When I was working in Africa I read a paper that proved that intravenous corticosteroids were of no benefit in cerebral malaria. Soon afterwards I had a patient with that foul disease whom I had treated according to the scientific evidence, but who failed to respond, at least as far as his mental condition was concerned – which, after all, was quite important. To save the body without the mind is of doubtful value.
I gave the patient an injection of corticosteroid and he responded as if by miracle. What was I supposed to conclude? That, according to the evidence, it was mere coincidence? This I could not do: and I have retained a healthy (or is it unhealthy?) skepticism of large, controlled trials ever since. For in the large numbers of patients who take part in such trials there may be patients who react idiosyncratically, that is to say, differently from the rest.
A paper in a recent edition of the New England Journal of Medicine brought back my experience with cerebral malaria. Animal experimentation had shown that progesterone, one of the class of steroids produced naturally by females, protected against the harmful effects of severe brain injury. The paper does not specify what exactly it was necessary to do to experimental animals to reach this conclusion, but it does say that it has been proven in several species. What is not said is often as eloquent as what is said.
If brevity is the soul of wit, verbosity is often the veil of ignorance. There was an instance of this in a recent article in the New England Journal of Medicine, with the title “Conduct Disorder and Callous-Unemotional Traits in Youth.” At considerable length and with much polysyllabic vocabulary, it told us much that we already knew (some of it true by definition). It mistook the illusion of progress for progress itself.
The paper starts with a definition:
The term “conduct disorder” refers to a pattern of repetitive rule-breaking behavior, aggression and disregard for others.
It sounds to me like a recipe for success in the modern art world, where “transgressive” is a term of the highest praise. But, says the paper, such problems have received increased attention recently, for two reasons: first, young people with conduct disorder sometimes “perpetrate violent events,” and second, the Diagnostic and Statistical Manual of Mental Disorders has modified its criteria for diagnosis. This latter seems to me an odd reason for increased attention. (Whose attention, by the way, the authors do not specify. The attention is like the pain in the room as described by Mrs Gradgrind. She thought there was a pain somewhere in the room, but couldn’t positively say that she had got it.)
The truth, the whole truth, and nothing but the truth: that is what one swears to tell in a court of law. One lies there and then. It is a noble ideal that one swears to, but one that in practice is impossible to live up to. Not only is the truth rarely pure and never simple, as Oscar Wilde said, but it is never whole, even in the most rigorous of scientific papers.
Not that scientific papers are often as rigorous as they could or should be. This is especially so in trials of drugs or procedures, the kind of investigation that is said to be the gold standard of modern medical evidence.
Considering how every doctor learns that the most fundamental principle of medical ethics is primum non nocere, first do no harm, it is strange how little interest doctors often take in the harms that their treatment does. Psychologically, this is not difficult to understand: every doctors wants to think he is doing good, and therefore has a powerful motive for disregarding or underestimating the harm that he does. But in addition, trials of drugs or procedures often fail to mention the harms caused by the drug or procedure that they uncover.
This is the royal road to over-treatment: it encourages doctors to be overoptimistic on their patients’ behalf. It also skews or makes impossible so-called informed consent: for if the harms are unknown even to the doctor, how can he inform the patient of them? The doctor becomes more a propagandist than informant, and the patient cannot give his informed consent because such consent involves weighing up a known against an unknown.
A paper in a recent edition of the British Medical Journal examined a large series of papers to see whether they had fully reported adverse events caused by the drug or procedure under trial. It found that, even where a specific harm was anticipated and looked for, the reporting was inadequate in the great majority of cases.
In my youth the government encouraged people to eat more eggs and butter and drink more milk for the sake of their health. Perhaps it was the right advice after a prolonged period of war-induced shortage, but no one would offer, or take, the same advice today. Nutritional advice is like the weather and public opinion, which is to say highly changeable.
How quickly things go from being the elixir of life to deadly poison! A recent paper from Sweden in the British Medical Journal suggests that, at least for people aged between 49 and 75, milk now falls into the latter category, especially for women.
Milk was once thought to protect against osteoporosis, the demineralization of bone that often results in fractures. It stood (partially) to reason that it should, for milk contains many of the nutrients necessary for bone growth.
On the other hand, it also stood (partially) to reason that it should do more harm than good, for consumption of milk increases the level of galactose in the blood and galactose has been found to promote ageing in many animals, up to and including mice. If you want an old mouse quickly, inject a young one with galactose.
In other words, there is reason to believe both that the consumption of milk does good and that it does harm. Which is it? This is the question that the Swedish researchers set out to answer.
Low back pain is a condition so common that, intermittently, I suffer from it myself. It comes and goes for no apparent reason, lasting a few days at a time. Nearly 40 years ago I realized that, though I had liked to think of myself as nearly immune from nervous tension, anxiety could cause it.
I was in a far distant country and I had a problem with my return air ticket. At the same time I suffered agonizing low back pain, which I did not connect with the problem of my ticket. When the problem was sorted out, however, my back pain disappeared within two hours.
In general, low back pain is poorly correlated with X-ray and MRI findings. Epidemiological research shows that the self-employed are much less prone to it than employees, and also that those higher in the hierarchy suffer it less than those lower – and not because they do less physical labor. Now comes evidence, in a recent paper from Australia published in the Lancet, that the recommended first treatment usually given for such pain, acetaminophen, also known as paracetamol, is useless, or at least no better than placebo (which is not quite the same thing, of course).
Hope springs eternal, but so do financial crises in hospitals. Once, while researching the history of the hospital in which I was working at the time, I discovered that it had been so short of money in the 1840s that it had been forced to sell some land to a railway company that wanted to build a line near the hospital. The physicians were against the sale, for they feared the noise of the trains might kill the patients, “especially the brain cases.” They were overruled, and when the first train went by they observed the patients anxiously to monitor the adverse effect on them. There was none.
However, psychiatric hospitals seem often to be built near railway lines, which act as a magnet to the patients who are suicidal. Patients of such hospitals who commit suicide while on the premises usually do so by hanging, while those who do so outside usually jump from a tall building or throw themselves in front of trains.
A paper from Germany in a recent edition of the British Journal of Psychiatry analyzes the characteristics of 100 suicides of psychiatric patients who threw themselves in front of trains conveniently near to the hospitals in which they were resident at the time. It took the authors ten years to collect their sample, whom they compared with other patients of the same age, sex and psychiatric diagnosis who did not throw themselves in front of trains. The object of the exercise was to see whether such suicides could be predicted and therefore prevented. The authors rather laconically remark that when a man throws himself in front of a train — and nearly two-thirds of the cases were men — it is likely that he really means to die.
There is no new thing under the sun, least of all panic at the approach of an epidemic of a deadly disease. In 1720, the preface to Loimologia, Nathaniel Hodges’ account of the Great Plague of London in 1665, first published in Latin in 1672, referred to the outbreak of plague in Marseilles:
The Alarm we have of late been justly under from a most terrible Destroyer in a neighbouring Kingdom, very naturally calls for all possible Precautions against its Invasion and Progress here…
In fact, though no one was to know it, no epidemic of plague was ever to occur in Western Europe again; and it is doubtful whether the precautions referred to made much difference.
The death rate from the Ebola virus is probably greater than that from bubonic plague, though of course the plague spread much faster and killed far more people in total than Ebola ever has: and at least we, unlike our plague-ridden ancestors, know the causative organism of the Ebola disease, even if we are not certain how the virus first came to infect Mankind.
You might have supposed that trust in the medical profession would have risen as medicine became more effective at warding off death and disease, but you would have been mistaken. In fact, precisely the reverse has happened throughout the western world, but particularly in the United States. Half a century ago, nearly three quarters of Americans had confidence in the medical profession qua profession; now only about a third do so.
According to international surveys reported in an article in a recent New England Journal of Medicine, Americans are among the most mistrustful of doctors of any western people. Asked whether, all things considered, doctors in their country could be trusted, 58 percent of Americans answered in the affirmative; by contrast, 83 percent of the Swiss answered positively. Positive answers were returned by 79, 78, and 76 percent of the Danish, Dutch and British respectively. Americans were 24th of 29 nations polled in their trust of doctors. Furthermore, just fewer than half of Americans in the lowest third of the income range thought that doctors in general could be trusted, and younger Americans were also less likely to trust their doctors than older ones.
Curiously enough, though, Americans were among the most satisfied of nations with their last encounter with their doctor. Only the Swiss and Danes were more satisfied than they, and then not by very much (64, 61 and 56 percent respectively). In other countries, then, people were more likely to trust doctors in general than be satisfied by their last visit to the doctor; in America, it was about the same proportion.
What, if anything, does this mean?
How informed is informed consent and does it matter much, or as much as medical ethicists say it does? Do doctors have a duty only to make sure that their message is sent, or also a duty to make sure that it is received, and if received that it is retained? The prayer of General Absolution in the Book of Common Prayer refers to those things which we have done and ought not to have done, and those things which we ought to have done and have not done. When it comes to informed consent, there are also those things which patients have heard and ought not to have heard, and those things which they ought to have heard and have not.
This is proven in a recent paper in the British Medical Journal. Patients with stable angina in ten hospitals in the United States were asked what they thought the benefits were of the percutaneous coronary procedures they were about to undergo. The scientific evidence on this matter is more or less universally accepted: such procedures improve angina symptoms but do not increase life expectancy or reduce the rate of heart attacks.
One of the more extraordinary experiences of my medical career was injecting rural African women with a long-term contraceptive in a Catholic mission hospital under a portrait of Pope Paul VI. The contraceptive was handed to me by an aged Swiss nun who was otherwise deeply orthodox, but who recognized that worn-out women who had already had ten children were in danger of their lives if they had any more. I refrained from remarking on the paradox: I had already learned that there is more to life than intellectual consistency.
In the west, of course, the problem of unwanted pregnancy is different: it arises mainly among teenagers of what used to be called the lower classes. Pregnancy rates among the latter in the United States are among the highest in the western world. According to a paper in a recent edition of the New England Journal of Medicine, such pregnancies cost the United States $10 billion a year: to me a suspiciously round figure, especially as it includes the cost of education foregone by the pregnant girls. Perhaps I am a cynic, but I am not altogether so sanguine about the economic value of modern education. Be that as it may, the Centers for Disease Control and Prevention (CDC) has set a goal of reducing teenage pregnancy by 20 percent between 2009 and 2015.
An experiment conducted in St Louis provided 1404 girls aged between 14 and 19 with free contraceptive advice and free long-acting contraceptive devices to see whether such provision would reduce the rate of unwanted pregnancy among them. The comparison group was that of similar girls in the rest of the United States who were not included in the experiment.
We live in the age of acronym. To read a medical journal is sometimes like trying to decipher a code; once, when I was a judge in a competition of medical poetry, I read a poem composed entirely of figures and acronyms:
RTA [road traffic accident]
ETA [expected time of arrival] 13.20 hrs
CGS [Glasgow Coma Scale] 3…
The last line of the poem, inevitably, was:
Sometimes one has the impression that the acronym has been devised before the thing that it is attached to has been decided. In a recent paper in the New England Journal of Medicine, for example, I came across the acronym SWEDEHEART. It stood for the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated According to Recommended Therapies. If the web system come before the acronym, however, you could see why the latter was necessary, the former being longer than the average tin-pot dictator’s list of honorific titles.
The paper in which the acronym occurred was yet another in which a common medical practice was shown to be valueless, or very nearly so. It turns out yet again that doctors do things not because they do the patients any good, but because they can do them.
When Hamlet tells Claudius that Polonius, whom he has just killed, is at dinner being eaten rather than eating, Claudius is puzzled. Hamlet explains that the worms are eating Polonius, and Claudius, still puzzled, asks Hamlet what he means by this
Nothing [replied Hamlet] but to show how a king may go a progress through the guts of a beggar.
In other words, we all come to the same end.
I thought of this passage when I read a paper about the death of Richard III in a recent edition of the Lancet. His remains were found recently buried under a car park in Leicester, a dismal provincial town in England, one of many ruined by planned modernization. The car park had once been a priory.
A long historical battle has raged over Richard’s real nature, whether he was hero or villain as per Shakespeare (few people think he might have been something in between the two). Certainly his remains, now more than 500 years old, have not been treated with undue respect: a team of forensic pathologists and archaeologists have examined them minutely for clues as to how he died at the battle of Bosworth Field in 1485.
The question is important because public health emergencies allow governments to ignore the usual restrictions or restraints upon their actions. In public health emergencies, governments can override property rights and abrogate all kinds of civil liberties such as freedom of movement. They can .r our goods and tells us where to go and where to stay. They do so only for our own good: health being the highest good, of course.
A recent edition of the New England Journal of Medicine discusses the issue in the context of the declaration of a public health emergency in Massachusetts by the governor of that state, Deval Patrick.
In most people’s minds, no doubt, a public health emergency would be something like the Black Death, the epidemic of plague that wiped out a third of Europe’s population in the fourteenth century. A natural disaster of large proportions might also count, not only because of the death and injury caused directly by the disaster, but by the epidemics which often follow such disasters.
What, then, was the public health emergency that “obliged” Patrick to declare that it existed and that he could and should take uncontrolled administrative measures to halt it?
When I visited the John F. Kennedy hospital in Monrovia during the long Liberian Civil War, it had been destroyed by a kind of conscientious vandalism. Every last piece of hospital furniture and equipment had been disabled, the wheels sawn off trolleys and gurneys, the electronics smashed. This was not just the result of bombardment during the war but of willful and thorough dismantlement.
There were no patients and no staff in the hospital; it was a ghost establishment, completely deserted. I was severely criticized for suggesting in a book that the painstaking destruction of the hospital, which shortly before had performed open heart surgery, was of symbolic significance.
I was pleased to see from an article in a recent edition of the New England Journal of Medicine that it had re-opened, but saddened to see that its problems were now of an even more terrifying nature than those it encountered during the civil war: for the hospital is at the center of the epidemic of Ebola virus disease, and two of its senior physicians, Sam Brisbane and Abraham Borbor, have recently died of it. The article in the journal lamented their passing and praised them for their bravery in not deserting their posts; they both knew of the dangers of refusing to do so.
Every few months I receive a computerized invitation from my doctor asking me to have a colonoscopy to screen for polyps in my bowel. I always tell myself that I am too busy just now, I will have it another time. But really I don’t want to have it at all, and I know that when the next invitation comes I will be too busy then as well.
I am also eager to find a rational reason, or at least a rationalization, for my refusal. I thought I found it in a paper from Norway in a recent edition of the New England Journal of Medicine.
The authors examined the death rate from colorectal cancer in Norway among the 40,826 patients between 1993 and 2007 who had had polyps removed at colonoscopy in that country (the records are more or less complete). They compared the number of deaths in that population with the expected death rate from the disease in the population the same age as a whole. The paper reports that 398 deaths were expected and 383 deaths were observed.
This small difference does not mean that colonoscopy does not work in preventing death from colorectal cancer, of course. This is because the relevant comparison is with people who had polyps not removed by colonoscopy rather than with the population as a whole.
The 40,826 patients who had polyps removed at colonoscopy, however, were not a random sample of the adult population because Norway does not have a screening program for colonic polyps. The patients had colonoscopy in the first place because they were symptomatic, for example bleeding per rectum. They were therefore much more likely to suffer from polyps or cancer in the first place than the rest of the population.
I happened to notice recently a report in a French newspaper of a study just published in the British Medical Journal, a study that had purportedly shown an increased incidence of cardiac death in people who took an antibiotic called clarithromycin. As I had myself taken this drug a couple of times in my life (though not, of course, quite as prescribed, because no one ever takes drugs quite as prescribed), I felt a certain personal interest in the question.
I needn’t have worried because the paper, from Denmark, claimed that the increased risk of cardiac death occurred only while the patient was taking the drug, not afterwards. But the closer I looked at the paper, the more darkness it seemed to shed on what doctors ought to do.
Denmark is a small country with a population of about 5.5 million, but it has the best health records in the world. This means that statisticians are able to churn out comparisons as Danish dairy farmers churn out butter.
The opening words of a novel are acknowledged to be among the most important of the book, my own favorite being Chesterton’s “The human race, to which so many of my readers belong.…” But rivaling these words for impact are those of the Methods section of the abstracts of two papers in a recent edition of the New England Journal of Medicine. The first was “We studied 102,216 adults from 18 countries,” surely the the equal of, say, “There was no possibility of going for a walk that day” (Jane Eyre). The second, by the same authors, was “We obtained morning fasting urine samples from 101,945 persons in 17 countries,” again easily the equal of “It was the best of times, it was the worst of times” (A Tale of Two Cities).
However, this was science, not literature. The object of the papers was to cast light on the association, long noted, between sodium intake in the diet and high blood pressure, and to help decide whether a reduction in the sodium intake of entire populations would be a worthwhile public health measure. High blood pressure is one of the principle causes of stroke and heart attack, which are themselves one of the principle causes of death in the world.
The dream of rejuvenating the aged by the infusion of young blood is much older than anyone living. It is said that the Scythians thought to make themselves strong by drinking the blood of their enemies killed in battle. And Dracula kept himself youthful by drinking the blood first of young maidens visiting Transylvania and later of maidens in England once he had moved there.
Blood is not the only tissue that has been thought to protect and rejuvenate the elderly. In the 1920s a Franco-Russian surgeon named Serge Voronoff transplanted monkey testes into men (some of them eminent, for example Kemal Ataturk) whose virility had declined, and claimed that it worked. He made a fortune but soon became the object of mockery and scorn, dying in prosperous obscurity in Switzerland in 1951.
There is always an air of charlatanry about those who claim to be able to turn the biological clock back (it is easy to find smooth-talking promoters of recaptured youth on the internet, for example), but a recent article in the New England Journal of Medicine suggests that some of the old ideas about the rejuvenating qualities of young blood may not have been quite so far-fetched after all. It is early days to proclaim that eternal youth is around the corner, and personally I am not sure I would want it even if it were, but according to the author a technique known as heterochronic parabiosis has retarded or reversed the aging process in mice. It is, of course, some distance from Mouse to Man.
What stands to reason is not always borne out by facts, for reality is often refractory to human wishes. There was a good illustration of this unfortunate principle in a recent edition of the New England Journal of Medicine.
It has long been known that low concentrations of high-density lipoproteins (HDL) and high concentrations of low-density lipoproteins (LDL) are associated, in a more or less linear fashion, with cardiovascular disease such as strokes and heart attacks. It would seem to stand to reason, therefore, that raising the HDL and lowering the LDL would lead to fewer cardiovascular “events,” as strokes and heart attacks are called.
One way to achieve this wished-for biochemical change is to treat patients at risk of such events with niacin, a B vitamin, in addition to the statins that they are already taking. The largest placebo-controlled trial of niacin ever undertaken, with 25,673 patients who had already had a stroke or heart attack, has shown that the addition of niacin, though it does indeed increase HDL and decrease LDL, has no effect on the rate of heart attack or stroke. Worse still, it gave rise to serious side effects, such as worsening of diabetes and unpleasant gastrointestinal, musculoskeletal and dermatological effects. One of the most unexpected findings of the trial was the excess of infections in people treated by niacin. If anything, the overall death rate in the niacin-treated group was higher than that in the placebo control group, though the difference was not statistically significant (which is not quite the same thing as saying that it was not real). The patients were followed up, on average, for nearly four years and at no time was treatment with niacin superior to that with placebo.
All medical journals these days feel the compulsion to be high-minded, but none is as high-minded as the Lancet. It is as if the editors had taken lessons both in moral philosophy and rhetoric from Mr. Pecksniff himself.
Mr. Pecksniff, you may remember, was the preposterous hypocrite in Dickens’ Martin Chuzzlewit, who introduces his daughters, Charity and Mercy, by adding “Not unholy names, I hope?” As Know thyself was inscribed over the entrance to the temple to Apollo at Delphi, and Abandon hope, all ye who enter here over the entrance to Dante’s hell, so Mr Pecksniff’s words, Let us be moral, must be inscribed over the entrance to the offices of the Lancet, figuratively if not literally
In the week before a Malaysian Airlines plane, taking many AIDS doctors and activists from Amsterdam to Melbourne for an international conference on AIDS, was shot down over eastern Ukraine, the Lancet published a statement called the Declaration of Melbourne, a typically sickly and nauseatingly unctuous statement of ethical principles. It began by saying something that, if not a lie exactly, was certainly not a truth:
We gather in Melbourne, the traditional meeting place of the Wurundjeri, Boonerwrung, Taungurong, Djajawurrung and the Wathaurung people, the original and enduring custodians of the lands that make up the Kulin Nation, to assess progress on the global HIV response and its future direction, at the 20th International AIDS Conference, AIDS 2014.
This, of course, is the purest 21st century Pecksniffery; and unless the signers of the declaration (who look extremely self-congratulatory in photos accompanying the article) can each and severally explain in what sense the Djajawarrung are the custodians of the lands on which the city of Melbourne is built, I suggest that they be banished to the outback for five years to live as pre-contact Australian Aborigines lived.
One of my first medical publications was on the nocebo effect, the unpleasant symptoms patients may suffer as a result of being made aware of potential side effects of a treatment they are about to receive or a procedure they are to undergo. Thus patients who were having a lumbar puncture were either told or not told they might suffer a headache afterwards; and lo and behold, those who were told that they might get headaches duly got headaches while those who were not told didn’t.
On the whole, as an article in a recent edition of the Journal of the American Medical Association points out, doctors are well aware of the placebo effect, that is to say the good that their treatment may do patients by means of mere suggestion, but have little awareness of the opposite nocebo effect, the harm that their treatment may do their patients by mere suggestion.
The nocebo effect poses an ethical dilemma for doctors, say authors of the article. On the one hand, doctors are supposed to do their patients no harm; on the other, they are supposed to be open and honest with their patients about the potential harms of drugs and other treatments. The dilemma is this: foreknowledge of those harms can harm some patients. Should the need for honesty trump the ethical injunction to do no harm?
Is there ever any good news without bad? Good and bad seem to be inextricably locked in a Hegelian dialectic, or perhaps Manichaean struggle would be a more accurate way of putting it. For example, tuberculosis became the captain of the men of death, the white plague, between the seventeenth and the nineteenth centuries. Then it began its long decline, accelerated by the discovery of the first effective anti-tuberculous drugs. Then, just as large numbers of people became more susceptible to tuberculosis because of the spread of the human immunodeficiency virus, the germ of tuberculosis developed resistance to the most effective drugs against it. It seemed that the disease might once more become what it had been not so very long before. But then, for the first time in 40 years, a new anti-tuberculous drug, bedaquiline, was developed by the pharmaceutical company Janssen. Good news has not retained the upper hand for very long, however. An article in a recent edition of the Lancet suggests that bedaquiline is not the answer to Mankind’s prayers, at least where tuberculosis is concerned.
The distinction between what the law permits and what the law enjoins is often blurred. An absence of proscription is sometimes mistaken for prescription. The more the law interferes in our lives, the more it becomes the arbiter of our morality. When someone behaves badly, therefore, he is nowadays likely to defend himself by saying that there is no law against what he has done, as if that were a sufficient justification.
The recent Supreme Court decision in the cases of Burwell v. Hobby Lobby Stores and Conestoga Wood Specialties Corp. v. Burwell illustrates the difficulties when two or more rights clash irreconcilably. The complex issues involved were the subject of an article in a recent edition of the New England Journal of Medicine. The matter is still far from settled. It seems to me likely that the Supreme Court will one day reverse itself when its philosophical (or ideological) composition has changed.
The two corporations were owned by strongly religious people. Corporations of their size were enjoined by the government to provide their staff with health insurance which would cover contraceptive services. However, some contraceptive methods violated the religious beliefs of the owners of the companies. Did the companies have the right to except these methods from the policies that they offered to their staff (who, incidentally, numbered thousands, many of whom would not be of the same religious belief)?
In principle medical research is supposed to result in unequivocal guidance to doctors as to how to treat their patients. As often as not, however, the waters are muddied as much as cleared. Two papers in a recent edition of the New England Journal of Medicine about atrial fibrillation and the cause of stroke illustrate this. It has long been known that people with a clinically-detected chaotic heart rhythm called atrial fibrillation (AF) have an increased incidence of stroke by embolism; and likewise that no cause of such stroke can be found in up to 40 percent of patients who suffer from one. Their strokes are called cryptogenic. The two papers addressed the question whether, if you monitor patients with cryptogenic stroke for long enough, some or many of them will turn out to suffer from AF. This is important, because it is generally agreed that, in patients with clinically detected and symptomatic AF, anti-coagulation reduces the subsequent risk of stroke. AF, however, is not an all or none phenomenon. Some people suffer it continuously, but others only occasionally and for only a few seconds at a time. The additional risk of stroke in the latter is unknown, but is an important question because the anticoagulation designed to reduce the risk of stroke is not itself without risk, including that of another kind of stroke, the haemorrhagic kind. In other words, the risk caused by treatment could outweigh its benefits.