Top 5 advances in medicine this week (🧵)

1. A tissue-integrated bionic knee

It's connected to underlying bone, nerves, and muscle

It has a more natural gait, beats current prosthetics in tasks like climbing stairs – and feels more like your own leg
science.org/doi/10.1126/sc… 2. Bone marrow transplant treats a fatal disease

ALSP is a rare genetic condition caused by loss of microglia

Here, bone marrow transplants replaced the microglia, halted disease progression, and maintained cognition and the ability to walk

science.org/doi/10.1126/sc…

Top 5 advances in medicine this week (🧵)

1. Adults can produce new neurons, after all

A decades-old problem is whether adults can produce new neurons. It’s been proven in mice – but never in humans

This is the stunning discovery that the full pathway of new neurons - from the stem cells to the neuroblasts – can be found in the adult hippocampus

Neural stem cells are the ‘parent’ cells, intermediate progenitor cells are the ‘children’ and neuroblasts are the ‘teenagers’ – on their way to becoming fully-formed neurons

Source: science.org/doi/10.1126/sc… 2. Specific targeting of chronic inflammation

Inflammation is the devil that drives disease. Cancer, cardiovascular disease, dementia – they’re all underpinned by inflammation

But it’s not acute inflammation – this protects us against infection. It’s chronic inflammation that’s the problem

This team found that the chromatin remodelling protein, WSTF, disappears in chronic inflammation but stays in acute inflammation

A cell-penetrating peptide that disrupts WSTF's degradation suppresses chronic inflammation – without affecting acute inflammation

(The active peptide is mNLS-CPP-WSTF – in the figure it's addressing the underlying pathology in a model of osteoarthritis)

Source: nature.com/articles/s4158…

How does exercise actually affect biology?

This study answers that – in humans – at scale: exercise reduced inflammation, reduced DNA damage, and made the immune system younger

And it turns out there might be an exercise-mimicking pill that replicates the benefit... This is the first human study of its kind

It does proteomics, metabolomics, single cell transcriptomics, and microbiome analysis at three times

1) At baseline

2) Immediately after exercise (a 5 km run)

3) After an exercise program (25 days – daily 5 km runs)

Top 5 advances in medicine this week (🧵)

1. A first-in-class GLP1 and amylin receptor agonist for obesity

This is an early trial in overweight/obese adults

Average weight loss was 24 % in under a year - at the cost of gastrointestinal side-effects

thelancet.com/journals/lance… Both GLP1 and amylin slow gastric emptying, reduce glucose spikes, and signal satiety

GLP1 also triggers insulin secretion, and amylin also slows gastric emptying long-term

Combining them might improve the durability of weight loss

Prevention beats cure, which is why it's so exciting that Lenacapavir, a twice-yearly HIV preventative, just got approved for the first time (by the FDA)

Why is it such a big deal?

When trialled (in women in South Africa and Uganda) there were 0 HIV infections

🧵 In the second big trial (in men, in 7 countries: United States, Brazil, Thailand, South Africa, Peru, Argentina, and Mexico) its efficacy was >95%

Are all of the benefits of GLP1s due to weight loss?

Weight loss helps - for sure - but GLP1s also have broader, direct benefits

Here are four examples:

1. The GLP1 receptor agonist, Semaglutide, improves pain in people with knee osteoarthritis It turns out that the GLP1 receptor is expressed within the knee joint

GLP1 can get into the knee, bind the receptor, and rebuild cartilage

Top 5 advances in medicine this week (🧵)

1. Improving leukemia treatment

Chronic lymphocytic leukemia (CLL) is a B cell cancer partially driven by a tyrosine kinase, BTK, and an anti-apoptotic protein, BCL-2

This phase 3 trial tests a combination of a BTK inhibitor (Ibrutinib) and a BCL-2 inhibitor (Venetoclax)

Ibrutinib-Venetoclax improved progression-free and overall survival vs. previous standards of care

Ibrutinib causes cardiovascular off-target effects in some patients, so cardio-safer versions are now being tested - and already have approval (with Venetoclax) in some countries

nejm.org/doi/full/10.10… 2. Long-term follow-up for a haemophilia B gene therapy

Haemophilia B causes bleeding due to deficiency in clotting factor IX - it usually affects males

This is a therapy that delivers a functional copy of the factor IX gene to the liver via an adeno-associated virus (AAV)

There's only 10 patients but, with a follow-up of 12 years, patients had fewer bleeds and most no longer needed factor IX infusions

It was safe, too - there was no increased clotting risk or chronic liver disease

This gene therapy used a wildtype factor IX, but newer therapies use a variant of factor IX that's more active - so the outcomes might get better yet

nejm.org/doi/full/10.10…

The power of placebo in 5 experiments (🧵)

1. Placebo improves symptoms in IBS - even if people know it's placebo

Placebo was presented as "placebo pills, an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS” 2. A placebo inhaler improves subjective symptoms in asthma - even though it has no effect on objective lung function

(Albuterol is the genuine asthma inhaler)

This is amazing: the first large, randomized trial to show that exercise improves survival after cancer

The benefit from the exercise program was like adding another cancer drug - without the side-effects Patients had surgery to remove colon cancer followed by chemotherapy, and were then randomized either to a structured exercise program or health advice alone

It was a big week of progress in medicine!

Here are the highlights: 🧵 1. The first ever bespoke CRISPR therapy

Source: nejm.org/doi/full/10.10…

Top 5 advances in medicine this week (🧵)

1. A new first-line option for liver cancer (FDA-approved)

2. A new medication to cut cholesterol (Phase 3 trial)

3. A possible emerging therapy for ALS (Phase 2b trial)

4. Updated CAR-T cells for lymphoma (Phase 1 trial)

5. Google's AI beats doctors (again) (RCT) 1. A new first-line option for liver cancer

Source: thelancet.com/journals/lance…

The 10 most striking Kaplan-Meier curves (that I have seen) 🧵

1. Dual GLP1/GIP agonist, Tirzepatide, for prevention of type 2 diabetes in people with obesity

It's easy to miss the dark blue line (15 mg group), because it never leaves the X axis: 2. HPV vaccination to prevent cervical cancer

In those who had the vaccine at the age of 12/13, there were 0 cervical cancer cases:

Antibiotic resistance is a growing problem, so it's good news that gepotidacin, an antibiotic with a unique mode-of-action, was just FDA approved

Here's a quick history🧵 Gepotidacin's pre-clinical discovery was reported (in Nature) in 2010

It was rationally designed by chemists at GSK

It inhibits bacterial replication through dual inhibition of DNA gyrase and topoisomerase IV, by binding new sites that are unaffected by resistance mechanisms

Top 5 advances in medicine this week (🧵)

1. Doctors vs. AI

This is an experiment where patient actors spoke either with a doctor or an AI chatbot (made by Google Research) by typing back and forth - they didn't know which they were speaking to

AI won for diagnostic accuracy, empathy, and patient confidence

Clearly AI isn't going to replace doctors, but this shows the potential for AI in healthcare

For example, we could have AI chatbots at the front door of emergency departments - triaging severity, doing the first part of the consultation, and helping doctors reach the diagnosis

nature.com/articles/s4158… 2. GLP1s might protect against dementia in people with type 2 diabetes

This is a meta-analysis of randomised trials, looking at GLP1 receptor agonists (or other diabetes medications) vs. usual care in people with type 2 diabetes

GLP1s (but not other diabetes medications) reduced the risk of dementia by almost 50%

Which type of dementia that is (Alzheimer’s, vascular, frontotemporal, Lewy body) isn’t yet clear

This might represent reduced neuroinflammation and blood-brain barrier protection with GLP1s (in addition to the other benefits on blood sugar and vessels)

jamanetwork.com/journals/jaman…

Top 5 advances in medicine this week (🧵)

1. The shingles vaccine reduces dementia risk by 20%

People born either side of Sept 2 1933 (in Wales) are equivalent, with one difference: eligibility for the shingles vaccine

Those who were vaccinated (due to their eligibility) had a 20% lower risk of dementia

This might be because shingles (or its treatment) increases dementia risk, or could be a shingles-independent benefit of the vaccine (or a bit of all three) - the effect is mainly in women, though why isn't yet clear

These data do provide causal evidence, but a randomised trial is planned to confirm the findings

Study: nature.com/articles/s4158… 2. An AI tool improves survival in hospitals

Most hospitals use an 'early warning system' to detect patient deterioration based on observations (like blood pressure)

The issue is that these measures are often poorly recorded (like breathing rate) or they're late signs (like low blood pressure)

This is an AI tool built on nursing notes rather than patient observations: if a nurse sees a patient more often, or notices a subtle change in the patient's appearance, the patient might be deteriorating

Tested in a huge cluster-randomised controlled trial vs. standard care, this improved survival in hospitals, and decreased the length of stay

nature.com/articles/s4159…

Top 5 advances in medicine from March (🧵)

1. Human cells make their own antibiotics

Proteins that are no longer needed are broken down in the proteasome, but it turns out that some of the peptides it produces are repurposed as antibiotics

These antibiotic peptides help us fight infection, but could also be used as therapeutics

The top hit (which is derived from a serine/threonine phosphatase) kills a range of bacteria, including Pseudomonas and E. coli, and stopped mice dying from sepsis just as well as a conventional antibiotic

nature.com/articles/s4158… 2. Year-long HIV protection in one dose

Lenacapavir prevents HIV with 99.9-100% efficacy when given twice per year (as a subcutaneous injection) - this is a new formulation that allows it to be given just once per year

It's not a vaccine, but a long-acting anti-retroviral that stops HIV from establishing infection

This is a phase 1 trial, so there’s no efficacy data, but the drug's plasma concentration stayed at higher levels than the 6-monthly formulation that achieved ≥99.9% efficacy, without safety concerns

The dose needs to be optimised, and it has to progress further through trials, but this has potential to expand access to an extremely effective tool for HIV prevention

thelancet.com/journals/lance…

Top 5 advances in medicine this week (🧵)

1. The first liver transplant from pig to human

This becomes the third whole organ to be transplanted from pigs (after hearts and kidneys) - it was proof-of-concept, so the liver was transplanted into a brain-dead patient for only 10 days

The liver functioned throughout: it produced bile and albumin, and maintained blood flow without rejection

The liver was transplanted alongside the patient's native liver - this could act as a bridge to definitive (human) transplant, but could also help solve the shortage of organs available for transplant

Study: nature.com/articles/s4158… 2. A new antibiotic with a unique mode-of-action

It was discovered by incubating bacteria from soil for a year to pick up slow-growing bacteria that've been previously overlooked, and screening them for compounds that kill other bacteria

The antibiotic binds a site in the bacterial ribosome that’s not targeted by any other antibiotic, which allows it to simultaneously block translation and to induce errors in proteins

It’s broad-spectrum (both Gram + and –) with efficacy in a mouse model, no apparent limiting toxicity, and seems to be unaffected by common resistance mechanisms

It needs some optimisation (e.g. to its large size) before human trials are started

nature.com/articles/s4158…

Top 5 advances in medicine this week (🧵)

1. An oncolytic virus for liver cancer

The virus has three anti-tumour mechanisms:

A) It lyses cancer cells

B) This releases neoantigens, which activate the anti-cancer immune response in combination with a virus-expressed PD1-PDL1-blocking fusion protein

C) It expresses cytokines (IL12, IL15, IL15Rα) which further stimulate the immune response

It's directly injected into the tumour, and it's edited to increase specificity for cancer

This is a single arm phase 1 trial, in patients with hepatocellular carcinoma refractory to two previous lines of therapy

A historical control group (not a randomised control group) had a median overall survival of 4.7 months, but median overall survival in this trial was 9.4 months (this is shown in the figure - the oncolytic virus is 'VG161')

Study: nature.com/articles/s4158… 2. The first large randomised trial of automated insulin in type 2 diabetes

Automated insulin delivery (AID), also known as an artificial pancreas, is a device that fits on the skin and adjusts its insulin dose depending on glucose levels (rather than manual insulin injections)

It has an evidence base in type 1 diabetes, but this is the first large trial in type 2 diabetes

The trial only ran for 13 weeks, but AID achieved better glucose control, better sleep quality, higher patient satisfaction, and reduced injection burden vs. manual insulin injections

nejm.org/doi/full/10.10…

Top 5 advances in medical science this week (🧵)

1. Potential for year-long HIV protection in one dose

Lenacapavir prevents HIV with 99.9-100% efficacy when given twice per year - this is a new formulation that allows it to be given just once per year

Lenacapavir is not a vaccine - it's a long-acting anti-retroviral that stops HIV from establishing infection

This is a phase 1 trial, so there’s no efficacy data, but the drug's plasma concentration stayed at higher levels than the 6-monthly formulation that achieved ≥99.9% efficacy, without safety concerns

The dose needs to be optimised, and it has to progress further through trials, but this has potential to expand access to an extremely effective tool for HIV prevention

thelancet.com/journals/lance… 2. High dose vitamin D helps in early multiple sclerosis (MS)

Low vitamin D is a risk factor for MS, an autoimmune condition that affects the brain and spinal cord

This is a randomised trial that tested high dose vitamin D (100,000 IU once every 2 weeks) as a monotherapy vs. placebo, in patients presenting with early signs of MS

High dose vitamin D significantly reduced the occurrence of inflammatory lesions (on MRI) vs. placebo

Vitamin D didn't reduce clinical relapses, but this confirms that it's a risk factor in MS, and suggests that high dose vitamin D, once every 2 weeks, could be added to improve current therapies

jamanetwork.com/journals/jama/…

Top 5 advances in medicine this week (🧵)

1. An untapped treasure trove of antibiotics

The proteasome breaks down proteins that are no longer needed, but it turns out that some of the peptides it produces are repurposed as antibiotics

The top hit is a peptide derived from a serine/threonine phosphatase

This peptide kills a range of bacteria, including Pseudomonas and E. coli, and stopped mice dying from sepsis just as well as a conventional antibiotic

Study: nature.com/articles/s4158…

Comment: nature.com/articles/d4158… 2. The first phase 3 trial of Ivonescimab vs. Pembrolizumab in non-small cell lung cancer (NSCLC)

PDL1-positive NSCLC with no oncogene driver is usually treated with the immunotherapeutic, Pembrolizumab (a PD1-inhibiting monoclonal antibody)

This phase 3 study tested Pembrolizumab vs. Ivonescimab (a bispecific antibody that blocks both PD1 and VEGF)

Ivonescimab almost doubled median progression-free survival vs. Pembrolizumab

There's no data on overall survival yet, and this trial was only conducted in one country (China), but this could add Ivonescimab as a new first-line option

Study: thelancet.com/journals/lance…

Comment: thelancet.com/journals/lance…

Top 5 advances in medicine this week (🧵)

1. Vitamin C modifies the amino acid, lysine, to form VitCyl-lysine

This is a novel post-translational modification: it promotes immunity and (in mice!) boosts anti-PD1 immunotherapy to kill cancer

Whether vitamin C can also boost immunotherapy in humans isn't yet clear, but trials are ongoing

Study: cell.com/cell/abstract/… 2. The blood-brain barrier (the BBB) breaks down as we get older – how does that happen?

The BBB is protected by a 'glycocalyx' barrier - this study found that we lose this glycocalyx layer with age

In experiments in mice, this causes leakage of inflammatory proteins (and even red blood cells) into the brain, leading to cognitive decline

The question is: can we stop this?

nature.com/articles/s4158…