Grapple them unto thy soul with hoops of steel.

What is a friend? I think I could parallel St. Augustine’s answer about Time: ‘What then is time? If no one asks me, I know what it is. If I wish to explain it to him who asks, I do not know.’ Friendship is such a universal concept, such an acknowledged need, I’m not sure why it is difficult to define. Perhaps it is so much a part of our Umwelt that the only aspect of it that becomes consciously discernible is its absence. It is our air…

But of late, it seems to me that its meaning has been further eroded, further diluted, by its use in social media. It is now a verb as well as a noun –all well and good if we are willing to enrol people as friends much as we might solicit them to join a political party, or consider anybody that smiles at us as worthy of the designation.

Obviously, friendship is a spectrum and simply because we use the same word to designate the entire range does not reveal much about the meaning or the importance of its constituents to us. In a sense, if used generically and without a more descriptive adjective, the word is an empty shell –‘Full of sound and fury, signifying nothing’ as Macbeth said of Life. And that life is actually not so full of friends -‘Which the poor heart would fain deny and dare not.’ to quote Macbeth out of context once again. We do not have as many friends as we think –nor is it even possible to sustain the emotional effort necessary to acquire and succour more than five, or so, close friends. http://nyti.ms/2baJQPL

So, I suspect we should be careful how we use the term and in what context –for what purpose. The number of ‘friends’ we think we have are akin to the denominator of a fraction. It’s the numerator –the number of close friends- that determine the size. The value… I would have thought this was so obvious as to be almost trite. Uninteresting. But maybe the idea that a friend is someone requiring at the very least, an ongoing personal, non-virtual, interaction is a generational thing. Am I just having a semantic argument with myself; am I merely a Cassandra unable to understand that it is only my opinion that is being contested, and that its tenets have already been superseded? Food for thought…

And yet, there are consequences. Sometimes it is best to check in the rear-view mirror from time to time.

*

I’ve always liked Jennifer. She is a twenty-something year old woman I have known for several years now. I first met her because of a minor abnormality of her pap smear, and have seen her every year or so since then. I think she sits in the same place in the waiting room each time, too; I always associate her with the seat in the corner by the window –the one partially hidden by the Areca palm. She’s a small person, and her never-varying outfit of jeans and sweatshirt seem to blend beautifully with the green of the plant. Even her dark, shoulder-length hair sometimes resembles the type of shadow I imagine the plant would cast if it could… I don’t know why I think that; maybe because they’re both quiet. Both still. Both background.

The other day when I saw her in her usual spot, she was typing away furiously on her cell phone. She looked on edge, and the troubled expression did not disappear even when she saw me smile and walk across the carpet to greet her.

There’s often an easy-to-spot anxiety in some patients –the kind I usually can’t hide when the dentist ushers me into his chair- but I knew Jennifer, and the referral note just said she was back for a repeat pap smear.

“You look worried today, Jennifer,” I said when we were both seated in my office. “Are you concerned about the pap smear?”

She’d put the phone in her pocket and was staring absently at a terra cotta woman sitting on an oak stand with her begging bowl. I’d had it there for years, so Jennifer had certainly seen it before. She shook her head, but left her eyes gently stroking its contours. “She always makes me relax… I’m glad she’s still here.” I could see her trying to disguise a sigh. “It’s nice that some things stay the same…” She was quiet for a moment as she thought about it. “…Stay the way they’re supposed to be,” she added to herself as she moved her eyes slowly over to my desk like sleeping birds and left them lying there. They didn’t see me, I don’t think.

I waited for her to continue, but she merely repositioned her attention onto her lap. “What do you mean?” I asked, when it became clear that she needed to talk about it.

Up flew the eyes to the box of tissues on the desk and she grabbed a handful to wipe away some tears. “It’s nothing about my pap smears,” she said in a hoarse voice. “I don’t need to take up your time…”

“The pap smear talk can wait for a bit, Jennifer. Tell me what’s upsetting you.” I smiled reassuringly, but her eyes never reached my face.

She took a deep and stertorous breath and then decided to send them on a reconnaissance flight in my direction. “Oh, it’s just my ‘friends’,” she said, making sure I understood that there were quote marks around the word. “I invited all 147 of them to like a business website that I’m starting…”

I have to admit that I was a bit confused. “Like? As in Facebook ‘like’ you mean?” I had no idea what message that sent. A friend had once asked me to ‘like’ her barbershop on Facebook and I had duly complied –it seemed simple enough… and if it made her feel good, what the heck, eh?

She nodded, although I could tell by her face that perhaps I shouldn’t have needed to clarify such an obvious point.

“And…?”

She took a deep breath and shrugged. “And, well I guess I don’t really have 147 friends.”

I didn’t ask her how she knew -I figured that was probably obvious, too. But I must have looked surprised, because she giggled at the notion. “I mean I didn’t really think they’d all like the page, but…”

I had to chuckle –I couldn’t help myself. “I don’t even know that many people, Jennifer. I mean not counting patients…” I quickly corrected, as her face interrogated me in disbelief.

“How many friends do you have on Facebook, doctor?”

I shrugged. “I don’t know… I mean, counting my kids and a few close friends… twenty, maybe…?”

She thought about that for a few seconds. “I don’t know how I got so many.” She glanced at the statue again. “Sort of like collecting tee shirts, I guess. They look so nice in the store, but I hardly ever wear them.”

A thought suddenly occurred to me. “Do you know how many ‘liked’ your… uhmm, page?” I tried to sound knowledgeable about the words, but to tell the truth, I was on slippery ground and I think it showed.

She caught her eyes, before they completed a roll and managed to salvage a serviceable smile out of what I’m sure was headed for a smirk. Then her eyes twinkled without her planning on it, and she giggled with delight at my expression. “Only seven, so far…”

It was my turn to nod, and I sat back in my chair as I did so. “Well maybe you come out the winner, then…”

She tilted her head, as cute as a button, and I could see the adult stirring behind the mirror of her eyes.

“Now you know what ‘friend’ really means…” I said, smiling.

Her eyes hovered around my face for a moment before they returned to their owner, and I think she blushed.

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Biding the Pelting of this Pitiless Storm

Hubris –the extreme arrogance that was so offensive to the old Greek gods that they reacted with punishment and an exile from grace- is that what this is? I’m not sure anymore… It’s not, perhaps, so obvious as the vaulting ambitions of a Macbeth or the arrogance of a Caesar, nor even the overweening pride of an Oedipus in the Sophoclean plays, and yet… And yet, viewed from a distance, it’s hard not to notice the similarities that inhere in the attitude that End justifies Means, that intentions trump consequences, that methodology is the servant of results –however narrowly beneficent we define them. And it’s important that we not be so blinded by those touted benefits that we ignore other, perhaps less harmful routes, to achieve them.

And what, you may reasonably ask, prompted this jeremiad? It was a study reported in the New England Journal of Medicine (NEJM) on the addition of a second and possibly more powerful prophylactic antibiotic during non-elective Caesarian Sections to reduce post-operative infection rates: http://www.nejm.org/doi/full/10.1056/NEJMe1610010?query=gynecology-obstetrics -certainly a worthy aim, to be sure. Who could possibly take issue with that? Well, in this era of increasing antibiotic resistance, and the unfortunate dearth of replacement antibiotics in the wings, I think not only the study, but also the idea demands more than a cursory analysis. This is not to criticize the intent, so much as to explore alternative roads to the same destination.

Few would argue that antibiotics, when they are deemed necessary, should be used according to the infecting bacterial sensitivities if they are available –or considered expectations as to sensitivities if they are not. It’s why we can no longer use penicillin for everything –not all infections would respond. Surgical prophylaxis (where there is not yet an infection) is one of the few exceptions, and even there, the antibiotics are chosen in anticipation of the type of bacteria that might reasonably be expected in the surgical field (although there are some who believe that their effect is merely that of decreasing the total bacterial load in the area whether or not the expected ones have been targeted). But, nevertheless, we toy with resistance at our peril.

I’ve chosen to link the editorial rather than the study itself because of the insights it offers. The full-length study to which it refers can be accessed via a link in that editorial, however.

As I mentioned, the study by Tita and colleagues, in a randomized trial, attempted to reduce post-operative infections by adding another broad-spectrum antibiotic (Azithromycin) to the usual antibiotic (cefazolin) in non-elective Caesarian sections (i.e. there was some condition in mother or baby that required urgent delivery) where the current infection rate was 12% -and it worked! Compared to the usual group that just received the cefazolin alone, they dropped the infection rate to 6.1% -not zero, but at least an improvement. And, ‘Neonatal outcomes, which were tracked up to 3 months, were similar in the two trial groups.’

But on closer analysis, 73% of the population in the study was obese -and that, plus the fact that the Caesarians were unplanned, certainly added to their risk of infections. So far, so good.

But, as the editorialist wonders, could the fact that these women were obese have meant that the usual dose of cefazolin was inadequate: ‘[…] should the potential pharmacologic benefit of higher doses of cefazolin alone be evaluated further before the addition of a second agent?’

Another consideration leading to the study of adding azithromycin to the regimen, was that it may be useful for eliminating a potentially  infective organism in the vagina –ureaplasma– that cefazolin doesn’t touch. Unfortunately, there are no prospectively adequate data for the contention that the organism was even present in the studied women.

And finally, the azithromycin was more beneficial in those women whose incisions were closed with staples, and there seems to be evidence that staples, themselves, may increase the post-operative infection rate.

So why, you may ask, have I chosen to comment on this rather obscure study –especially since it seems to have demonstrated the benefits it expected? First of all, I think we have to be careful that we don’t lose sight of the forest as we wend our way through the undergrowth. There do seem to be other options that could be explored before the addition of yet another antibiotic –and indeed should be anyway, given the non-zero infection rate even with the addition of azithromycin. Such things as more ‘stringent adherence to infection-control protocols’, avoiding the use of staples in this high-risk population, or even re-calculating the dose of the standard prophylaxis (cefazolin) to account for differing patient weights before deciding to add the new antibiotic.

I don’t mean to be the new Cassandra, issuing thundering prophesies of doom that will not be heeded anyway, or aspersing well-intentioned attempts to improve our lot… And yet we must not forget that consequences follow actions, not precede them. To be fair, we do try our best to anticipate and thereby avoid, or at least minimize them, but history is riddled with examples of unintended outcomes. The road to disaster is paved with should’ves –only seen with clarity, after arrival.

It seems to me that, wherever possible, we should be exploring options that reduce the likelihood of incurring bacterial resistance. And the answer may not lie in the reliance on new antibiotics -new guns for our on-going war with the microscopic world. It’s a battle in which we cannot hope for more than a temporary truce while we search for peace. Without that, as the map makers of old were said to write on unexplored regions, Here be dragons.

 

Uterine Transplants

I just knew it was going to happen; I could feel it in the air: a live and healthy baby delivered from a transplanted uterus.

It was the womb’s turn. After all, people have been trying to transplant stuff since anatomy began. Unfortunately, before the concepts of physiology, infection and immune rejection were appreciated, they all failed. Miserably.

There were exceptions, of course, such as the successful kidney transplant between identical twins in 1954 -where their immune systems were obviously identical as well- but until the ability to avoid the toxicity of anti-rejection drugs was improved, organ exchanges were limited to the desperate or the foolhardy.

A few solitary successes occurred late in the 19th century with skin grafting, but until good immune suppressors like cyclosporin (1970) were developed, most organs –that is to say, most patients– didn’t survive for more than two or three weeks.

And then it took off. Kidney transplants are now routine; heart transplants -while more dramatic because of the need for a healthy organ from an individual who is unfortunately unable to use it any more- no longer garner headlines like Dr. Christian Barnard’s first success in 1967.

And the list of organs being transplanted is beginning to read like an anatomy textbook. Everything from pancreas to lung, combo packs like heart/lung, and even an entire face in 2013. If you can name it, somebody somewhere is trying to transplant it. So it was surprising that the poor uterus was left sitting in the shadows for so long.

In fairness, though, it had been attempted several times before in various medical centers, with little success –ie  ability to do what the uterus was designed to do: incubate and deliver a  live, healthy baby. Not until the 2013 transplant in Gothenburg Sweden, with Dr. Brannstrom’s surgical team was a live baby born from a uterus a year after it was installed. Everything seemed to work –the recipient began to menstruate regularly- so one year after the transplant, having cryopreserved an embryo beforehand, it was placed into the uterus and followed closely as it developed.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61728-1/abstract

The baby was born prematurely (at 31 weeks and 5 days, rather than at the average 40 weeks) because, although blood supply to the uterus was apparently normal, the patient developed pre-eclampsia (pregnancy-related high blood pressure) and there were some problems with the baby’s heart rate that apparently mandated delivery.

Were these complications the result of the transplanted organ (the donor was an unrelated 61 year old post-menopausal woman), the immosuppressants (she was on a triple therapy consisting of tacrolimus, azathioprine, and corticosteroids), or just bad luck? And would such a transplant be able to function normally –like a transplanted heart, say- and contract efficiently enough to enable labour and vaginal delivery? Or would a caesarian section be required in all cases? It’s probably too early to say.

So congratulations to the parents and the transplant team. Fortunately, the need for uterine transplantation is uncommon, and adoption, or even surrogacy remain as other less drastic options. But it seems to me there are issues that, despite the success, have yet to be adequately addressed.

Ethical issues, for one thing. Unlike, say heart or kidney transplants where death may ensue if transplantation is not available in a timely fashion, the uterus is not essential for the continuation of life. And the procedure entails sophisticated, difficult and risky surgery that is frought with possible life-theatening complications in and of itself –including, of course, rejection of the organ despite the immunosuppressants. The surgery, by the way, is far more arduous and byzantine than the routine hysterectomies that are over-performed around the globe –extra tissue has to be obtained along with additional dissection to be able to reconnect the arteries and veins efficiently. So both donor and recipient are at increased risks…

But what troubles me the most I suppose, are the possible long term effects of the immunosuppressants on the developing foetus growing inside the transplanted organ. Azathioprine, for example. It interferes with DNA synthesis, and inhibits the proliferation of quickly growing cells… That seems a lot like what needs to happen in a rapidly growing foetus, doesn’t it? Azathioprine is a pregnancy Category D substance: to be used in life-threatening emergencies only when no safer drug is available. And there is positive evidence of human foetal risk. Even tacrolimus doesn’t have a lot of available human studies in pregnancy.

No doubt safer and more predictable immunosuppressants will be found, but for now I remain concerned that we may be trading something away. Just because we can do something, doesn’t mean we should. Unlike other organ transplants where the risk is assumed by the recipient alone, uterine transplants for reproduction share the risks with a rapidly developing and vulnerable foetus which might not manifest any problems until years in the future.

I realize I may be dismissed as a male Cassandra, a person who cannot see dawn through the warp and weft of the cobwebs of his past, but sometimes we have to stand back for a moment. Sit down and think things through. Decide whether we’ve gained more than we’ve lost, and whether it will be too late to change our minds if and when some damage is revealed.

In this case, one would be well to think of Mabeth’s dilemma:

I have no spur to prick the sides of my intent, but only Vaulting ambition, which o’erleaps itself