRRK2 G2019S genetic variants. Interesting: induction of autophagy (with trehalose) rescues animal models ( to read more about this).
  • The interplay between stress and Parkinson’s using an animal model of synuclein pathology spreading ( to read more about this).

  • One of the major mitochondrial protein import pathways – the presequence pathway – is facilitated by Parkinson’s-associated PINK1 & PARKIN activity (& antagonized by the ubiquitylase USP30). Mutations in PINK1 or PARKIN impair the system ( to read more about this).
  • New study suggests that both in vitro & in vivo TREM2 deficiency shifts microglia from an anti-inflammatory to a proinflammatory activation status. This aggravates proinflammatory responses to α-syn & exacerbates α-syn–induced neurodegeneration ( to read more about this).
  • Researchers have a new report suggesting that the absence of or hyperstimulation of microglia affects α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s ( to read more about this).
  • Modified exosomes with the neuron-specific rabies viral glycoprotein (RVG) peptide were used to deliver alpha -synuclein targetting aptamers. They reduced the neuropathological & behavioral deficits in a mouse model of Parkinson’s ( to read more about this).
  • New study demonstrates that neuronal expression of Transcription factor EB (TFEB) is sufficient to prevent neurodegeneration in A53T–α-syn model of Parkinson’s, while oligodendrocyte expression of TFEB rescues a multiple systems atrophy (MSA) mouse model ( to read more about this).
  • New study reports the neuroprotective & anti‐inflammatory effects of progesterone in the gut myenteric plexus of a Parkinson’s mouse model ( to read more about this).

  • New research suggest that the inhibition of Triggering receptors expressed on myeloid cells-1 (TREM-1) can rescue neuroinflammatory responses in models of Parkinson’s & that this effect may occur via the activation of autophagy & anti-inflammatory pathways ( to read more about this).
  • Competitive autophagy inhibition (in the form of a virus expressing a dominant-negative form of the Unc-51 like autophagy activating kinase) significantly improved a mouse model of Parkinson’s (MPTP – to read more about this).
  • Little is known about the function of the 98 isoform of Parkinson’s-associated alpha synuclein. Now Chinese researchers report that “injection of α-syn-98 aggregates into the brain triggers α-synuclein pathology & an inflammatory response” ( to read more about this).
  • By imaging brain circuits in an awake parkinsonian mouse model, researchers provide evidence that Parkinson’s-associated anxiety is caused by impaired postsynaptic D2 receptor-dependent dopaminergic transmission in prefrontal cortex ( to read more about this).
  • Researchers use rabies virus glycoprotein-coated exosomes as vehicles for delivery of microRNA minicircles into the brain to correct a mouse model of Parkinson’s. Decreased a-syn aggregation, reduced the loss of dopamine neurons & improved the symptoms ( to read more about this).

 

Clinical research

  • Further nation wide (S. Korea) evidence of an association between inflammatory bowel disease & Parkinson’s. Corticosteroid use showed a preventive effect on developing PD in patients with Crohn’s disease, but not ulcerative colitis. “Among 2110 patients receiving anti-tumor necrosis factor (anti-TNF), none of the treated patients experienced #Parkinsons during 9950 person-years” ( to read more about this).
  • Phospho-S129 alpha-synuclein is present in human plasma but is not detectable in cerebrospinal fluid (CSF – to read more about this).
  • Small numbers, but interesting trend: Long-term metformin therapy (>2 years) has been suggested to be associated with lower incidence of neurodegeneration (including Parkinson’s) among elderly veterans with Type 2 diabetes. Larger replication required ( to read more about this).
  • Researchers provide validation of a mobile version of the BRadykinesia Akinesia INcoordination (BRAIN) tap test – an online keyboard tapping task that has been previously validated to assess upper limb motor function in Parkinson’s ( to read more about this).

  • Researchers present work on a wearable electrochemical microneedle sensor for continuous monitoring of Levodopa – are we moving towards better management of treatment for Parkinson’s? ( to read more about this).
  • Researchers show that modulating the activity of the subthalamic nucleus in patients with Parkinson’s disease normalizes signatures of widespread network connectivity towards those found in healthy controls ( to read more about this).
  • A US Food and Drug Administration review has found NO increased risk of prostate cancer resulting from use of the Parkinson’s drug entacapone ( to read more about this).
  • A study of 284 people with de novo Parkinson’s (204 coffee & 80 non-coffee drinkers) found that coffee consumption & tremor severity are inversely related in the male subjects (coffee drinkers had lower tremor scores than non-coffee drinkers in general to read more about this).

  • The benefits of pilates in Parkinson’s – a systematic review & meta-analysis. Preliminary evidence: “benefits on lower-body function appear to be superior to those of other conventional exercises” Conclusion: More research (larger sample size) required ( to read more about this).
  • New research suggests inner retinal thinning could be a biomarker for cognitive impairment in de novo Parkinson’s. Analysis of 74 PD vs 53 matched control participants found sig. reductions in the thickness of retinal nerve fiber layer in cases of PD ( to read more about this).
  • Researchers have a manuscript on bioRxiv discussing genetic modifiers of risk & age at onset in GBA-associated Parkinson’s & Lewy body dementia ( to read more about this).
  • Interesting discussion of the use of digital technology & media in German Parkinson’s community. Use of computers, smartphones, & the internet was age dependent, & advanced patients with higher motor impairment used smartphones less often ( to read more about this).
  • 2206 Parkinson’s patients in Sweden screened for 8 mutations known to be associated with PD (SNCA copy number variants & 7 point mutations in LRRK2 & SNCA were analyzed). 1/4 of cases had family history, but just 13 (<1%) individuals had a genetic variant ( to read more about this).
  • Researchers report that saccadic eye-movements are impaired in early Parkinson’s & are predictive of cognitive decline in several domains ( to read more about this).

  • New research suggests that women experience complications & access most healthcare services sooner & more frequently than men after a diagnosis of Parkinson’s ( to read more about this).
  • Dual targeting of the subthalamic nucleus & caudal zona incerta for deep brain stimulation (DBS) in Parkinson’s is safe, accurate & effective, with outcomes that compare favourably to existing published data on subthalamic nucleus DBS ( to read more about this).
  • Hypothalamic involvement in #Parkinsons (as shown by a large body of histopathological evidence) does not appear to be detectable by MRI‐based volumetric quantification (Click here to read more about this).
  • Researchers reaffirm that an altered microbiome exists in people with Parkinson’s, & support the notion of a proinflammatory gut microbiome environment could be a trigger for PD pathogenesis ( to read more about this).
  • New study involving 155 Ethiopian Parkinson’s patients reports one of the highest rates of severe sleep disorders to date. The prevalence of possible/definite excessive day-time sleepiness “is amongst the highest in the world” ( to read more about this).
  • People with Parkinson’s have a higher risk of melanoma. Now researchers have a bioRxiv manuscript demonstrating specific, shared genetic architecture between Parkinson’s & melanoma, manifesting at the level of gene expression ( to read more about this).

  • New research suggests people with Parkinson’s are more sensitive to & have a lower threshold for pain, supporting a “hypothesis that enhanced top‐down processing of pain may contribute to the development of chronic pain” (Click here to read more about this).
  • New research highlights the importance of RANTES-Th17 pathway in progressive dopamine neuronal loss & associated Parkinson’s pathology. Levels of IL-17 & RANTES are higher in serum of PD patients (vs controls – click here to read more about this).
  • Convergence insufficiency in Parkinson’s causes visual symptoms, such as double vision. Researchers have conducted a pilot study to see if convergence insufficiency could serve as a marker of cognitive impairment ( to read more about this).
  • Researchers built & validated a MRI compatible balance simulator that can be used in brain imaging studies investigating balance controlling areas of the brain & how these areas are affected in Parkinson’s. Interesting 1st results ( to read more about this).

  • Mutations in the glucocerebrosidase (GBA) gene cause Gaucher disease & are associated with Parkinson’s. In a new bioRxiv manuscript, researchers use nanopore sequencing as a high-throughput method to identify GBA mutations in a PD cohort ( to read more about it).
  • Researchers & collaborators conducted flow cytometry analysis on monocytes from people with Parkinson’s & found reduced viability. They are also unresponsive to specific stimuli. Interestingly, some of the results were sex associated ( to read more about this).
  • Research report that the incidence of falling was higher among 2063 Parkinson’s patients compared to 2063 controls (2.1 vs. 0.7 falls/person, respectively; P < .0001), highlighting the feasibility of using body‐worn sensors to monitor falls ( to read more about this).
  • New study suggests that cerebrovascular risk factors (including prior stroke) are associated with Parkinson’s, an effect similar to their association with Alzheimer’s (Click here to read more about this).
  • Data from the Parkinson’s Progression Markers Initiative (PPMI) has been published regarding the prediction of PD progression. Results suggest that baseline clinical, cerebrospinal fluid, & brain imaging measures in early PD predict change in UPDRS & DAT binding, but predictive value of the models is low. But adding the short-term change of possible predictors improved the predictive value ( to read more about this).

 

New clinical trials

  • New clinical trial registered to investigate transcranial pulsed current stimulation (tPCS) in the OFF state in Parkinson’s patients (Click here to read more about this).
  • Interesting new clinical trial registered looking at dietary supplementation with cofactors N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside & serine in Parkinson’s & Alzheimer’s (Click here to read more about this).
  • The Parkinson’s Foundation PDGeneration: Mapping the Future of Parkinson’s (PDGENE)” study has been registered. 600 participants being requested. Assessing feasibility, impact, & participant satisfaction of certified genetic testing as part of clinical care (Click here to read more about this).

  • New clinical trial registered exploring the effects of clinical pilates exercise program on postural control & balance in individuals with Parkinson’s (Click here to read more about this).
  • New clinical trial registered to assess whether HMG-CoA reductase inhibitors (think: cholesterol reducing statins, like simvastatin or lovastatin) prevent Ldopa-induced dyskinesia in Parkinson’s. The study is called STAT-PD; seeking 120 participants (Click here to read more about this).
  • A new clinical study evaluating Denali Therapeutic’s LRRK2 inhibitor, DNL151, in Parkinson’s has been registered. A Phase 1b, randomized, placebo-controlled, double-blind study of safety, tolerability, pharmacokinetics, & pharmacodynamics in 24 subjects (Click here to read more about this).

 

Clinical trial news

  • The US FDA has approved Nourianz (istradefylline) tablets as an add-on treatment to levodopa/carbidopa in Parkinson’s to help with the management of OFF periods ( to read more about this).
  • IRLAB Therapeutics announced data from their recent Phase IIa study of IRL790 (a D3 antagonist) in Parkinson’s with L-dopa induced dyskinesia provides further evidence of improved daytime movement quality. Phase IIb/III study to start in the first half of 2020 ( to read more about this).

  • A randomized, single-blind clinical trial in Iran of 20 mild to moderate Parkinson’s patients found that treadmill training of mild to moderate intensity had significant & persistent benefits for the balance, functional capacity, & quality of life ( to read more about this).
  • The US FDA has approved a supplemental Biologics License Application (sBLA) to US WorldMeds for MYOBLOC® (rimabotulinumtoxinB – aka botox) injection for the treatment of chronic sialorrhea (drooling) in adults with Parkinson’s (Click here to read more about this).

 

Other news

  • Gain therapeutics has received funding support from Eurostars-2 joint programme to develop drugs for the treatment of Gaucher disease, GM1 Gangliosidosis & GBA-associated Parkinson’s ( to read more about this).
  • D&D Pharmatech Inc announced today that it has completed a $137.1 million Series B round of financing from U.S. & Korean investors. Proceeds will be used to help fund Parkinson’s-focused subsidary “Neuraly” in Phase II clinical studies ( to read more about this).

  • The Movement Disorder Society has provided an update of the MDS research criteria for prodromal Parkinson’s (the period of time before PD diagnosis to read more about this).
  • The Michael J Fox Foundation is funding a nearly $5 million initiative to expand genetic research in three areas underrepresented in Parkinson’s research. This can lead to a deeper understanding of the condition and new ways to measure and treat the disease ( to read more about this).
  • The Brian Grant Foundation has launched its Parkinson’s Exercise Class Finder, an easy-to-use online tool that allows people with PD to search for exercise classes in their areas ( to read more about this).

 

Review articles/videos

  • A thought-provoking piece about “the double-edged sword that is CIRM’s legacy” & the “need to temper public hope” regarding cell-based therapies for conditions like Parkinson’s ( to read more about this).
  • A brief pros & cons of using marijuana in the management of Parkinson’s ( to read more about this).

  • A useful review providing a practical, stage-based guide to pharmacological management of both motor & non-motor symptoms of Parkinson’s (Click here to read more about this).
  • Basically everything you need to know about oxidative stress in Parkinson’s ( to read more about this).
  • Interesting video of Dr Richard Gordon discussing his research on the role of the inflamasome in Parkinson’s, & how this is leading to new clinical trials:

  • Interesting interview with Dr Ram Bhatt (ICBII), discussing the development of “Specific Molecular Architecture for Recognition & Therapy” (or SMART) blood-brain barrier permeable technology to address conditions like Parkinson’s & Alzheimer’s ( to read more about this).
  • A good review of lysophagy & its potential implications for Parkinson’s, Alzheimer’s and lysosomal storage disorders ( to read more about this).
  • Interesting editorial discussing how the non-receptor Src family kinase Fyn may be influencing NLRP3 inflammasome signaling in Parkinson’s ( to read more about this).
  • A useful overview & primer on neurogenic orthostatic hypotension in Parkinson’s ( to read more about this).

  • A thorough review of everything we know about GBA and Parkinson’s ( to read more about this).
  • Could NADPH-oxidase (NOX) inhibitors be useful against Parkinson’s? Interesting review ( to read more about this).
  • Dr Tilo Kunath was awarded the Tom Isaacs award for 2019. The award is given to a researcher who has made significant contributions to involving the Parkinson’s community in research (Click here to read more about this).

 

* * * * * * * * * * * *

And there it is, just some of the highlights from August 2019 – another very busy month of Parkinson’s research. Hopefully there will be bits and pieces of interest for everyone in the list. Much of the material used here was collected from the Science of Parkinson’s Twitter feed (and there is a lot more posted there each day).

Any thoughts/feedback would be greatly appreciated (either in the comments below, or contact me directly).

And now: on to September! (Good grief Christmas is coming!)


EDITOR’S NOTE: The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.

In addition, many of the companies mentioned in this post are publicly traded companies. That said, the material presented on this page should under no circumstances be considered financial advice. Any actions taken by the reader based on reading this material is the sole responsibility of the reader. None of the companies have requested that this material be produced, nor has the author had any contact with any of the companies or associated parties. This post has been produced for educational purposes only.


2 comments

  1. A Cyclopath

    Amazing amount of information shared in such an easy to read format. Thank you so much for all your hard work putting this together – it’s top of my ‘must read’ list every month.

    Like

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