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Outpatient Antibiotic Overprescribing Rampant

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Clinicians prescribed antibiotics without an infection-related diagnosis nearly half of the time and one in five prescriptions were provided without an in-person visit, according to research being presented at IDWeek 2018. The study, which is the first to look at overall outpatient antibiotic prescribing, analyzed more than half a million prescriptions from 514 outpatient clinics.

Previous research has found antibiotics often are prescribed for certain symptoms (such as a sore throat or cough) when they shouldn’t be.

Most of these types of illnesses are caused by viruses and therefore don’t benefit from antibiotics, which only treat bacterial infections.

“We looked at all outpatient antibiotic prescribing and results suggest misuse of these drugs is a huge problem, no matter the symptom,” said Jeffrey A. Linder, MD, MPH, lead author of the study and chief of the Division of General Internal Medicine and Geriatrics at Northwestern University Feinberg School of Medicine, Chicago.

“We found that nearly half the time, clinicians have either a bad reason for prescribing antibiotics, or don’t provide a reason at all. When you consider about 80 percent of antibiotics are prescribed on an outpatient basis, that’s a concern.”

The research, which was funded by the Agency for Healthcare Research and Quality (AHRQ), analyzed 509,534 outpatient antibiotic prescriptions given to 279,169 patients from November 2015 through October 2017 by 2,413 clinicians at 514 clinics. The prescribers included physicians, attending physicians, nurse practitioners, and physician assistants in specialties including primary care internal medicine, obstetrics/gynecology, family medicine, dermatology, cardiology, and gastroenterology. Researchers determined 46 percent of antibiotics were prescribed without an infection-related diagnosis: 29 percent noted something other than an infection diagnosis (such as high blood pressure or annual visit) and 17 percent were written without a diagnosis indicated. Researchers hypothesize that some of that is related to sloppy diagnosis coding, but much of it reflects antibiotic prescribing for vague or inappropriate reasons, such infections that are caused by viruses, said Dr. Linder.

Of the 20 percent of antibiotics that were prescribed outside of an in-person visit, most were by phone (10 percent). Others were via an electronic health record system that allows prescription writing but there is no opportunity to gather information about symptoms or testing (4 percent), refill (4 percent) and online portal (1 percent). There are some cases where that may be appropriate, such as for women who suffer from recurrent urinary tract infections or teens taking antibiotics for acne. Researchers will analyze which of those prescriptions were appropriate in the next phase of research.

“Despite 40 years of randomized controlled trials showing antibiotics don’t help for most coughs and sinus infections, many people are convinced they will not get better without an antibiotic and specifically call the doctor requesting one,” said Dr. Linder.

“At busy clinics, sadly the most efficient thing to do is just call in an antibiotic prescription. We need to dig into the data more, but we believe there is a lot of antibiotic prescribing for colds, the flu and non-specific symptoms such as just not feeling well, none of which are helped by antibiotics.”

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Paternal Transmission Of Epigenetic Memory Via Sperm

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Studies of human populations and animal models suggest that a father’s experiences such as diet or environmental stress can influence the health and development of his descendants. How these effects are transmitted across generations, however, remains mysterious.

Susan Strome’s lab at UC Santa Cruz has been making steady progress in unraveling the mechanisms behind this phenomenon, using a tiny roundworm called Caenorhabditis elegans to show how marks on chromosomes that affect gene expression, called “epigenetic” marks, can be transmitted from parents to offspring. Her team’s most recent paper, published October 17 in Nature Communications, focuses on transmission of epigenetic marks by C. elegans sperm.

In addition to documenting the transmission of epigenetic memory by sperm, the new study shows that the epigenetic information delivered by sperm to the embryo is both necessary and sufficient to guide proper development of germ cells in the offspring (germ cells give rise to eggs and sperm).

“We decided to look at C. elegans because it is such a good model for asking epigenetic questions using powerful genetic approaches,” said Strome, a distinguished professor of molecular, cell, and developmental biology.

Epigenetic changes do not alter the DNA sequences of genes, but instead involve chemical modifications to either the DNA itself or the histone proteins with which DNA is packaged in the chromosomes. These modifications influence gene expression, turning genes on or off in different cells and at different stages of development. The idea that epigenetic modifications can cause changes in gene expression that are transmitted from one generation to the next, known as “transgenerational epigenetic inheritance,” is now the focus of intense scientific investigation.

For many years, it was thought that sperm do not retain any histone packaging and therefore could not transmit histone-based epigenetic information to offspring. Recent studies, however, have shown that about 10 percent of histone packaging is retained in both human and mouse sperm.

“Furthermore, where the chromosomes retain histone packaging of DNA is in developmentally important regions, so those findings raised awareness of the possibility that sperm may transmit important epigenetic information to embryos,” Strome said.

When her lab looked at C. elegans sperm, they found the sperm genome fully retains histone packaging. Other researchers had found the same is true for another commonly studied organism, the zebrafish.

“Like zebrafish, worms represent an extreme form of histone retention by sperm, which makes them a great system to see if this packaging really matters,” Strome said.

Her lab focused on a particular epigenetic mark (designated H3K27me3) that has been well established as a mark of repressed gene expression in a wide range of organisms. The researchers found that removing this mark from sperm chromosomes causes the majority of the offspring to be sterile. Having established that the mark is important, they wanted to see if it is sufficient to guide normal germline development.

The researchers addressed this by analyzing a mutant worm in which the chromosomes from sperm and egg are separated in the first cell division after fertilization, so that one cell of the embryo inherits only sperm chromosomes and the other cell inherits only egg chromosomes (normally, each cell of an embryo inherits chromosomes from both egg and sperm). This unusual chromosome segregation pattern allowed the researchers to generate worms whose germ line inherited only sperm chromosomes and therefore only sperm epigenetic marks. Those worms turned out to be fertile and to have normal gene expression patterns.

“These findings show that the DNA packaging in sperm is important, because offspring that did not inherit normal sperm epigenetic marks were sterile, and it is sufficient for normal germline development,” Strome said.

While the study shows that epigenetic information transmitted by sperm is important for normal development, it does not directly address how the life experience of a father can affect the health of his descendants. Strome’s lab is investigating this question with experiments in which worms are treated with alcohol or starved before reproducing.

“The goal is to analyze how the chromatin packaging changes in the parent,” she said.

“Whatever gets passed on to the offspring has to go through the germ cells. We want to know which cells experience the environmental factors, how they transmit that information to the germ cells, what changes in the germ cells, and how that impacts the offspring.”

By demonstrating the importance of epigenetic information carried by sperm, the current study establishes that if the environment experienced by the father changes the epigenetics of sperm chromosomes, it could affect the offspring.

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Father’s Nicotine Use Can Cause Cognitive Problems In Children And Grandchildren

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A father’s exposure to nicotine may cause cognitive deficits in his children and even grandchildren, according to a study in mice publishing on October 16 in the open-access journal PLOS Biology by Pradeep Bhide of Florida State University in Tallahassee and colleagues. The effect, which was not caused by direct secondhand exposure, may be due to epigenetic changes in key genes in the father’s sperm.

Exposure of mothers to nicotine and other components of cigarette smoke is recognized as a significant risk factor for behavioral disorders, including attention deficit hyperactivity disorder, (or ADHD) in multiple generations of descendants. Whether the same applies to fathers has been less clear, in part because in human studies it has been difficult to separate genetic factors (such as a genetic predisposition to ADHD) from environmental factors, such as direct exposure to cigarette smoke.

To overcome this difficulty, Deirdre McCarthy, Pradeep Bhide and colleagues exposed male mice to low-dose nicotine in their drinking water during the stage of life in which the mice produce sperm. They then bred these mice with females that had never been exposed to nicotine. While the fathers were behaviorally normal, both sexes of offspring displayed hyperactivity, attention deficit, and cognitive inflexibility. When female (but not male) mice from this generation were bred with nicotine-naïve mates, male offspring displayed fewer, but still significant, deficits in cognitive flexibility. Analysis of spermatozoa from the original nicotine-exposed males indicated that promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning, suggesting that these modifications likely contributed to the cognitive deficits in the descendants.

Nicotine and cigarette smoke have been previously shown to cause widespread epigenetic changes, Bhide said.

“The fact that men smoke more than women makes the effects in males especially important from a public health perspective. Our findings underscore the need for more research on the effects of smoking by the father, rather than just the mother, on the health of their children.”

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Nutrition Has A Greater Impact On Bone Strength Than Exercise

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ANN ARBOR—One question that scientists and fitness experts alike would love to answer is whether exercise or nutrition has a bigger positive impact on bone strength. University of Michigan researchers looked at mineral supplementation and exercise in mice, and found surprising results–nutrition has a greater impact on bone mass and strength than exercise. Further, even after the exercise training stopped, the mice retained bone strength gains as long as they ate a mineral-supplemented diet.

“The longer-term mineral-supplemented diet leads to not only increases in bone mass and strength, but the ability to maintain those increases even after detraining,” said David Kohn, a U-M professor in the schools of dentistry and engineering.

“This was done in mice, but if you think about the progression to humans, diet is easier for someone to carry on as they get older and stop exercising, rather than the continuation of exercise itself.”

The second important finding is that the diet alone has beneficial effects on bone, even without exercising. This surprised Kohn, who expected exercise with a normal diet to fuel greater gains in bone strength, but that wasn’t the case.

“The data suggests the long-term consumption of the mineral-supplemented diet could be beneficial in preventing the loss of bone and strength with age, even if you don’t do exercise training,” he said.

Combining the two amplifies the effect.

Most other studies look at effects of increasing dietary calcium, Kohn said. The U-M study increased calcium and phosphorous, and found benefits to increasing both.

This isn’t to suggest that people run out and buy calcium and phosphorus supplements, Kohn said. The findings don’t translate directly from mice to humans, but they do give researchers a conceptual place to start.

It’s known that humans achieve peak bone mass in their early 20s, and after that it declines. The question becomes how to maximize the amount of bone when young, so that when declines do begin, people start from a better position, Kohn said.

In addition to testing bone mass and strength, Kohn and colleagues performed a full battery of mechanical assessments on the bone, which is important because the amount of bone doesn’t always scale with or predict the mechanical quality of the tissue.

They tested the mice after eight weeks of training and supplemented diet or normal diet, and then after eight weeks of detraining.

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