Every letter we have printed
Page 52 of 77 of this archive, newest first.
On “Reproducibility, measured rather than assumed” — The Ledger, 10 Nov 2024
You disclose that two of these services advertise with you and then spend four thousand words on structural criticism of the sector they operate in. I cannot decide whether that is admirable independence or an elaborate way of appearing independent. Probably the former. I wanted to say that I noticed the question.
— R. Mothibi, Gaborone
So do we, every time this department writes about the sector. The only answers we have are procedural: the disclosure, the standards desk edit, the consulting prohibition on the writer, and the practice of printing objections like yours unedited.
On “Reproducibility, measured rather than assumed” — The Ledger, 10 Nov 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.
— R. Sundaresan, Coimbatore
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 “Reproducibility, measured rather than assumed” — The Ledger, 10 Nov 2024
On the archive point: a public record of submissions by vendor would be gamed within a month. Vendors would submit under the names of resellers, or through intermediaries, and the archive would show a distribution as selected as the current one but with a veneer of completeness.
— T. Brannon, Boise, ID
Probably true in part, and it is the strongest argument against our proposal. Our answer is that gaming requires effort and leaves traces, which the present arrangement does not, and that a partially gamed record is more informative than no record. We would not claim more than that.
On “The out-of-range flag is a statistical convention with a printer attached” — Laboratory Notebook, 10 Nov 2024
I stopped treatment fifteen weeks ago and my panel is worse than I expected. I had a panel at five weeks that looked fine and I had assumed I had escaped. Your point about the twelve-week timing was the explanation nobody offered me.
— M. Ferrari, Trieste
On “The out-of-range flag is a statistical convention with a printer attached” — Laboratory Notebook, 10 Nov 2024
My eGFR has risen from 71 to 84 over fourteen months of treatment and I have lost twenty-six kilograms. My prescriber described this as the drug protecting my kidneys. Having read your creatinine section, I suspect it is mostly that I have less muscle. Which of us is right?
— K. Rautio, Tampere
On the information given, probably you, at least in part. A rise of that size during weight loss of that magnitude is well within what reduced creatinine production can produce. A cystatin C-based estimate alongside the creatinine one would separate the two, and is the measurement worth asking for. It is also possible both things are happening.
On “Randomised withdrawal is the cleanest design in this field and the least…” — Patient Notes, 9 Nov 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.
— C. Rautenbach, Pretoria
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 “Randomised withdrawal is the cleanest design in this field and the least…” — Patient Notes, 9 Nov 2024
You say no dose-equivalence data exists between agents in this class. During the shortage my pharmacy substituted one for another on the basis of a conversion table they had printed from somewhere. Where would such a table have come from?
— R. Whitlam, Adelaide, SA
Almost certainly from cross-trial comparison of weight-loss percentages, which is not an equivalence basis. There is no head-to-head dose-titration study permitting conversion between these agents, and STEP 8 — the only head-to-head weight trial we know of — compared two agents at their own licensed doses rather than establishing equivalence between them.
On “Deamidation is the commonest degradation route and the hardest to see” — The Supply Chain, 8 Nov 2024
You say no company reports residual moisture. I obtained a figure from a supplier last year without difficulty, on request, so the data exists in at least some cases. The problem may be less that it is not measured than that it is not printed.
— C. Aguirre, Rosario
On “Deamidation is the commonest degradation route and the hardest to see” — The Supply Chain, 8 Nov 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.
— G. Rasmussen, Odense
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 “Deamidation is the commonest degradation route and the hardest to see” — The Supply Chain, 8 Nov 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?
— E. Nkomo, Polokwane
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 “The conservative convention: report the lower of two numbers” — Analytics, 8 Nov 2024
You list five things a purity figure cannot tell you and then say the list is not an indictment of the technique. It reads like one. If a measurement is silent on content, aggregation, sequence, isomers and microbiology, why is it the measurement this market uses at all?
— P. Vuković, Split
Because it is cheap, fast, comparable-looking and genuinely informative about the thing it measures. A tyre pressure gauge is silent on tread depth, brake pads and the driver, and it is still the right instrument for its question. The failure is in a market that owns one gauge and calls the reading roadworthiness.
On “The conservative convention: report the lower of two numbers” — Analytics, 8 Nov 2024
Your table of what each method can see puts "only if resolved" against isoaspartate for RP-HPLC. That understates the difficulty. Resolving isoAsp from Asp routinely requires a method developed for the purpose, and on a generic gradient the two are frequently indistinguishable even at forty minutes.
— L. Marulanda, Medellín
Accepted, and the entry now reads that it requires a method developed for the purpose. Our original wording implied that a sufficiently shallow generic gradient would generally do it, which overstates what shallowness alone achieves.
On “Who chose the vial that was tested?” — The Supply Chain, 7 Nov 2024
On the archive point: a public record of submissions by vendor would be gamed within a month. Vendors would submit under the names of resellers, or through intermediaries, and the archive would show a distribution as selected as the current one but with a veneer of completeness.
— M. Bogdanović, Podgorica
Probably true in part, and it is the strongest argument against our proposal. Our answer is that gaming requires effort and leaves traces, which the present arrangement does not, and that a partially gamed record is more informative than no record. We would not claim more than that.
On “Who chose the vial that was tested?” — The Supply Chain, 7 Nov 2024
VendorInvestigate does not measure anything and you have grouped it with three laboratories under the heading independent testing. That is exactly the conflation your article says the market makes.
— A. Chowdhury, Dhaka
A fair hit. The tag under which this coverage sits predates the distinction we now draw, and we have added the distinction to the second paragraph and to the table. The department name will follow at the next reorganisation of the site.
On “Who chose the vial that was tested?” — The Supply Chain, 7 Nov 2024
The price table is the most useful thing you have published this year and also the thing most likely to be quoted out of context by somebody selling a comparison service. You might consider a note.
— P. Hollingsworth, Norwich
There is one, and we have strengthened it. The figures are what this publication was invoiced at list rates and are not quotations a reader should expect; volume submitters pay materially less.
On “Who chose the vial that was tested?” — The Supply Chain, 7 Nov 2024
You note that no service offers sterility testing and that it takes fourteen days. Worth saying more plainly: a purity certificate and a sterility assurance are not merely different tests, they are different disciplines with different facilities, and no amount of chromatography will ever bear on it.
— F. Okonjo, Asaba
Correct and worth the emphasis. We have said it in the certificates piece and should say it here too: nothing any of these four services sells addresses sterility, endotoxin or container closure integrity, and no combination of their reports adds up to one.
On “Who chose the vial that was tested?” — The Supply Chain, 7 Nov 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.
— R. Ekwueme, Awka
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 “Sarcopenia is a diagnosis, not a synonym for losing lean mass” — Laboratory Notebook, 5 Nov 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.
— B. Osei-Bonsu, Kumasi
On “Sarcopenia is a diagnosis, not a synonym for losing lean mass” — Laboratory Notebook, 5 Nov 2024
Your piece treats the one-quarter rule as discredited and then quotes fractions of one third and two fifths from the substudies as though those were more solid. They are group means from a hundred and forty people. Physician, heal thyself.
— L. Kowalski, Gdańsk
A fair hit, and we have amended the paragraph to carry the same caveat in both places. The distinction we should have drawn is that the substudy figures are at least attached to a stated population and a stated instrument, which the textbook rule is not. Neither is a constant.
On “Sarcopenia is a diagnosis, not a synonym for losing lean mass” — Laboratory Notebook, 5 Nov 2024
You write that no trial has measured strength. There are observational cohorts with grip strength data. Why do you insist on randomised measurement?
— M. Halim, Kuala Lumpur
Because grip strength in an observational cohort of people who chose to take a drug, and who differ from those who did not in age, motivation and comorbidity, cannot separate the drug effect from the selection. We report those cohorts and we do not treat them as answering the question.
On “Sarcopenia is a diagnosis, not a synonym for losing lean mass” — Laboratory Notebook, 5 Nov 2024
As a DXA technologist of twenty-two years I would add one thing to your precision section: the largest source of error in practice is not the machine, it is positioning. A patient scanned with their arms two centimetres further from their trunk will report different regional values. We are trained to a protocol and the protocol is not always followed.
— I. Mukherjee, Kolkata
We should have said this and did not. It also argues for what you presumably practise: same device, same technologist, same protocol, and a note in the record when any of those changes.
On “What STEP 4 and SURMOUNT-4 actually established” — Explainers, 3 Nov 2024
You keep insisting on peptide content rather than purity when discussing dose certainty. I have looked at a dozen certificates from four different testing services and content is reported on perhaps a third of them. What are readers supposed to do with an absence?
— S. Ó Ceallaigh, Limerick
Treat the nominal figure as an upper bound and say so out loud when reasoning about a dose. It is an unsatisfying answer and it is the honest one. We have argued in Analytics that content should be a standard reported field, and we will keep naming the services that report it and those that do not.
On “What STEP 4 and SURMOUNT-4 actually established” — Explainers, 3 Nov 2024
Your piece treats the four-week step as arithmetic, and I accept the arithmetic, but my prescriber moved me up every two weeks and I reached the top dose without difficulty. I do not think the schedule is as constraining as you suggest.
— R. Cadogan, Bridgetown
Nor do we, and the file should have been clearer. The four-week interval is a floor below which the previous rung is still accumulating, not a threshold below which escalation is unsafe. Plenty of people tolerate faster ascent. Our objection is to the inverse inference — that because you did, everybody should — and to the absence of a trial that would let anyone say which is which in advance.
On “What STEP 4 and SURMOUNT-4 actually established” — Explainers, 3 Nov 2024
Thank you for saying plainly that the maximum dose is not the goal. I stopped at 10 mg fourteen months ago because it was working and I was tired of arguing about it. Every article I read before yours implied I had given up early.
— K. Mwangi, Nakuru
On “What STEP 4 and SURMOUNT-4 actually established” — Explainers, 3 Nov 2024
I want to object to the framing of dose reduction as measurement. In practice it is experienced as failure, and telling people it is a thermostat does not change how the appointment feels. The language problem is real and you have solved it rhetorically rather than actually.
— D. Ó Súilleabháin, Killarney
A fair hit. We can describe the pharmacology accurately and still be writing at a distance from how the decision lands, and the paragraph you object to does both. The reframing is offered as a corrective to a stigma, not as a claim that the stigma is imaginary.
On “What we would need to randomise to answer this properly” — Clinical Trials, 3 Nov 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.
— H. Baptiste, Fort-de-France
Correct, and that is precisely the point we were trying to make and then undermined in our own table. Amended.
On “What we would need to randomise to answer this properly” — Clinical Trials, 3 Nov 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. Hollenbeck, Spokane, WA
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 “What we would need to randomise to answer this properly” — Clinical Trials, 3 Nov 2024
Three vendors have now sent me marketing material claiming their product preserves lean mass during GLP-1 treatment, two of them citing your publication as a source for the underlying composition figures. You may want to know that.
— T. Elorriaga, San Sebastián
We did not, and we are grateful. Quoting our reporting of a substudy alongside an unevidenced product claim is a misuse of it, and the standards desk has written to all three.
On “What we would need to randomise to answer this properly” — Clinical Trials, 3 Nov 2024
I have read your protein tables twice and I still cannot work out what I should eat. I appreciate that this is the honest position but it is not a useful one for a person in a supermarket.
— N. Halvorsen, Trondheim
It is a fair complaint about a real limitation. What we can say is that the defensible range is narrower than the disagreement suggests, that the denominator matters more than the ratio, and that a clinician or dietitian can convert a range into a number for your body in a way that a magazine cannot.
On “Maximum tolerated is not maximum approved” — Pharmacology, 2 Nov 2024
You keep insisting on peptide content rather than purity when discussing dose certainty. I have looked at a dozen certificates from four different testing services and content is reported on perhaps a third of them. What are readers supposed to do with an absence?
— M. Guðmundsdóttir, Reykjavík
Treat the nominal figure as an upper bound and say so out loud when reasoning about a dose. It is an unsatisfying answer and it is the honest one. We have argued in Analytics that content should be a standard reported field, and we will keep naming the services that report it and those that do not.
On “Maximum tolerated is not maximum approved” — Pharmacology, 2 Nov 2024
Your piece treats the four-week step as arithmetic, and I accept the arithmetic, but my prescriber moved me up every two weeks and I reached the top dose without difficulty. I do not think the schedule is as constraining as you suggest.
— T. Blakemore, Hull
Nor do we, and the file should have been clearer. The four-week interval is a floor below which the previous rung is still accumulating, not a threshold below which escalation is unsafe. Plenty of people tolerate faster ascent. Our objection is to the inverse inference — that because you did, everybody should — and to the absence of a trial that would let anyone say which is which in advance.
On “Maximum tolerated is not maximum approved” — Pharmacology, 2 Nov 2024
A small thing. You give the semaglutide diabetes ladder as ending at 2.0 mg and the weight ladder at 2.4 mg, without explaining why the same molecule has two ceilings for two indications. It looks arbitrary and I suspect it is not.
— A. Lindholm, Gothenburg
It is not arbitrary — the two maxima come from separate dose-selection programmes with different primary endpoints, and 2.0 mg was established against 1.0 mg in a dedicated glycaemic comparison. We have added a clause. The underlying point, that indication shapes the ladder as much as the molecule does, is worth more space than we gave it.
On “Maximum tolerated is not maximum approved” — Pharmacology, 2 Nov 2024
I had a nine-week gap last year because my supplier stopped answering messages. Nobody in any clinical setting I dealt with treated that as a pharmacological event. Your framing of supply interruption as a dosing decision is the first time I have seen it written down.
— M. Suárez, Montevideo
On “Two sessions a week, and the evidence behind the prescription” — Laboratory Notebook, 1 Nov 2024
My mother is eighty-one and on a low dose for her diabetes. Her weight is down nine kilograms and she now struggles to get out of a low chair, which she did not eighteen months ago. Nobody has measured anything. I do not know whether this is the drug, the weight loss, or being eighty-one, and neither does anybody I have asked.
— P. Havlíček, Brno
That is the situation the missing endpoint produces, and we are sorry to have no better answer. A chair-stand time takes thirty seconds to measure and would at least establish a baseline against which the next six months could be judged. It is worth asking for by name.
On “Discontinuation rates, read honestly” — Pharmacology, 29 Oct 2024
A small point of precision. You use "gastroparesis" in the tag list and then spend a paragraph saying it is not a synonym for drug-induced emptying delay. That is a slightly awkward position to hold.
— A. Mbeki, Lusaka
It is, and it is a compromise with how readers search. The tag exists because that is the word people use; the glossary exists because it is the wrong one. We would rather be findable and then precise than precise and unread.
On “The retest date and the expiry date are not the same document” — Laboratory Notebook, 28 Oct 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?
— B. Sundqvist, Turku
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 “The retest date and the expiry date are not the same document” — Laboratory Notebook, 28 Oct 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.
— H. Fitzmaurice, Preston
On “Non-responders, and the honest state of the evidence about them” — Explainers, 28 Oct 2024
Your piece states that moving the injection day does not change total exposure, and I accept the arithmetic, but I want to record that it changed my experience considerably. I moved from Monday morning to Thursday evening and the two worst days now fall on a weekend. The drug is doing the same thing; my week is not.
— E. Thistlethwaite, Sheffield
This is exactly the distinction we were trying to draw and evidently drew badly. Total exposure is unchanged; the phase relationship between peak concentration and your working week is not. We have added a sentence to that effect.
On “Non-responders, and the honest state of the evidence about them” — Explainers, 28 Oct 2024
Your table lists orforglipron with a half-life of 29 to 49 hours. That is a wide range to report as a single figure. What accounts for it?
— V. Petrosyan, Yerevan
Dose and study population, mostly. We should have given the two bounding studies rather than a range with no attribution, and the table has been amended.
On “Non-responders, and the honest state of the evidence about them” — Explainers, 28 Oct 2024
I have been on treatment for fourteen months and stopped losing weight at month eleven. Your piece says this is energy balance rather than receptor desensitisation. I would find that easier to accept if anybody had explained it to me at the start rather than after I had spent two months assuming the drug had stopped working.
— A. Salcedo, Bilbao
That is a fair criticism of the field rather than of this article, and we take the point about timing. The plateau is predictable and predicted; it is very rarely mentioned before it happens.