Study shows vitamin D3 could help heal or prevent cardiovascular damage

Medical Xpress: Study shows vitamin D3 could help heal or prevent cardiovascular damage

Cornerstone Therapy in Atopic Dermatitis

Moisturizers recommended, but product choice largely comes down to patient choice

For patients with atopic dermatitis, moisturizers may be the most important treatment. However, with impaired skin barrier functions, thinner stratum corneum cell layers, and larger follicular pores, atopic dermatitis patients are vulnerable to adverse skin reactions.

Selecting a moisturizer without sensitizing agents is a good start, but beyond that, the choice most often comes down to individual preference, wrote the authors of the 2014 American Academy of Dermatology treatment guidelines for atopic dermatitis topical therapies.

Moisturizers were described as the “cornerstone of therapy” in atopic dermatitis in the guidelines, but the products differ greatly by ingredients, which can improve the condition or make it worse. There is also considerable debate over which delivery systems work best — i.e., creams, ointments, oils, gels, or lotions.

Clinical trials comparing moisturizers in head-to-head trials are few and far between, and of the trials that have been conducted, the findings are inconsistent. In one study cited in the 2014 guidelines, of 39 people with mild to moderate atopic dermatitis, there was no difference in efficacy among patients who used hydrolipid cream with glycyrrhetinic acid; creams containing ceramides, cholesterol, and free fatty acids; or an over-the-counter petroleum-based skin protectant. Another study showed similar results for an over-the-counter oil-based moisturizing cream and a palmitoylethanolamide-containing prescription emollient device.

In the United Kingdom, the guidelines are more specific. For mild-moderate atopic dermatitis, occlusive emollient creams are recommended, depending on barrier thickness, lipid content variability, disease severity, and body site. For moderate to severe atopic dermatitis, occlusive emollient ointment is recommended. For severe atopic dermatitis, occlusive ointment with zero water content is advised.

In the Asian-Pacific region, consensus guidelines recommend regularly moisturizing, while taking into account humidity, climate, skin type, degree of dryness, disease duration and severity, age, treatment compliance, and adjuvant properties.

Moisturizers with Natural Ingredients

In a published review on the role of moisturizers with herbal and other natural ingredients for dermatitis, Schandra Purnamawati, MD, and colleagues at the Universitas Gadjah Mada in Indonesia, recommended moisturizers as a key treatment in atopic dermatitis, along with trigger avoidance and other therapeutic treatments.

Although few, clinical trials of moisturizers with natural oils show that some natural ingredients can lead to significant improvements in dermatosis, Purnamawati et al wrote. Among the most powerful of the ingredients are natural oils with a ratio of more linoleic acid (LA) than oleic acid (OA).

“High linoleic acid concentrations are believed to accelerate skin barrier repair and development, improving skin hydration, and ameliorate AD severity, making them perfect for steroid sparing,” the team wrote. “Safflower oil, sunflower seed oil, and sea buckthorn seed oil are natural oils with the highest LA/OA ratios.”

A recent study of Bangladesh pre-term infants showed that moisturizers with sunflower seed oil provided an “excellent barrier repair,” reducing the risk for developing nosocomial infections by 41%. In contrast, olive oil, which has a low LA/OA ratio, can significantly deteriorate the skin barrier.

Most skin conditions benefit from restoring skin ceramide levels, the authors noted. For atopic dermatitis, they recommended only moisturizers that contain natural or synthetic ceramides.

“According to Chamlin et al, topical mixtures of three key stratum corneum [SC] lipids consisting of ceramide, cholesterol, and free fatty acids in optimal proportions [3:1:1 molar ratio] can accelerate barrier repair following various external, acute, or sustained skin barrier disruption,” Purnamawati and colleagues continued. “Unlike non-physiologic lipid mixtures such as petrolatum, physiologic lipids (ceramides, cholesterol, and free fatty acids) can traverse both intact and disrupted SC.”

Herbal Ingredients

The review details the following about what is known to date about various herbal ingredients:

  • Aloe vera: Newer moisturizers tend to contain anti-inflammatory ingredients, such as aloe vera, but these and other natural anti-inflammatories may not be suitable for patients with allergies; moisturizers with 0.1%, 0.25%, and 0.5% of aloe vera extract applied for 2 weeks can increase skin hydration without transepidermal water loss, a study cited in the review showed
  • Bisabolol: A chamomile extract, bisabolol has been shown to produce significant improvements in pruritus and other symptoms associated with atopic dermatitis, and a randomized, double-blind clinical trial of 278 AD patients showed that when combined with heparin, α-bisabolol, applied twice daily for 8 weeks, “significantly” improved symptoms
  • Shea butter: Derived from butyrospermum parkii kernels, shea butter consists mostly of stearic and oleic acids (85-90%), and also contains, albeit in small amounts, triterpene acetate and cinnamate esters, which can have anti-inflammatory and anti-tumor properties
  • Glycyrrhetinic acid: A licorice root extract, glycyrrhetinic acid contains anti-inflammatory, antiviral, and anti-tumor effects, and contains additional properties that are beneficial in atopic dermatitis — licochalcone A, B, and D; a study involving children with mild to moderate atopic dermatitis showed that a moisturizer containing licochalcone and applied twice daily improved symptoms over atopic dermatitis patients treated with hydrocortisone lotion
  • Niacinamide: The vitamin niacinamide was shown to improve skin barrier functions by increasing epidermal ceramides and other intercellular lipids levels by promoting serine palmitoyltransferase upregulation; applied twice daily, moisturizers with niacinamide were shown to decrease transepidermal water loss, reduce inflammation, and increase stratum corneum thickness
  • Palmitoylethanolamide: The endogenous lipid palmitoylethanolamide derives from the fatty acid N-acylethanolamine, and resembles stratum corneum components and functions as peroxisome proliferators activated receptor α agonist; moisturizers with this ingredient contain both anti-inflammatory and analgesic properties, and a clinical trial of 2,456 patients with severe atopic dermatitis who were taking topical corticosteroids showed that these moisturizers improved pruritus, dryness, and eczema
  • Zinc gluconate: A zinc salt, zinc gluconate, from gluconic acid, has been shown to reduce skin inflammation, with recent evidence showing that its anti-inflammatory effect may target peroxisome proliferator-activated receptors-α, human β-defensin-2, and the calcium-binding protein psoriasin, the review noted
  • Combination ingredients: In addition, a combination of glycyrrhetinic acid (from the herb liquorice), Vitis vinifera (grape seed extract), and telmesteine in combination with shea butter (emollient) and hyaluronic acid (humectant), make up the product MAS063DP (Atopiclair); this was the first product approved by the U.S. Food and Drug Administration for allergic contact dermatitis, with some studies suggesting it can be used as monotherapy for both pediatric and adult mild-to-moderate atopic dermatitis

German Carmakers Exposed Monkeys And Humans to Diesel Fumes in Secret Tests

Everyone is outraged.

Controversy has erupted after reports revealed German carmakers have collaborated on experiments in which monkeys and human participants were intentionally exposed to toxic diesel fumes.

 The secret experiments, which took place in both the US and Germany, were part of a ‘clean diesel’ research initiative funded by Volkswagen, the world’s largest automaker, with BMW and Daimler. Public outcry over the revelations has been swift.

“These tests on monkeys or even humans are in no way ethically justified,” said Steffen Seibert, spokesperson for German Chancellor Angela Merkel. “The indignation felt by many people is completely understandable.” The story broke after a report in The New York Times detailed a previously unknown 2014 experiment commissioned by the European Research Group on Environment and Health in the Transport Sector (EUGT) – a now-disbanded research institution funded by the three carmakers. Among other studies it oversaw, EUGT chose the Lovelace Respiratory Research Institute in Albuquerque, New Mexico, to conduct an experiment that might ostensibly show how harmless diesel fumes were: by forcing a group of monkeys to inhale diesel exhaust for 4 hours. The animals, 10 cynomolgus macaque monkeys, bred exclusively for medical experiments, were held in chambers into which exhaust fumes from a Volkswagen Beetle running on a treadmill was directly pumped.

 To keep the animals calm and occupied during the experiment, lab workers had set up a TV the animals could view from their gas chambers.

“They like to watch cartoons,” one of the Lovelace researchers, Jake McDonald, said in a sworn deposition last year in a lawsuit brought against Volkswagen in the US by Volkswagen diesel owners. What McDonald and the other researchers didn’t know at the time, though, was that the whole experiment was actually a sham. The Beetle they’d been supplied with was part of the ‘dieselgate’ emissions cheating scandal uncovered in 2015 – in which some 11 million VW cars around the world were fitted with illegal ‘defeat devices’ capable of masking levels of toxic nitrogen dioxide pollution pumped out by the car’s exhaust. When the cars detected they were being examined for emissions testing purposes, pollution controls throttled back the nitrogen dioxide output – whereas in regular use on the road, the engines would output diesel fumes at levels that breach emissions standards. What this means is, in the 2014 experiment, the monkeys thankfully weren’t getting a full blast – not that they had it easy.

 In a separate, comparative test, they also had to inhale fumes produced by an older-model 1999 Ford diesel pickup – before being anaesthetised and intubated, then having their lungs washed out so their bronchial tubes could be examined.

In a statement on Saturday, Volkswagen said it “distances itself clearly from all forms of animal abuse”, but that was before German media produced new reports of similar experiments involving human participants. These tests, conducted by Aachen University in Germany in 2013 and 2014, and also commissioned by the EUGT, saw 25 young healthy adults inhale varying concentrations of nitrogen dioxide for several hours each. While it appears the university secured ethics approval to conduct the research – in addition to written consent from all those who took part – it’s just another black mark against the carmakers implicated in the diesel emissions scandal, especially with what we know about how bad nitrogen dioxide is for us. “Vile,” is how German environment minister Barbara Hendricks described the revealed experiments. “That a whole branch of industry has apparently tried to discard scientific facts with such brazen and dubious methods makes the entire thing even more horrific.”

Novel Feeding Tube May Help Stroke Dysphagia

Electrical pharyngeal stimulation boosted readiness for decannulation

A novel feeding tube device that electrically stimulates the throat in stroke patients with dysphagia substantially increased readiness to lose the tracheostomy tube, the sham-controlled PHAST-TRAC trial showed.

In the treated group, 49% were ready for removal of their tube, as determined by fiberoptic endoscopic examination of swallowing, after 10 minutes of treatment a day for 3 days compared with 9% in the sham control group (17 versus 3 patients, P<0.001), Philip Bath, MBBS, MD, of the University of Nottingham in England, reported here at the International Stroke Conference (ISC).

For those not ready for decannulation at that point, four responded with repeated open-label treatment for a total of almost 60%. None of the responders needed to be re-intubated.

“[There] is this observation that people are sitting in your ICU and can’t get out because they need airway control, but they don’t need anything else. If you could sort out the dysphagia, that’s a big win,” Bath told MedPage Today.

Larry Goldstein, MD, of the University of Kentucky in Lexington and chair of an ISC press conference where the results were discussed, cautioned that the data was preliminary and did not include certain key clinical endpoints of interest.

“It would be important to know whether patients began oral nutrition earlier, were able to avoid [percutaneous endoscopic gastrostomy] tube placement, and whether the rate of pneumonia is decreased,” he told MedPage Today.

While the 70-patient randomized trial did not include a formal cost analysis, “there’s a hint there it might be financially worthwhile” based on a “profound difference in length of stay” — half of the responders were released by day 17 or 18 days compared with median more like 40 days in nonresponders.

When the results were combined with the “comparable” ones from the pilot study, the odds ratio for readiness for tube removal was 10.49. “You don’t see an odds ratio like that every day,” Bath said.

The device involves a regular feeding tube with ring electrodes on the outside to stimulate the back of the throat, with the idea that it will stimulate nerves leading to any remaining undamaged area of the brain that controls swallowing and get it to reorganize to become dominant. The device has European approval but the FDA will require a U.S. trial, which is under way (PhEED, set to start enrolling in March in an non-ICU population in rehabilitation wards), Bath said.

If the trial is positive, Goldstein speculated that it could also prove useful for the larger group of stroke patients with dysphagia who are not intubated.

The treatment starts at no current then amps up until the patient expresses it is uncomfortable, then backs down by a quarter and remains at that level for 10 minutes.

“You would expect [response] to be current dependent,” Bath said in an interview. However, “the people who responded required reasonably high currents but actually lower currents than the people who didn’t respond. One of the predictors of nonresponse was people who had been in the intensive care unit for many weeks or even months … It’s quite possible that the lack of response is because of atrophy [of the swallowing system]. So we believe that if you’re going to do this, you’re going to want to do it quickly — once the person is off the ventilator but still dysphagic.”

Bath cautioned it was a small trial with sequential design, that the person programming the device was unblinded, and that long-term results could not be examined because all nonresponders were allowed pharyngeal stimulation with the device after the initial study- or sham-treatment.

Pulmonary Embolism Causes <1% of Syncope, Study Confirms

Rarity of lung clots contradicts PESIT data

Researchers confirmed in a retrospective study that pulmonary embolism is unlikely to cause syncope that results in a trip to the emergency room.

Fewer than 1% of nearly 1.7 million patients treated at emergency departments for syncope had pulmonary embolism, according to databases from Canada, Denmark, Italy, and the U.S., reported Giorgio Constantino, MD, of Italy’s Ospedale Maggiore Policlinico in Milan, and colleagues.

Pulmonary embolism was responsible for syncope in just 0.06% to 0.55% of those cases, they wrote in JAMA Internal Medicine; among those admitted, PE was the cause in 0.15% to 2.10%.

“Pulmonary embolism was rarely identified in patients with syncope. Although pulmonary embolism should be considered in every patient, not all patients should undergo evaluation for pulmonary embolism,” the authors concluded. “The unnecessary exposure to radiation and the risk of contrast allergy is significant. Furthermore, the false-positive rate of tests, such as the D-dimer assay and computed tomographic pulmonary angiograms, is high, leading to more tests and overdiagnosis and including risks of unnecessary anticoagulation.”

“Pulmonary embolism has always been considered an uncommon cause of syncope,” according to Constantino’s group. The new data confirm this belief and fly in the face of the PESIT study, which estimated the prevalence of pulmonary embolism to be as high as 3.7% in patients going to the emergency department with syncope.

Still, no studies so far have been perfect.

“Because PESIT used a structured algorithm to assess for the presence of pulmonary embolism, one could hypothesize that previous studies, as well as clinical practice, might have underestimated pulmonary embolism prevalence. Even in the present study, some pulmonary embolism diagnoses could have been missed because they were not suspected, and therefore no information relevant to pulmonary embolism was reported in the administrative data,” the investigators acknowledged.

To identify as many cases of pulmonary embolism as possible, they determined the prevalence of lung clots at 90-day follow-up (assuming they were also there at emergency department arrival) and determined it lay in the 0.14%-0.83% range of all those who fainted and went to the emergency room (or 0.35%-2.63% of the hospitalized subset).

“Even in this case, pulmonary embolism was identified in less than 1% of patients, suggesting that, even if some pulmonary embolism had been missed at first evaluation, most were not clinically relevant,” Constantino and colleagues emphasized.

The findings make it hard to justify initiating standard diagnostic algorithms for pulmonary embolism in every syncope patient, they concluded.

Does Preschool Make a Long-Term Difference?

Study followed children from Chicago’s Child-Parent Center well into adulthood

Many studies have attempted to analyze the effects of preschool on later development in at-risk children. But one appearing Monday in JAMA Pediatrics is the first to follow these kids into mid-adulthood, looking at outcomes at age 35. In this 150-Second Analysis, F. Perry Wilson, MD, looks at those outcomes and the limitations of this type of study.

Does preschool matter? A strong endorsement this week in a study appearing in JAMA Pediatrics which found that participants in Chicago’s “Child Parent Center” program had significantly higher educational attainment at 35 years of age, the longest follow-up of any early childhood intervention study.

The Child-Parent Center (CPC) program is the second oldest federally funded early childhood program (after Head Start). It was launched in 1967 in the most disadvantaged areas of Chicago and has grown substantially since then. The program takes a standardized approach but is unique in several ways.

First, the preschool programs are based within the primary school the children will eventually attend, making the transition to school easier. Second, the program continues up to third grade, providing resources and support even during routine education. Finally, the program demands a fair amount of parental involvement – 2.5 hours per week, in fact. Which I will guiltily admit is way more time than I spend in my kids’ school.

The study suggests that kids who went to these CPCs did better much later in life, but there are major issues with studies like this. CPC attendance wasn’t randomized. Are we seeing the beneficial effect of the intervention itself, or are parents who seek out these interventions more invested in their children and so their kids do better?

You have to find a good control group. To do this, the authors built a model predicting CPC attendance using a variety of demographic and socioeconomic variables. They then matched CPC kids with similar kids who did not attend a CPC.

Matching worked pretty well.

As you can see, in both groups, risk factors were fairly similar, and indicative of significant risk. Roughly half of the kids in both groups had a home environment problem by age 5. Around three-quarters were kids of single mothers. Half in both groups had moms who hadn’t completed high school.

Nevertheless the CPC group did a bit better than the comparison group.

Compared to kids who didn’t participate in CPC, those who did were more likely to finish high school, more likely to attend college, and even more likely to obtain a master’s degree.

So what about cost? The current manuscript doesn’t provide details, but the same group published a cost-benefit analysis in 2011 which found that the preschool program cost about $8,500 per participant, but accrued an average societal benefit of $92,000 – more than a 10-fold return on investment. That ROI was driven largely by higher earnings, more taxes paid, lower crime rates, and less smoking.

There was also evidence of a dose-effect, whereby kids who were in the program longer had better outcomes than kids who had less exposure.

Because of the non-randomized nature of the study, it’s not definitive. But it is encouraging, and compels consideration of broader adoption of early childhood programs in at-risk neighborhoods.

Molecular Imaging Flags Risk of AAA Rupture

Uptake of 18F-sodium fluoride (18F-NaF) can point to active vascular calcification associated with high-risk atherosclerotic plaque and may be a marker of high-risk abdominal aortic aneurysms (AAAs), according to a molecular imaging study.

Uptake of the biomarker on positron emission tomography (PET) and CT was significantly higher in the AAA (aortic diameter exceeding 40 mm) than in nonaneurysmal regions of the same aorta in the 20 patients studied. It was also significantly higher than in aortas of 20 controls in the prospective SoFIA3 study from researchers led by Rachael Forsythe, MD, of University of Edinburgh.

In a 72-person longitudinal cohort, the highest tertile of 18F-NaF uptake had aneurysms expand 3.10 mm per year versus 1.24 mm annually for the lowest tertile (P=0.008). The highest tertile also had triple the risk of AAA repair or rupture (15.3% versus 5.6%, log-rank P=0.043).

In this group with a baseline aneurysm diameter of 48.8 mm, 26.4% had their aneurysm repaired and 4.2% had a rupture and died without repair over 1.5 years of follow-up, Forsythe’s group reported in the Feb. 6 issue of the Journal of the American College of Cardiology.

“Fluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events,” the SoFIA3study authors concluded from their single-center, proof-of-concept study.

“This is the first study to demonstrate that an imaging biomarker of disease activity can add to the risk prediction of AAA and to suggest that this approach might refine clinical decisions regarding the need for surgery and improve patient outcomes,” they said. “We suggest that 18F-NaF uptake again relates to microcalcification and is particular to the most diseased areas associated with tissue disruption and loss of integrity.”

“Importantly, areas of fluoride uptake did not correspond to regions of macrocalcification on CT, suggesting the importance of dynamic calcification process,” noted an accompanying editorial.

In that commentary, Parmanand Singh, MD, of Weill Cornell Medical College, and Jagat Narula, MD, PhD, of Icahn School of Medicine at Mount Sinai, both in New York City, emphasized that “earlier detection of high-risk aneurysms is important to render appropriate care to the highest risk patients.”

“Despite significant advances in aortic imaging, pharmacotherapy and surgical interventions over the past decade, patients with AAA complications continue to have high rates of mortality,” they wrote. “The identification of aortic features linked to aortic vulnerability is crucial, both in guiding selection of patients for preemptive surgical repair and for optimizing timing of intervention to prevent complications. Noninvasive molecular imaging holds promise to identify markers of aortic instability earlier in the course of disease progression, and could offer a major advance in the diagnosis, surveillance and management of AAA.”

Oral Antibiotic Rx Remain High

Despite recommendations to limit the use of oral antibiotics, dermatologists continue to prescribe them in high numbers, according to a large, retrospective analysis of U.S. prescribing trends from 2004 to 2013.

However, spironolactone prescriptions increased nearly fourfold over that same time period, which is a good sign that alternatives may be gaining traction, the researchers said, writing in the Journal of the American Academy of Dermatology.

 “Given concerns about antibiotic resistance and other complications associated with oral antibiotic use, it is encouraging to observe an increase in the use of alternative agents such as spironolactone for the treatment of acne in female patients,” said John S. Barbieri, MD, MBA, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, and colleagues.

The number of spironolactone prescriptions marched steadily upward over time in the analysis, which was based on review of claims data representing 12 million to 14 million annual covered lives.

Dermatologists prescribed 2.08 courses of spironolactone per 100 acne patients in 2004, increased to 4.10 courses per 100 patients in 2010 and 8.13 courses in 2013.

However, oral antibiotic usage remained much higher over the entire study period, the results showed. Dermatologists prescribed 26.24 courses of antibiotics per 100 acne patients in 2004. That number appeared to dip slightly to 22.90 courses per 100 patients in 2010, but returned to 27.08 courses in 2013.

“Whereas we initially observed a slight decrease in oral antibiotic use, this trend has reversed in recent years,” the researchers said.

It is uncertain why oral antibiotic use seemed to decrease but then increase again, although the team noted that the shift upward followed the “dramatic decrease” in use of drospirenone-containing combined oral contraceptive pills starting in 2009: “It is possible that because of concerns about the safety of drospirenone-containing combined oral contraceptive pills, clinicians shifted their prescribing behavior toward the use of more oral antibiotics.”

Use of combined oral contraceptive pills dominated the group of systemic oral agents in this claims dataset, from 34.31 courses per 100 acne patients in 2004, which declined somewhat to approximately 30 courses per 100 patients in 2010 and 2013.

The analysis included a total of 594,776 courses of oral antibiotic treatment, 527,288 courses of combined oral contraceptives, 61,042 courses of spironolactone, and 108,664 courses of isotretinoin. The study also includes prescribing data for non-dermatologists.

The authors suggested that dermatologists identify patients who might benefit most from alternatives to oral antibiotics, including spironolactone, isotretinoin, and oral contraceptives.

Oral antibiotics are among the most commonly prescribed treatments for acne that cannot be managed with topical therapies, the researchers noted. In fact, dermatologists are the highest prescribers per capita of antibiotics compared with any other medical specialty.

 Excessive use of antibiotics persists throughout medicine despite ongoing concerns about excessive use of antibiotics due to emerging antibiotic resistance, as well as adverse effects that include pharyngitis and inflammatory bowel disease, Barbieri et al wrote.

Guidelines from the American Academy of Dermatology (AAD) and others recommend that the oral antibiotic treatment duration be limited to 3 to 6 months, although a subset of patients may require longer treatment.

The duration of oral antibiotic therapy in the analysis by Barbieri and colleagues was indeed a median of 126 days for patients receiving care from dermatologists, and 129 days for those treated by non-dermatologists. However, the sheer numbers of prescriptions were a cause of concern, with the authors calling for “judicious use” and “stewardship” of antibiotics.

“Like the authors of prior studies, we observe that prescribing behavior for oral antibiotics and the use of concomitant topical retinoids are not well aligned with current guidelines, although additional research is needed to understand the optimal duration of therapy with oral antibiotics.”

Despite concerns over current levels of antibiotic use, Barbieri et al said they were hopeful that use of antibiotic alternatives will “continue to grow,” particularly following recent data suggesting that routine potassium monitoring may be unnecessary for healthy women taking spironolactone for acne.

 “Increasing the use of concomitant topical retinoids, and additional work to identify those patients who would benefit most from alternative agents such as spironolactone, combined oral contraceptive pills, or isotretinoin represent potential opportunities to improve the care of patients with acne,” the team concluded.

Biologics Storage: Getting It Just Right

Is your patient’s refrigerator the problem with the inefficacy of biologic therapies?

Jack Cush, MD, discusses the ideal storage conditions

Biologics agents such as adalimumab (Humira), golimumab (Simponi), and ustekinumab (Stelara) should be stored at a temperature of 2-8°C (35.6-46.4°F). Several studies have identified a prevalent problem of unacceptable refrigeration storage of biologics used to treat immune-mediated inflammatory disorders (IMID), such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

 Dutch researchers studied 50 patients who received golimumab packaged with a temperature sensor that recorded sample temperature every 5 minutes. Patients were told to store their medication as usual. Temperature deviations were defined as any duration below 0°C and >30 minutes below 2°C or above 8°C.

After 3 months, data from 276 injectors and nearly 2.5 million temperature assessments showed that only one in eight (11.6%) were stored within the recommended temperature range. In addition, 11.2% were stored >30 minutes below 0°C and 33.2% were stored >1 week above 8°C. The authors suggested these findings may affect drug effectiveness in IMID-patients.

In 2016, another group from the Netherlands performed a similar observational study of patients given biologics with a temperature sensor. A majority (87.0%) of patients returned their temperature recordings to the pharmacy.

Only 6.7% stored their biologic within the recommended temperature range. Over 24% stored their drug for more than 2 hours below 0°C (median duration 3.7 hours) and 2% stored drug at temperatures above 25°C (median duration 11.8 hours).

An editorial in the Journal of Gastroenterology and Hepatology pointed out that none of these investigators studied the clinical impact of these missteps in drug storage. Thus it is unknown if the efficacy, viability, bioavailability or even the immunogenicity of these agents would be altered under these temperature variations. Changes in the complex protein structure of biologics may result from freeze-thawing or prolonged storage at elevated temperatures, and may lead to denaturation, irreversible formation of protein aggregates, and loss of biological activity.


  • Store biologics at 2-8°C; when taken out of the refrigerator, agents should be kept at room temperature less than 25°C
  • Studies have shown that etanercept (Enbrel) may be safely stored at room temperature conditions of 25°C ± 2°C (77°F) for up to 1 month
  • Discard drugs that have been frozen or improperly storage (call pharmacy or manufacturer for a replacement)
  • Pharmacists and nurses must counsel patients on the importance of storage conditions
  • There are companies developing apps to monitor drug temperature and usability
  • Manufacturers should develop and incorporate temperature-sensitive warning devices that can be incorporated into packaging.
  • Tell patients to avoid storing biologics in lower CRISPER Drawers, were the temperature is always lower (usually below 2°C or below 36°F). The lower temperature in the Crisper is optimal for storing produce and meats.

Finally, I advise patients who are traveling to either take their biologic a few days earlier or later to avoid traveling with drug, or if they travel with a biologic, keep it in a cool, dark, and dry place. Remove the agent from the refrigerator, wrap the injectable syringe in bubble wrap or light insulation (no need for an ice chest or dry ice), put it in a purse or briefcase, and bring the box label. The syringe is safe on planes and hotels as long as it’s at room temperature, away from sunlight or heat.

New study reveals how MRSA infection can permanently harm immune function

Methicillin-resistant Staphylococcus aureus bacteria (yellow) and a dead human white blood cell.

Infections of the skin or other soft tissues by the hard-to-treat MRSA (methicillin-resistant Staphylococcus aureus) bacteria appear to permanently compromise the lymphatic system, which is crucial to immune system function.

“MRSA-induced impairment persisted long after the infection was resolved and the inflammation had stopped” – Timothy Padera

In a report published online in Science Translational Medicine, Harvard Medical School investigators based at Massachusetts General Hospital describe findings that MRSA infection impairs the ability of lymphatic vessels to pump lymphatic fluid to lymph nodes in mouse models, which may contribute to the frequent recurrences of MRSA infection experienced by patients.

“We found that MRSA produces toxins that kill the muscle cells critical to the pumping of lymph,” said senior study author Timothy Padera, HMS associate professor of radiation oncology at Mass General.

“MRSA with a genetic deficiency that lowers the amount of toxin produced does not kill lymphatic muscle cells, which both supports the role for bacterial toxins in the post-MRSA impairment of lymphatic function and may also suggest a possible treatment strategy,” he added.

Serious skin infections called cellulitis are reported in about 14 million U.S. patients annually, with as many as 30 percent caused by MRSA. Serious cases requiring intravenous antibiotics lead to 500,000 hospitalizations each year, and 50,000 of those patients will have recurrent infections that require hospital readmission within a month.

Patients with lymphedema—swelling and fluid buildup caused by damage to or blockage of the lymphatic system—are particularly prone to recurrent infections, which can exacerbate existing lymphedema. But until now, no studies have investigated the potential interactions between bacterial infections and lymphatic function.

In contrast to the cardiovascular system, in which blood is propelled through arteries and veins by the pumping of the heart, in the lymphatic system, lymphatic fluid—which carries immune cells and other important factors—is pumped along by the contraction of the lymphatic vessels, driven by lymphatic muscle cells.

Persistent Impairment

Experiments in mouse models of MRSA tissue infections revealed that the infection itself cleared within 30 days and associated inflammation was gone within 60 days. But the lymphatic vessels in MRSA-infected tissues showed abnormalities, including increased vessel diameter and weaker, less frequent contractions, that were still present 120 days after the induction of infection.

Close examination revealed that the number of lymphatic muscle cells surrounding lymphatic vessels was depleted as late as 260 days after infection.

“We had assumed that we would find results similar to our previous measures of impaired lymphatic function in inflammation that was not associated with an infection,” Padera said. “But while lymph pumping was restored after the resolution of sterile inflammation, MRSA-induced impairment persisted long after the infection was resolved and the inflammation had stopped.”

“This persistence long after bacteria have been cleared can be explained by the loss of lymphatic muscle cells,” he said.

Exposure of cultured mouse and human lymphatic or smooth muscle cells to the proteins produced by MRSA led to the death of these cells, and detailed analysis of MRSA-produced proteins identified a significant number of known pathogenic toxins.

Since expression of many MRSA toxins is controlled by a genetic element called the accessory gene regulator (agr), the team tested a mutant form of MRSA lacking the agr against several types of cultured cells and in their animal model.

The agr-mutant MRSA did not produce the muscle cell-killing proteins, and lymphatic function—including the strength and frequency of vessel contraction—was significantly better in mice infected with the mutant strain than in animals infected with a nonmutated strain.

“Our results strongly suggest that targeting the action of the agr during and after MRSA infection may preserve lymphatic muscle cells and, as a result, lymphatic function,” Padera said. “Now we need to confirm whether MRSA infection leads to impaired lymphatic function in humans and identify the specific MRSA toxins that cause the death of lymphatic muscle cells.”