PD-1 is a cancer pathway that's been known for some time to the cognoscenti. On PodMed this week, Rick and I talk about a study in NEJM, which is incidentally where all the studies we talk about this week are published, that appears to bring manipulation of this pathway to fruition in folks with Hodgkin's lymphoma. Good news indeed, as well as proof of concept. What did they do? First, a little background is appropriate.
PD-1, in that often inscrutable scientific fashion that is happily absent here when it comes to naming, stands for programmed death. In this case it refers to a way our bodies use to damp down an immune response by T cells, one of the army of cells mobilized to protect us but which need to be called off when the deed is done. We can think of PD-1 as running up the surrender flag so T cells chill out. Turns out cancer cells do the same, running up the surrender flag to call off T cells that might otherwise attack and kill them. Oh so clever cancer cells! This property partially explains why our immune systems fail to recognize these invaders and dispatch them, and it's also something researchers have been struggling to exploit for some time. Indeed, antibodies to manipulate this pathway have been developed and used clinically, with this study reporting such an antibody for Hodgkin's.
Hodgkin's, of course, is rather a curiosity when it comes to immune system manipulation. The problematic cells in the disease known as 'Reed-Sternberg cells' actually reside within a veritable army of immune cells, yet somehow evade detection and destruction. PD-1 utilization is alive and well in this type of cancer, and the authors reveal that host infection with Epstein-Barr virus also up-regulates this mechanism. Accordingly, 23 patients with Hodgkin's lymphoma who had either relapsed or had refractory disease were enrolled in this study to receive the monoclonal antibody 'nivolumab.' Previous treatment of these folks included some pretty heavy hitting therapy: stem cell transplantation and an antibody 'brentuximab vedotin.'
Here's the good news: "An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease." Wow! That's very impressive. Side effects could be problematic with nivolumab: "Overall, drug-related adverse events were reported in 18 patients (78%). The most common were rash (in 22%) and a decreased platelet count (in 17%). Drug-related grade 3 adverse events, which were reported in 5 patients (22%), included the myelodysplastic syndrome, pancreatitis, pneumonitis, stomatitis, colitis, gastrointestinal inflammation, thrombocytopenia, an increased lipase level, a decreased lymphocyte level, and leukopenia." These drug effects were manageable and the authors conclude that inhibition of the PD-1 pathway may be a very important therapeutic target in patients with this disease, and we agree. Rick also opines that examination of additional tumor types will likely result in more applications for this strategy.
Other topics this week include the use of progesterone in traumatic brain injury, a new type of blood thinner, and US healthcare and equality, as mentioned before, all in NEJM. Until next week, y'all live well.
How would you characterize your typical diet? Fast food heavy, dining out, carb loading? Now a new study Rick and I discuss on PodMed this week provides further support that we might all benefit from adoption of the so-called 'Mediterranean diet,' as published in the BMJ. That's the conclusion at least if you're persuaded by the life-preserving capabilities of telomeres, those protective ends of chromosomes that shorten as we age. Huh? How's telomere length related to diet? Let's take a look at the study.
Researchers looked at data from the Nurses Health Study, specifically from almost 4700 of the 121,700 original enrollees, all female registered nurses who began the study in 1976. This analysis relies on a group selected because they were free of major chronic diseases, including cardiovascular disease and cancer, having been identified as healthy controls in other analyses of this data set, had completed food questionnaires, and had had their white blood cells analyzed for telomere length.
So what about this diet? While the traditional Mediterranean diet is described as having a" high intake of vegetables, fruits, nuts, legumes, and grains (mainly unrefined); a high intake of olive oil but a low intake of saturated lipids; a moderately high intake of fish; a low intake of dairy products, meat, and poultry; and a regular but moderate intake of alcohol (specifically wine with meals)" the questionnaire utilized in this study gave point values to each component of the diet in what is called the 'Alternate Mediterranean diet score.' The score allowed quantitation of each additional dietary choice. Additional dietary analyses were also employed.
What about those telomeres? As Nobel Prize recipient Carol Greider, our colleague here at Johns Hopkins describes, telomeres are like those little plastic tips on the ends of shoelaces. As time goes on these get shorter and shorter, with short telomeres associated with cancer, some autoimmune diseases, and aging. Nurses enrolled in this study had their telomere length assessed just once. This was correlated with their diet score, and lo and behold! Those women who reported greater adherence to a Mediterranean diet also had longer telomeres, and the relationship was dose-response; the more adherent a woman was the longer her telomeres were.
Potential confounders were also considered in this study, with women who had higher adherence to the Mediterranean diet also smoking less, exercising more, weighing less, and also being slightly older at the time their blood was drawn. Still, the authors conclude that the study provides more evidence for the potential benefit of adopting a more Mediterranean-style diet. Since we like that kind of food, Rick and I are happy to do so, but we're still waiting for the smoking gun with regard to the exact relationship between telomeres, aging and disease.
Other topics this week include unsafe infant sleeping practices in Pediatrics, circumcision recommendations from the CDC, and taking asthma drugs daily or only as needed in the Lancet. Until next week, y'all live well.
When was the last time you consumed a school lunch? As Rick and I quip on PodMed this week, we have a collective and not-so-fond memory of 'mystery meat' and the like. Things have changed quite a bit these days, a study on the nutritional value of home-packed versus school-provided lunches as published in JAMA Pediatrics demonstrates, and while we're at it, seems like breakfast at school is another good idea, per a second study in the same issue.
The lunch study examined the nutritional content of lunches from home of 242 elementary and 95 intermediate school students from 12 schools located in the Houston, TX, area. The content of these lunches was compared with the guidelines found in the National School Lunch Program, begun in 2012, based on a 2009 (!) Institute of Medicine report. I'll leave this huge legislative delay alone for the moment, and note that these were the first updates to nutritional recommendations for children for more than 30 years.
Here's what the study determined, "Compared with the NSLP guidelines, lunches brought from home contained more sodium (1110 vs ≤640 mg for elementary and 1003 vs ≤710 mg for intermediate students) and fewer servings of fruits (0.33 cup for elementary and 0.29 cup for intermediate students vs 0.50 cup per the NSLP guidelines), vegetables (0.07 cup for elementary and 0.11 cup for intermediate students vs 0.75 cup per the NSLP guidelines), whole grains (0.22-oz equivalent for elementary and 0.31-oz equivalent for intermediate students vs 0.50-oz minimum per the NLSP guidelines), and fluid milk (0.08 cup for elementary and 0.02 cup for intermediate students vs 1 cup per the NSLP guidelines). About 90% of lunches from home contained desserts, snack chips, and sweetened beverages, which are not permitted in reimbursable school meals. The cost of lunches from home averaged $1.93 for elementary and $1.76 for intermediate students. Students from lower-income intermediate schools brought significantly higher-priced ($1.94) lunches than did students from middle-income schools ($1.63)." While the authors conclude that efforts should be undertaken to educate parents to pack more nutritional lunches, we take a slightly different tack and opine that perhaps all children should be encouraged to eat school-provided lunches.
Ditto for the breakfast study. Turns out that while school breakfast programs have been in place for some time in many low income areas, barriers to children actually eating breakfast at school include the need to arrive early as well as stigma associated with the program. This study looked at 446 public elementary schools and assessed the impact of serving breakfast in the classroom. While the authors were aiming at whether such a strategy improved academic performance this outcome was not significant, which Rick considers not surprising as the study wasn't long enough. Things that did show immediate improvement were the number of children who benefited, reductions in tardiness and improvements in overall attendance. I suggest in the podcast a sliding scale for all parents, so that all children can have breakfast in the classroom. There is abundant evidence for the benefits of breakfast on school performance, and such a strategy would reduce stigma. While we're at it, why not include lunch, too?
Other topics this week include two new agents to reduce potassium levels in people with chronic kidney disease in NEJM, a new agent for treating chronic cough in the Lancet, and two medications for managing Marfan syndrome in NEJM. Until next week, y'all live well.
Man or machine? This debate increasingly occurs in many venues as computers and other devices created for our convenience, comfort and ease continue to be invented and disseminated. But there's one area where the machine remains inferior to the efforts of man, as Rick and I discuss on PodMed this week: CPR or cardiopulmonary resuscitation. That's as featured in the Lancet this week and also presented at the American Heart Association meeting taking place concurrently.
This trial is unique in that it is pragmatic. Rather than being conducted under ideal clinical or laboratory conditions, instead this trial randomized actual patients who had experienced out-of-hospital myocardial infarction (MI) or heart attack being transported from the field via ambulance. The subjects were randomized in a 1:2 ration, respectively, to either mechanical CPR using a device known as a LUCAS-2, or manual CPR. A total of 4471 subjects who experienced cardiac arrest not as a result of trauma were included, with randomization taking place depending on which response vehicle arrived on the scene first, one equipped with the mechanical device or not. Sixty percent of those in the mechanical group actually received CPR using the device while 11 (less than 1%) of the manual group did so.
The primary outcome was survival at 30 days post-MI, with secondary outcomes event survival, survival to 3 months, survival to 12 months, and survival with favorable neurological outcome at 3 months. Clearly the favorable neurological data is very important as this is compromised in many survivors.
There was no significant difference in 30 day survival among those who received mechanical CPR versus those who received manual: 6% versus 7% respectively. Longer term survival was also similar between groups, but those who received mechanical CPR had worse neurological outcomes than those who had manual CPR. A low rate of adverse events was also seen in those treated with the LUCAS-2: three patients with chest bruising, two with chest lacerations, and two with blood in mouth. 15 device incidents while the LUCAS-2 was employed.
The authors conclude, and we agree, that the results of this trial argue against use of mechanical devices to perform CPR. They're expensive, personnel using them require training, and they don't achieve the desired objective of improving survival odds for those having an out-of-hospital cardiac arrest. Since almost half a million such events occur each year in the US alone, getting our arms around the best way to conduct CPR is clearly important. Rick and I agree that we're glad this study was done. In a real world environment, under conditions where the expectation would be that the machine would perform better while jostling around in the back of an ambulance, it didn't. Yet one more example of assumptions disproved, so kudos to the authors.
Rick makes the point that out-of-hospital CPR is very simple, consisting of chest compressions only, and that more efforts need to undertaken to simply convince the public that they're the best chance someone who's experienced an MI has to make it alive to the hospital. Other topics this week on our heart-only issue include a better understanding of HDL cholesterol in NEJM, appropriate duration of dual antiplatelet therapy after stenting in the same journal, and police work and sudden cardiac death in the BMJ. Until next week, y'all live well.
When confronted with the reality of death, the majority of people asked about their preferences say they'd like to die at home, surrounded by friends and family, and with minimal pain and discomfort. Yet the sad fact remains that many people are unable to achieve that goal, Rick and I discuss on PodMed this week, in spite of abundantly available hospice services.What are the barriers to more widespread utilization of hospice and can a cost analysis help provide evidence that such services are not only humane but cost-effective? That's the substance of a study published this week in JAMA.
Researchers crunched numbers from a 20% sample of Medicare fee-for-service beneficiaries who died in 2011, all with a cancer diagnosis. Patients with brain, pancreatic, metastatic malignancies or other poor-prognosis cancers enrolled in hospice before death were matched to similar patients who died without hospice care, resulting in almost 87,000 enrollee records for the analysis, about 60% of whom were enrolled in hospice care at the end of life. The final cohort consisted of 18,165 patients with poor prognosis cancers who were enrolled in hospice and the same number who were not, matched on age, sex, region, time from poor-prognosis diagnosis to death, and baseline care utilization.
Here's what the analysis showed: "After matching, 11% of nonhospice and 1% of hospice beneficiaries who had cancer-directed therapy after exposure were excluded. Median hospice duration was 11 days. After exposure, nonhospice beneficiaries had significantly more hospitalizations (65% [95% CI, 64%-66%], vs hospice with 42% [95% CI, 42%-43%]; risk ratio, 1.5 [95% CI, 1.5-1.6]), intensive care (36% [95% CI, 35%-37%], vs hospice with 15% [95% CI, 14%-15%]; risk ratio, 2.4 [95% CI, 2.3-2.5]), and invasive procedures (51% [95% CI, 50%-52%], vs hospice with 27% [95% CI, 26%-27%]; risk ratio, 1.9 [95% CI, 1.9-2.0]), largely for acute conditions not directly related to cancer; and 74% (95% CI, 74%-75%) of nonhospice beneficiaries died in hospitals and nursing facilities compared with 14% (95% CI, 14%-15%) of hospice beneficiaries. Costs for hospice and nonhospice beneficiaries were not significantly different at baseline, but diverged after hospice start. Total costs over the last year of life were $71 517 (95% CI, $70 543-72 490) for nonhospice and $62 819 (95% CI, $62 082-63 557) for hospice, a statistically significant difference of $8697 (95% CI, $7560-$9835)." Wow. That's a lot of resources saved at the end of life, and as I query Rick in the podcast, wonder what would have happened if hospice had been utilized sooner than the median of 11 days found in this study?
It's revealing to look at what the authors consider to be major barriers to more hospice utilization. They cite the penalty exacted by the Medicare administration against hospices with extended hospice stays, current lack of reimbursement for end-of-life discussions to physicians by the same agency, and finally, the requirement that patients forego any treatment with a curative intent in order to enroll as all having a chilling effect on enthusiasm for earlier adoption of hospice services. Yet at least one myth, that of potential increased costs relative to hospice care, is clearly dispelled by this study. Our hope is that the evidence provided here will help inform discussion around overcoming barriers and toward adoption of a more compassionate model of medical care at the end of life.
Other topics this week include Ebola treatment of two patients here in the US in NEJM, Tdap vaccination during pregnancy in JAMA, and four popular weight loss diets compared in Circulation. Until next week, y'all live well.
Nephrolithiasis. That's such a descriptive word; literally nephro for kidney and lithiasis for stone formation. Would that more terminology was so very definitive! However, as Rick and I discuss on PodMed this week, the term doesn't begin to describe the amazing pain most people report as a result of kidney stones, formed in the kidney and then passed down into the ureters on their way to the urinary bladder. Good news then in a literature review from the American College of Physicians, published in Annals of Internal Medicine, suggesting a range of dietary choices, supplements and medications to avoid forming kidney stones once you've done so in the past.
Here's what the paper states as the magnitude of the problem, "The lifetime prevalence of nephrolithiasis is 13% for men and 7% for women, with a 5-year recurrence rate after an initial event of 35% to 50% without treatment. Stones are caused by an interaction between genetics and environmental exposure." That's a whole lot of painful events it would be great to avoid. How can we do that?
One strategy that seems to offer benefit is increasing fluid intake to the degree that at least 2 liters of urine are produced daily. Beverages to be avoided in achieving this goal are sodas acidified with phosphoric acid, usually of the cola variety. Rick advises that such information is readily available on the labeling of the product, and that some sodas use citric acid instead, which doesn't confer risk.
Evidence on diet was a bit scattered as several different types of diets were studied. Most seemed to suggest that some dietary evaluation and advice regarding diet composition was of benefit in reducing stone recurrence, and that analysis of the stone composition was necessary in providing dietary advice.
What about medications? Thiazide diuretics, citrate therapy, and allopurinol may all provide benefit depending on the stone composition, and combination therapies may be attempted but evidence isn't abundant for additional benefit in stone formation reduction.The paper suggests that drug monotherapy be attempted after increased fluid intake fails to reduce stone formation or in people in whom increased fluid is contraindicated. And while the stone composition seems to give an indication of strategies to employ to reduce stone formation, the paper does not recommend that course as the evidence is insufficient, and also stops short of recommending blood chemistry or urine chemistry as informative.
How about the increasing number of people who are found to have existing stones incidentally? While not addressed specifically in this paper, Rick muses that the strategies identified here may help keep stones from growing bigger or may even reverse them, so they're well worth trying when stones are found. As I reveal on the podcast, both Rick and I have had this experience in the past, so no cola drinks for us!
Other topics this week include a vaccine for Dengue in NEJM, the import of nonobstructive coronary artery disease on heart attack and death in JAMA, and bleeding with dabigatran in JAMA Internal Medicine. Until next week, y'all live well.
Metformin. That's the word on the street for the best oral diabetes drug for those who are just beginning therapy for the disease, now affirmed by a study in JAMA Internal Medicine. And as Rick and I marvel on PodMed this week, how is it that a comparative effectiveness study of common diabetes medications hasn't been undertaken before? And another marvel: why do so many physicians continue to prescribe medicines other than metformin for initial diabetes therapy, in view of the fact that the American Diabetes Association and a host of other professional and advocacy organizations have been advocating metformin for years? Let's hope this study will convince more of them to adopt evidence-based prescription.
This study looked at 15, 516 patients who were part of the Aetna health insurance network and who began oral glucose lowering therapy from July 1, 2009, through June 30, 2013. Four categories of medication were identified: metformin, a sulfonylurea, a thiazolidinedione, or a dipeptidyl peptidase 4 inhibitor (DPP-4). Review of the charts showed that just under 58% of patients were started on metformin, followed by 23% on the sulfonylureas, just over 13% on the dipetptidyl peptidase 4 inhibitors, and 6.1% on the thiazolidinediones. Out-of-pocket spending for the filling of the initial prescription was significantly higher for DPP-4 inhibitors and thiazolidinediones, the paper states.
What was the likelihood that an additional agent for the management of blood glucose would be required per agent initiated? "In unadjusted analyses, use of medications other than metformin was significantly associated with an increased risk of adding a second oral agent only, insulin only, and a second agent or insulin (P < .001 for all). In propensity score and multivariable-adjusted Cox proportional hazards models, initiation of therapy with sulfonylureas (hazard ratio [HR], 1.68; 95% CI, 1.57-1.79), thiazolidinediones (HR, 1.61; 95% CI, 1.43-1.80), and dipeptidyl peptidase 4 inhibitors (HR, 1.62; 95% CI, 1.47-1.79) was associated with an increased hazard of intensification." Well. Happily, there were no increased risks associated with agents other than metformin, including low blood sugar, ED visits, or in this short term follow-up, cardiovascular events.
Why did so many physicians choose agents other than metformin for initial therapy? In those who have kidney disease metformin is contraindicated, but as Rick quips in the podcast, it's extremely unlikely that 42% of patients in this study had such an issue. He attributes the prescribing behavior to the influence of pharmaceutical companies, both in advertising to physicians and patients, who may come in asking for a certain medication as a result of direct-to-consumer advertising. He also muses that physicians may choose other agents in deference to more up-to-date therapies. To this I must counter that we have abundant clinical experience with metformin and it's very inexpensive. Rick cites other benefits: less weight gain and other side effects. In sum then, we agree with the investigators and guidelines already in place that metformin should be the first line agent of choice in oral management of serum glucose in folks with diabetes, and that's really the evidence based conclusion.
Other topics this week include both an editorial and study from Sierra Leone on Ebola in NEJM, a look at an LDL variant and aortic valve calcification in JAMA, and blood pressure lowering after stroke in the Lancet. Until next week, y'all live well.
Do you consume cow's milk or provide it to your children if you're a parent? Turns out many people are making a switch from cow's milk to other 'milk' alternatives such as almond milk, soy milk, or coconut milk, or to milk from another animal source such as goats. When queried on the switch parents in particular cite allergy concerns and antibiotic exposure as motivational factors, but, as Rick and I discuss on PodMed this week, such a strategy may have a much greater negative impact on children’s' health than any upside. That's based on a study of vitamin D levels and milk consumption in the Canadian Medical Association Journal (greetings Tom, our Canadian colleague ).
Researchers gleaned data from an ongoing Canadian study known by the acronym TARGet Kids!, described as a partnership between child health researchers in the departments of medicine, pediatrics, and family and community medicine at the University of Toronto. The current study recruited children from 1 to 6 years of age and who did not have chronic illness or a medical condition impacting growth. Almost 3000 children were enrolled and serum 25-hydroxyvitamin D measurements were obtained from each child, as well as extensive information from parents on type of milk consumed and how much. Additional data, including age, sex, body mass index, daily vitamin D supplementation, consumption of margarine, skin pigmentation, and outdoor play time were also obtained.
Turns out that "each 250-mL cup of non–cow’s milk consumed was associated with a 3.1% decrease in 25-hydroxyvitamin D level. " Furthermore, the authors report, "We identified a dose-dependent association between consumption of non–cow’s milk beverages in early childhood and decreased serum levels of 25-hydroxyvitamin D. This association was modified by cow’s milk consumption, which suggests a trade-off between the consumption of cow’s milk fortified with higher levels of vitamin D and non–cow’s milk beverages with lower vitamin D content." Children of darker skin pigmentation who did not consume cow's milk were at higher risk for lower vitamin D levels in the absence of supplementation.
Okay, I query Rick in the podcast, what about outdoor playtime? He opines that exposure to sunlight is inadequate to overcome a loss of dietary vitamin D such as is seen when cow's milk is eliminated from the diets of children. Indeed, the authors of this paper point out that in the US and Canada, cow's milk is required to contain about 40 IU of vitamin D per 100ml, and is the major source of vitamin D for kids. Seems prudent therefore, for parents to supplement their kids with vitamin D if they choose an alternative to cow's milk. Does this also mean they should ask their child's pediatrician to measure their serum vitamin D? Rick's opinion is that if they supplement to the level supplied in cow's milk that may not be necessary. In any case mentioning this dietary choice to your child's pediatrician seems like the right thing to do.
Other topics this week include the persistence of banned substances in dietary supplements in JAMA, knowledge of the presence of central venous catheters in Annals of Internal Medicine, and the cost impact of MD versus hospital ownership of medical practices in JAMA also. Until next week, y'all live well.
Who knew that transplanting poop, otherwise known as fecal material, stool, gut microbiota and other less scientifically rigorous terms, could successfully treat at least one modern scourge, Clostridium difficile infection? Now Rick and I talk about frozen, encapsulated fecal microbiota transplant administered orally on this week's PodMed, and as reported in JAMA. In spite of the substantial yuck factor, turns out the strategy works in the vast majority of patients. Good news indeed for those with this increasingly common cause of fulminant diarrhea that may result in death.
Researchers with previous experience in fecal transplant to treat C. dif infection, as it is fondly abbreviated in medical circles, mused that while direct transplant either right into the large bowel or administered via a nasogastric tube worked well in the majority of patients, several limitations were apparent. These included the need to transplant fresh material from a donor related to the patient, who has previously been screened for the organism, and placement of a infusion device to accomplish the transplant. They hit upon the idea that screened, frozen material could be used instead, and had used this in a previous study for infusion via a nasogastric tube. It was a short leap to aliquoting transplant material into capsules and administering them orally.
The current study enrolled twenty patients ranging in age from 11 to 89 years, to receive the capsules. All of the subjects had had at least three previous episodes of mild to moderate C. dif infection and had failed treatment with the usual antibiotic therapy, or had been hospitalized at least twice with severe C. dif infection. The fact that one of the subjects was only 11 years old points to the disturbing recent increase in infections among the pediatric population. Each subject was given 15 capsules of fecal transplant material on two consecutive days by an investigator. Those who failed to respond were offered an additional course of treatment.
Here are the very impressive results as reported in the paper: No serious adverse events...were observed. Among 20 patients treated, 14 had clinical resolution of diarrhea after the first administration of FMT [fecal microbiota transplant] remained symptom free at 8 weeks. All 6 nonresponders were re-treated at a mean of 7 days after the first procedure. Of these 6, 5 patients had resolution of diarrhea after the second treatment. However, 1 patient relapsed within the predetermined 8-week follow-up after initial diarrhea resolution, resulting in an overall rate of diarrhea resolution of 90%. The only variable significantly associated with response to first treatment was overall health score prior to FMT. Patients who needed a second treatment to achieve resolution of diarrhea had lower pretreatment health scores (were more symptomatic) than patients who had diarrhea resolution after a single administration.. Wow. That's pretty good. So what about those capsules?
Fecal donors were healthy, non pregnant adults 18 to 50 years of age, taking no medications and having a normal body mass index. Clearly no previous history of C. dif infection was necessary and all donors were screened for infectious disease according to blood bank procedures. Previous to stool donation all donors were requested to avoid allergenic foods but otherwise to eat normally. Their stool was frozen and stored for 4 weeks to allow rescreening of donors before their microbiota were transplanted. All in all, sounds like a fairly innocuous procedure to me, and one that may also be readily expanded. Rick and I agree that such a strategy sounds promising indeed to stem the tide of C.dif infection.
Other topics this week include a really cool use of stem cells to treat macular degeneration and dystrophy in the Lancet, an update on Ebola projections in NEJM, and exercise and depression in teenagers in JAMA Pediatrics. Until next week, y'all live well.