Every letter we have printed
Page 64 of 77 of this archive, newest first.
On “Sarcopenia is a diagnosis, not a synonym for losing lean mass” — Patient Notes, 13 Jun 2024
I train four times a week, eat a hundred and sixty grams of protein and my appendicular lean mass has fallen by 1.8 kg over ten months while every lift has gone up. Your section on mass against function was the first thing I have read that made that seem normal rather than a failure.
— C. Bąkowski, Łódź
On “Sarcopenia is a diagnosis, not a synonym for losing lean mass” — Patient Notes, 13 Jun 2024
Small correction to your table: the S-LiTE exercise prescription was two supervised group sessions and two individual sessions weekly, not two sessions in total. The distinction matters because "add some exercise" is not what was tested.
— A. Kirkbride, Leeds
Correct, and that is precisely the point we were trying to make and then undermined in our own table. Amended.
On “Sarcopenia is a diagnosis, not a synonym for losing lean mass” — Patient Notes, 13 Jun 2024
I am sixty-eight, I have lost nineteen kilograms over fourteen months, and my consultant has twice told me my lean mass is fine on the basis of a handheld bioimpedance device in the clinic corridor. Having read your piece on what that device measures, I am no longer sure what I have been reassured about.
— R. Ekwueme, Awka
Nor are we. A handheld device measures impedance across the upper body and infers the rest, and the inference is least reliable exactly where you sit: older, substantial weight change, changing hydration. That is not a criticism of your consultant’s judgement, which may be sound on other grounds, but the device is not the evidence for it.
On “Rapid weight loss moves eight analytes for reasons that have nothing to do…” — Patient Notes, 13 Jun 2024
You describe the low-T3 pattern during energy restriction as benign adaptation. There is a body of opinion holding that it represents a genuine hypometabolic state requiring treatment. I do not hold that view but your readers will encounter it.
— D. Mazzarella, Catania
They will, and we should have named it in order to say why we do not report it. There is no randomised evidence that treating the low-T3 pattern of energy restriction improves any outcome, and there is a mechanistic argument that suppressing an adaptive response is unlikely to help. We report it as adaptation for those reasons and would report a trial that changed the picture.
On “Rapid weight loss moves eight analytes for reasons that have nothing to do…” — Patient Notes, 13 Jun 2024
My HbA1c was 6.1 before starting and 6.0 after four months. My clinic recorded this as no improvement in glycaemic control. My continuous monitor says my average glucose fell by a fifth over the same period. Which is measuring what?
— A. Mbeki, Lusaka
Both are measuring correctly and the discrepancy is worth pursuing with your clinic rather than with us. A 0.1-point change is well inside the reference change value for HbA1c, so the assay has not detected a change; whether that is because the change is genuinely small or because something is affecting your glycation is not answerable from the numbers alone.
On “Stepping down against stopping: two decisions treated as one” — Clinical Trials, 12 Jun 2024
The claim that stopping does not leave you worse off than baseline is a group-level claim about trial arms. Individuals can and do overshoot. Your phrasing invites readers to conclude otherwise.
— V. Petrosyan, Yerevan
Correct, and the distinction matters. We have added a clause: no arm overshot at a group level, which is not the same as no participant overshooting. The trials do not report individual overshoot rates and we have not found them published anywhere.
On “Stepping down against stopping: two decisions treated as one” — Clinical Trials, 12 Jun 2024
I take this for kidney disease, not for weight. Every piece of writing I encounter about stopping is about the weight coming back. It has taken me a year to find anybody willing to say plainly that the renal benefit accrued over years of treatment and nobody has tested what happens if I stop.
— E. Thistlethwaite, Sheffield
On “Stepping down against stopping: two decisions treated as one” — Clinical Trials, 12 Jun 2024
As a prescriber I would push back on your framing of the maintenance gap. We are not practising without evidence; we are practising on pharmacological inference, which is what clinicians do in every field where the trial has not been run. Calling it unevidenced makes reasonable practice sound reckless.
— H. Nakagawa, Fukuoka
A fair objection and we have adjusted the wording. Our intention was to locate the absence with the people who could have funded the trial rather than with the clinicians managing without it, and on rereading the original paragraph did not achieve that.
On “What VendorInvestigate charges to answer the pyrogen question” — The Supply Chain, 11 Jun 2024
I have worked in aseptic fill for nineteen years and your section on media fills understates one thing. The scale is not the hard part. Running the simulation with every intervention the real process contains — every stopper jam, every environmental sample, every gowning break — is the hard part, and a simulation that omits the interventions is theatre with a growth medium in it.
— M. Bogdanović, Podgorica
That is a better statement of the point than ours and we have amended the section to make the interventions explicit. The scale figure without the intervention requirement is exactly the sort of number that gets quoted as reassurance.
On “What VendorInvestigate charges to answer the pyrogen question” — The Supply Chain, 11 Jun 2024
Your table of responses records four declines citing research-use-only status, and you call that a legally sound answer. It is also the answer that ends the conversation. What would you have a supplier say instead?
— A. Chowdhury, Dhaka
Something like: this product is sold for research use, is not represented as a sterile injectable, and here is what we nonetheless do — aseptic fill in a classified environment, bioburden to a stated specification, post-use filter integrity testing. Three of our correspondents said close to that. It concedes nothing legally and tells a reader a great deal.
On “What VendorInvestigate charges to answer the pyrogen question” — The Supply Chain, 11 Jun 2024
You write that recombinant factor C is insensitive to the glucan branch of the cascade. It would be worth adding why anybody cares: cellulose filter media and certain paper wrappings shed glucans, and a laboratory that has chased a false positive through three repeat assays will never willingly go back to a reagent that responds to them.
— P. Hollingsworth, Norwich
On “What VendorInvestigate charges to answer the pyrogen question” — The Supply Chain, 11 Jun 2024
Your endotoxin table gives vial 12 at 112 EU per vial and then declines to say whether that is dangerous. I understand why. It is still frustrating to read a figure of that size next to the sentence "arithmetic, not a safety assessment".
— F. Okonjo, Asaba
We understand the frustration and we are going to keep doing it. The figure sits at roughly a third of the hourly systemic allowance for a 70 kg adult if the whole vial were administered at once, which is a comparison a reader can make. What we cannot do is turn a single determination on one vial into a statement about a person, and pretending otherwise would be the more serious failure.
On “What “LC-MS: conforms” tells a reader, which is almost nothing” — Laboratory Notebook, 10 Jun 2024
A small defence of the linear MALDI instrument. It is fast, it tolerates dirty samples, and for a synthesis chemist checking that a chain has grown by the residue intended it is entirely fit for purpose. The problem is not the instrument. It is printing its output on a release document.
— S. Bergqvist, Malmö
This is the same objection a reader made about the twelve-minute purity gradient two years ago, and it was right then as well. The criticism is of the use, not the tool.
On “Reflux, early satiety, and the volume the stomach will accept” — Patient Notes, 8 Jun 2024
I want to push back on the ginger paragraph. You describe the evidence as transferred from pregnancy and chemotherapy, which is accurate, and then include it in the table anyway. Either it belongs or it does not.
— A. Salcedo, Bilbao
It belongs, labelled. The table is a map of what is recommended and on what basis, not a list of endorsements, and excluding widely used low-risk measures because their evidence is transferred would make the map less useful rather than more honest. We have made the column heading clearer.
On “Reflux, early satiety, and the volume the stomach will accept” — Patient Notes, 8 Jun 2024
Your figures show diarrhoea at thirty-two per cent and constipation at twenty-three per cent in the same trial arm. I assumed one of these was an error until your mechanism section. It would be worth putting that explanation before the table rather than after it.
— H. Nakagawa, Fukuoka
On “Reflux, early satiety, and the volume the stomach will accept” — Patient Notes, 8 Jun 2024
The gallbladder section says some of the excess is attributable to weight loss rather than the drug. If the drug causes the weight loss, is that not a distinction without a difference for the person who ends up in theatre?
— E. Thistlethwaite, Sheffield
For the individual, largely yes. For the question of whether one molecule is safer than another, or whether the risk would fall on slower loss, the distinction is the whole question. We should have made clear that it is a mechanistic distinction rather than a consoling one.
On “Adverse events by dose, adverse events by week” — Pharmacology, 6 Jun 2024
Your figures show diarrhoea at thirty-two per cent and constipation at twenty-three per cent in the same trial arm. I assumed one of these was an error until your mechanism section. It would be worth putting that explanation before the table rather than after it.
— A. Mbeki, Lusaka
On “Adverse events by dose, adverse events by week” — Pharmacology, 6 Jun 2024
I want to push back on the ginger paragraph. You describe the evidence as transferred from pregnancy and chemotherapy, which is accurate, and then include it in the table anyway. Either it belongs or it does not.
— D. Mazzarella, Catania
It belongs, labelled. The table is a map of what is recommended and on what basis, not a list of endorsements, and excluding widely used low-risk measures because their evidence is transferred would make the map less useful rather than more honest. We have made the column heading clearer.
On “Adverse events by dose, adverse events by week” — Pharmacology, 6 Jun 2024
As an anaesthetist I read the perioperative section with interest and one objection. You frame disclosure as the patient obligation. In my experience the failure is more often ours: the pre-assessment questionnaire in my own institution did not include these drugs until eighteen months after the first guidance appeared.
— C. Rautenbach, Pretoria
A fair correction and we have amended the text. If the question is not on the form, the absence of an answer is not a patient failure. We would be interested to hear from readers in other institutions about whether their pre-assessment documentation has caught up.
On “Adverse events by dose, adverse events by week” — Pharmacology, 6 Jun 2024
The gallbladder section says some of the excess is attributable to weight loss rather than the drug. If the drug causes the weight loss, is that not a distinction without a difference for the person who ends up in theatre?
— R. Whitlam, Adelaide, SA
For the individual, largely yes. For the question of whether one molecule is safer than another, or whether the risk would fall on slower loss, the distinction is the whole question. We should have made clear that it is a mechanistic distinction rather than a consoling one.
On “Adverse events by dose, adverse events by week” — Pharmacology, 6 Jun 2024
You note that symptom burden does not predict weight outcome. This is the single most useful sentence I have read about this treatment. I spent four months believing that feeling well meant it was not working and considered increasing my dose on that basis alone.
— P. Kovalenko, Lviv
The folk model that suffering indexes efficacy is widespread and the published analyses do not support it. It is also actively harmful when it drives escalation, which is why we gave it a line in the closing section rather than burying it in the tables.
On “A lyophilised peptide is not stable. It is slow.” — Laboratory Notebook, 5 Jun 2024
Eleven days in customs, and you describe it as a structural feature rather than a scandal. Why the restraint? A shipper advertising a cold chain that demonstrably does not survive a routine examination is making a claim it cannot support.
— A. Chowdhury, Dhaka
The restraint is about where the fault lies. Customs authorities are performing a lawful function and owe nobody a thermal record. The claim of end-to-end control is the thing we criticise, and we do criticise it, in the article and again in the closing. What we will not do is convert an unavoidable feature of international freight into an allegation against the shipper who could not see it either.
On “A lyophilised peptide is not stable. It is slow.” — Laboratory Notebook, 5 Jun 2024
Your section on freezing reconstituted solution stops short of the obvious question, which I will therefore ask. If a phosphate buffer shifts pH substantially on freezing, does that not mean the freezer is actively worse than the refrigerator for a buffered formulation, rather than merely unproven?
— M. Bogdanović, Podgorica
For a phosphate-buffered formulation, plausibly yes, and the mechanism is well documented. We stopped short because the magnitude is formulation-specific and because most reconstituted research vials are in unbuffered water or bacteriostatic water, where the argument is about the interface rather than about pH. We should have made that distinction in the text instead of leaving a gap for you to find.
On “A lyophilised peptide is not stable. It is slow.” — Laboratory Notebook, 5 Jun 2024
I have shipped temperature-sensitive material commercially for eleven years and your coolant arithmetic is right but generous. You assume the pack starts fully frozen. In practice packs are pulled from a freezer that is opened forty times a day, and a pack that starts at minus four with a soft core has lost a fair share of its budget before the box is closed.
— F. Okonjo, Asaba
A good point and one we had not considered properly. The latent heat calculation assumes a fully solid pack at its melting point, and a partially thawed pack is exactly as much worse as the missing solid fraction. We have added a sentence and would welcome any data you can share on pack condition at packing.
On “Choosing a needle for a subcutaneous peptide” — Patient Notes, 4 Jun 2024
Nothing in this file addresses what to do when you realise mid-week that you have made an error. I gave double my dose on a Sunday and could find no guidance anywhere about what that meant.
— S. Tovmasyan, Gyumri
A real gap and we will address it properly rather than in a reply. The short version is that it is a pharmacokinetic question — how much excess exposure, over what half-life — and a clinical one about symptom burden, and neither is answerable in the abstract. It also belongs in the titration file, which currently discusses omission and not excess.
On “Choosing a needle for a subcutaneous peptide” — Patient Notes, 4 Jun 2024
I gave myself a tenth of my intended dose for five weeks. I had been using insulin syringes, ran out, and used the 1 mL syringes that came with the vials, which are marked in millilitres. I did not notice because the plunger was in roughly the same place. Nobody warned me these were different scales.
— N. Bujanović, Sarajevo
This is the error we rank first for magnitude and we are grateful for the account, because it happened exactly as the mechanism predicts: a substitution that produced no visible signal. The one structural defence is to buy syringes deliberately and keep to a single type rather than using whatever arrives in the parcel.
On “Choosing a needle for a subcutaneous peptide” — Patient Notes, 4 Jun 2024
A quibble on your dead-space figure. You give two to seven microlitres for insulin-type needles, which is right for fixed-needle syringes, but the detachable pen needle plus syringe hub combinations sold in this market are considerably worse and you should say so.
— E. Vandenberghe, Ghent
Accepted and amended. The figure we gave applies to integrated fixed-needle insulin syringes; detachable arrangements on a luer fitting can retain an order of magnitude more, which at small injection volumes is a substantial loss. The table now distinguishes them.
On “A tested vial is evidence about a vial” — The Ledger, 4 Jun 2024
I submitted a vial to one of these services last year, got a result three points below what the vendor advertised, and did not know what to do with it. Your article explains why: I had one measurement on one vial, no method comparison, and no way to know if my vial was representative. I still do not know what to do with it, but I understand the shape of not knowing.
— L. Whitcombe, Christchurch
That is a better summary of this article’s practical content than our own closing paragraphs. The one thing we would add is that your result is worth publishing wherever you can, because buyer-submitted results are the scarcest and most informative category in the entire corpus.
On “A tested vial is evidence about a vial” — The Ledger, 4 Jun 2024
I run analytical services and I object to the framing of your blind comparison. You bought our cheapest tier, published the number it produced alongside a competitor’s most thorough package, and called the result a spread. It is not a spread. It is three different products, priced accordingly, and your own table says so two columns to the right of the headline figure.
— J. Mbatha, Durban
This is the objection we thought was most likely and we think it is partly right. The comparison is of standard products at standard prices, which is what buyers actually purchase, and we said so. But the presentation invites the reading you object to, and the figure caption now states the tier alongside each result rather than leaving it to the method columns.
On “A tested vial is evidence about a vial” — The Ledger, 4 Jun 2024
Your suggestion that laboratories publish the fact of a submission while keeping the result confidential is the first proposal I have read in this area that a laboratory could actually implement without breaching a client obligation. I have raised it internally.
— C. Nightingale, Plymouth
We would be glad to report the outcome either way, including if the answer is no and the reason is commercial. The proposal is only useful if somebody adopts it, and a published refusal is more informative than silence.
On “Background rates, and why they matter for attribution” — Pharmacology, 3 Jun 2024
Your figures show diarrhoea at thirty-two per cent and constipation at twenty-three per cent in the same trial arm. I assumed one of these was an error until your mechanism section. It would be worth putting that explanation before the table rather than after it.
— H. Ravensworth, York
On “Background rates, and why they matter for attribution” — Pharmacology, 3 Jun 2024
I want to push back on the ginger paragraph. You describe the evidence as transferred from pregnancy and chemotherapy, which is accurate, and then include it in the table anyway. Either it belongs or it does not.
— E. Marchetti, Bologna
It belongs, labelled. The table is a map of what is recommended and on what basis, not a list of endorsements, and excluding widely used low-risk measures because their evidence is transferred would make the map less useful rather than more honest. We have made the column heading clearer.
On “Three services, one lot, and a spread of two and a half points” — Analytics, 3 Jun 2024
Your selection-effect model assumes a supplier publishes results above a fixed threshold. Real behaviour is surely more complicated: a supplier might publish a poor result on a batch it has withdrawn, or publish everything for a period to establish credibility and then stop. The arithmetic is fine and the behavioural assumption is a cartoon.
— E. Beauchamp, Ottawa, ON
Agreed, and the figure caption now says illustrative arithmetic rather than model. The point survives the simplification, which is that a small amount of selection produces a large apparent effect, but we should not have dressed a demonstration as an estimate.
On “Three services, one lot, and a spread of two and a half points” — Analytics, 3 Jun 2024
As a buyer I found the section on who chose the vial genuinely clarifying and slightly deflating. I have been treating vendor-published reports as equivalent to my own submissions for two years, and on your account they are not equivalent by an amount that cannot be measured.
— L. Dziedzic, Wrocław
That is the correct reading, and the unmeasurable part is the honest part. We would add only that vendor-published reports are not worthless — a vendor willing to commission testing at all is behaving better than one that will not — they are simply weaker in a specific way.
On “What we asked twenty suppliers about stability data” — The Supply Chain, 2 Jun 2024
Your table of degradation pathways lists racemisation and then says it is essentially never reported. If it is never reported, on what basis do you list it as a real risk rather than a theoretical one?
— K. Sivertsen, Bergen
On the basis of the synthesis and analytical literature, where epimer formation during solid-phase assembly and during storage at extremes of pH is well characterised. What is missing is not evidence that it occurs but evidence about how much of it is present in any particular commercial vial, which is a different absence and the one we should have named.
On “What we asked twenty suppliers about stability data” — The Supply Chain, 2 Jun 2024
The mean kinetic temperature explanation is the clearest I have read anywhere, including in the training my employer paid for. I have printed the sidebar and put it on the wall of the dispatch room.
— J. Vasilenko, Chisinau
On “What we asked twenty suppliers about stability data” — The Supply Chain, 2 Jun 2024
On amber glass: it is not merely cheap, it is standard in the wider chemical supply trade for anything with a chromophore. The fact that this market ships peptides in clear glass is a sign of who is doing the filling more than of any decision about photostability.
— T. Oyelowo, Abeokuta
On “What we asked twenty suppliers about stability data” — The Supply Chain, 2 Jun 2024
Parcel 7 reached thirty-eight degrees for nearly four hours and you then tell readers not to worry unduly. I accept the solid-state argument. I would still like to know what the material looked like on analysis, and your article does not say.
— S. Bergqvist, Malmö
A fair criticism of the reporting. Parcel 7 was submitted for purity determination on arrival and returned a figure within a percentage point of the supplier’s stated value, which is consistent with the solid-state argument and proves very little on its own, since we had no pre-shipment measurement on that vial. The design fault is ours: a shipment study without a paired baseline sample cannot answer the question we most wanted answered, and the next round will.
On “What we asked twenty suppliers about stability data” — The Supply Chain, 2 Jun 2024
Your section on freezing reconstituted solution stops short of the obvious question, which I will therefore ask. If a phosphate buffer shifts pH substantially on freezing, does that not mean the freezer is actively worse than the refrigerator for a buffered formulation, rather than merely unproven?
— N. Halvorsen, Trondheim
For a phosphate-buffered formulation, plausibly yes, and the mechanism is well documented. We stopped short because the magnitude is formulation-specific and because most reconstituted research vials are in unbuffered water or bacteriostatic water, where the argument is about the interface rather than about pH. We should have made that distinction in the text instead of leaving a gap for you to find.
On “The anatomy of the most reproduced page in this trade” — Explainers, 1 Jun 2024
You put every documentary finding to the company before publication, which is admirable and also means you are letting companies that do not reply escape coverage entirely. Silence should have a cost.
— N. Ó Broin, Sligo
It does, and we should make it more visible. Non-response is recorded in the dossier register and published there. What we will not do is publish an inference we cannot support merely because nobody objected to it, and that constraint does protect the unresponsive. We accept the trade knowingly.