CO2 emissions must be nil by 2070 to prevent disaster: U.N.

The world must cut CO2 emissions to zero by 2070 at the latest to keep global warming below dangerous levels and prevent a global catastrophe, the U.N. warns.

An environmental activist anchors a large balloon in a 2009 file photo.

By 2100, all greenhouse gas emissions — including methane, nitrous oxide and ozone, as well as CO2 — must fall to zero, the United Nationals Environment Programme (UNEP) report says , or the world will face what Intergovernmental Panel on Climate Change (IPCC) scientists have described as “severe, widespread and irreversible” effects from climate change.

Finite carbon budget

The UNEP report published on Wednesday is based on the idea that the planet has a finite ‘carbon budget’. Since emissions surged in the late 19th century, some 1,900 Gigatonnes (Gt) of CO2 and 1,000 Gt of other greenhouse gases have already been emitted, leaving less than 1,000 Gt of CO2 left to emit before locking the planet in to dangerous temperature rises of more than 2C above pre-industrial levels.

Jacqueline McGlade, UNEP’s chief scientist, told The Guardian that scientific uncertainties about the remaining carbon budget had diminished and the real uncertainty now was whether politicians had the will to act.

“The big uncertainty is whether you can put enough policies in place from 2020-2030 — in the critical window — to allow the least-cost pathways [to lower emissions and temperatures] to still stand a chance of being followed,” she said. “The uncertainties have shifted from the science to the politics.”

All scenarios in the UNEP report now require some degree of ‘negative CO2 emissions’ in the second half of the century, through technologies such as carbon capture and storage or, possibly, controversial, planetary wide engineering of the climate known as geo-engineering. UNEP is “extremely interested” in the subject and is planning a report in the months ahead.

Consideration should also be given to compensatory schemes for investors in fossil fuels companies to address the ‘stranded assets’ issue, Ms. McGlade added.

She acknowledged “donor fatigue” ahead of a pledging conference for the Green Climate Fund on Thursday — which has so far racked up close to $10bn (£6.4bn) — and called for up to 20 per cent of the final money pot to come from citizen bonds for local environment projects, with the remaining 80 per cent split between public and private sources.

Maroš Šefèoviè, the European Commission’s vice-president for energy union told a Brussels press conference that the report would be of use in preparing bloc positions for next month’s Lima climate summit.

The EU has not, however, supported UNEP’s call for zero greenhouse gas emissions by 2100 .

Climate neutrality

Christiana Figueres, the United Nations Framework Convention on Climate Change (UNFCCC)’s executive secretary, said: “This important report underscores the reality that at some point in the second half of the century, we need to have achieved climate neutrality — or as some term it zero net or net zero — in terms of overall global emissions.” A key theme in the emissions gap study is the cost-effectiveness of taking early action and the dangers of not doing so.



Organisms That Cause Sepsis Are Changing, and Sepsis Management and Recognition Has Improved.

Preface: Nice summary of the changing pathogenic organisms causing severe sepsis.  This summary also displays how improved sepsis recognition and management has decreased mortality from 40% to 28% over the last decade.


Mortality decreased from 40% to 28% overall. Although gram-negative organisms predominated, infection with an anaerobe or methicillin-resistant Staphylococcus aureus carried the highest mortality risk.


Recent studies suggest that mortality from severe sepsis is decreasing. But is this trend seen with all causative pathogens, and how large is the mortality reduction? Using data from the Nationwide Inpatient Sample — an administrative dataset approximating a 20% sample of all nonfederal, short-term, general, and specialty hospitals serving adults in the U.S. — researchers in California explored organism-specific severe sepsis mortality trends in the country from 1999 through 2008.


The data for 5,033,257 severe sepsis hospitalizations revealed that such hospitalizations had increased but that in-hospital mortality had decreased significantly — from 40.0% to 27.8% — over the study period. Among the 38.5% of cases for which the causative pathogen was reported, gram-negative bacteria predominated (51.5%; most commonly Escherichia coli and Pseudomonas), followed by gram-positive bacteria (45.6%; most commonly methicillin-sensitive Staphylococcus aureus and streptococci), anaerobes (1.7%), and fungi (1.2%). Although mortality was lower for cases with reported organisms than for those with unknown or unreported ones (26.6% vs. 36.1%), it declined similarly between groups over the study period.


After adjustment for demographic parameters, comorbidity, number of pathogens, and number of organ failures, mortality risk was highest overall for anaerobic organisms (hazard ratio, 1.31; 95% confidence interval, 1.23–1.40). Among gram-positive organisms, methicillin-resistant S. aureus was a significant predictor of mortality (HR, 1.38; 95% CI, 1.33–1.44). Gram-negative pathogens — particularly Pseudomonas and Serratia — carried the lowest risk.



Both the increase in severe sepsis hospitalizations and the impressive reduction in mortality are likely attributable to higher awareness and improved management of the condition following release of the Surviving Sepsis Campaign guidelines. That gram-negative pathogens are more common but less deadly is surprising and indicates a reversal of previous findings.


Organisms that cause sepsis are changing, sepsis management and recognition has improved



Ani C et al. Variations in organism-specific severe sepsis mortality in the United States: 1999–2008. Crit Care Med 2014 Sep 23; [e-pub ahead of print]. (

3 natural pain relievers that are as powerful as drugs, without the side effects .

Unfortunately, acute or chronic pain is something that everyone in their life experiences at one time or another. Even though this is a powerful reminder from the body that something is either healing or going terribly wrong, a way to manage the pain is often required in order to live a functional lifestyle.

The first resort to manage this type of pain has typically been prescriptions or over the counter drugs. These medications do have side effects, however, and people are beginning to realize there are more natural solutions that can be as effective or more powerful than drugs. Here are 3 of them.


Often called Indian Frankincense, boswellia originates in the dry areas of India, Africa, and the Mediterranean. It is a remarkable plant and is becoming better known for its anti-inflammatory properties. Inflammation is the root of chronic pain. The unique acids (boswellic acids) block the overproduction of cytokinetic activity in damaged tissues while enhancing blood flow to the joints. This combination has also been shown to increase joint mobility and loosen stiff joints.

Boswellia has shown great success at reducing inflammatory conditions such as Crohn’s, rheumatoid arthritis, osteoarthritis, ulcerative colitis, and other painful conditions. Many studies have shown that it is as effective as NSAID’s, which are the most commonly prescribed drug for issues related to inflammation and chronic pain.


Another powerful anti-inflammatory food with exceptional pain relief properties, turmeric is an ancient spice commonly used in Indian and Asian cuisine. Turmeric has shown to work better than many other pain-killing drugs at relieving arthritis, joint pain, stiffness, muscle spasms, and other chronic pain conditions.

A natural painkiller and COX-2 inhibitor, turmeric has been shown to be a safe and effective remedy due to its ability to not only stop inflammation, but to suppress nerve related pain as well. This makes it exceptional for those who suffer from fibromyalgia.


Astaxanthin (asta-zan-thin) is a deep red coloured phytonutrient synthesized by microalgae called Haematococcus, and is also known as the “King of Carotenoids”. It’s grown in fresh water using sophisticated techniques that encourage the algae to grow its own powerful medicines protecting it from oxidation, UV radiation, and other environmental stressors.

Even though astaxanthin may not be as powerful as leading pharmaceutical anti-inflammatories, it is found to be one of the strongest ones in nature. Several double blind, placebo controlled animal and clinical trials shows that astaxanthin naturally inhibits many of the known inflammation mediators, which eases inflammation and pain without side effects.

It has been used effectively for joint pain, muscle recovery, and other painful conditions. Since astaxanthin is fat soluble (unlike most antioxidants) it gets carried by fat molecules directly to your muscles, tissues, and organs where it is needed most, like your brain, breast tissue, prostate tissue, skeletal muscles, and retina.

Of course, the effectiveness of these remedies relies on several factors, including the individual’s current lifestyle and dietary habits. To learn from someone who has recovered from debilitating pain naturally with a completely holistic approach (who now enjoys radiant health on a daily basis), check out Advice from a Survivor – How To Live A Healthy Life. If you’re looking for to eliminate the source of pain, the first step is almost always to Balance Your Inner Ecosystem.


Learn more:

The Large Hadron Collider has observed two brand new particles.

Two never-before-seen “heavy-weight” baryon particles have been detected by the world’s favourite particle accelerator, the Large Hadron Collider. The discovery could help scientists understand more about the interactions of elementary particles.
Physicists from CERN in Geneva have discovered two new types of baryon particlesnamed Xi_b’- and Xi_b*- (before you ask, no, we’re not sure how to pronounce them).

Baryon particles are subatomic particles such as hyperons that are made up of three strongly-bonded tiny elementary particles called quarks – which are generally thought to be some of the smallest units of matter.

Xi_b’- and Xi_b*- were both predicted to already exist by the quantum physics models, but they’d never been seen before this and scientists weren’t sure of their exact mass – something they’ve now managed to calculate. And the heavy-weight subatomic particles impressively big – both are more than six times as massive as protons.

The new baryons were spotted in the Large Hadron Collider (LHC), the particle accelerator most famous for (probably) finding the Higgs boson.

The LHC works by accelerating two opposing beams of particles to speeds approaching the speed of light, and when they collide, they create an extremely hot explosion, which allows never-before-seen particles and types of matter to form very briefly.

In this split-second after-collision is when all the magic happens and physicists can find proof for things they’ve previously only ever hypothesised using formulae.

Just like baryons, protons are almost made of three tightly-bound quarks, but what’s particularly fascinating about Xi_b’- and Xi-b*- is that each of their quarks has a different spin, or direction in which they configure. Both subatomic particles contain one beauty quark (which accounts for most of their weight), one strange quark and one down quark.

As Nicholas St. Fleur explains for The Atlantic:

“The finding helps physicists narrow down the different ways that quarks can be arranged, which provides clues into understanding the forces that keep them and the most basic building blocks of matter held together”.

The results have been submitted to Physical Review Letters, but appear online now on ArXiv.

“There are maybe three-to-five such particles discovered each year,” Patrick Koppenburg, a CERN scientist from the Netherlands’ Nikhef Institute, told The Wall Street Journal. “Here we have two in one go, which is quite extraordinary.”

The researchers have also studied the relative production rates of the baryons, their widths – which can measure how unstable they are – as well as other details of their decay.

All of the results matched up with what they’d predicted of the baryons based on the theory of Quantum Chromodynamics (QCD).

QCD is part of the Standard Model of particle physics, which describes the forces that govern our Universe. Understanding more about the QCD will help refine our knowledge of the Standard Model and possibly even advance it one day.

“If we want to find new physics beyond the Standard Model, we need first to have a sharp picture,” said Patrick Koppenburg, the physics coordinator of the LHCb, the instrument that detected the baryons, in a press release. “Such high precision studies will help us to differentiate between Standard Model effects and anything new or unexpected in the future.”

Of course, particle discoveries are always pretty controversial. St. Fleur reports for The Atlantic:

“In 2011, a collaboration between CERN and the Italian OPERA experiment announced finding faster-than-light neutrinos, a discovery that was later undone after further investigation, as ScienceInsider reported in 2012. Even now, some physicists still debate whether or not physicists actually found the Higgs Boson.”

But although it will take some more peer-reviewed research for the discovery to become widely accepted, it’s still a pretty exciting first step.

“This is a very exciting result. Thanks to LHCb’s excellent hadron identification, which is unique among the LHC experiments, we were able to separate a very clean and strong signal from the background,” said Steven Blusk from Syracuse University in New York, who wasn’t involved in the research, in the CERN press release. “It demonstrates once again the sensitivity and how precise the LHCb detector is.”

Neuroscientists ‘rediscover’ entire brain region linked to reading.

Neuroscientists have ‘rediscovered’ a large part of the brain that disappeared from the scientific literature during the early 1900s. Now that it’s been properly analysed, it’s thought to be involved in crucial mental processes such as reading and recognising faces.
Neuroscientists in the US have accidentally rediscovered a forgotten region of the brain while investigating how reading skills develop over time in children.

“We couldn’t find it in any atlas,” one of the team, Jason Yeatman from the University of Washington’s Institute for Learning and Brain Sciences, told Laura Geggel at LiveScience. “We’d thought we had discovered a new pathway that no one else had noticed before.”

What they’d found was a region that, for reasons unknown, dropped out of the scientific literature describing human brains about a century ago, but continued to have a known prescence in the brains of other primates.

First discovered in 1881 by German neurologist Carl Wernicke, region is called the vertical occipital fasciculus (VOF). This flat, 5.5-centimetre cluster of long nerve fibres running vertically along the rear of the brain was found by Wenicke during a monkey brain dissection, and while it was later found in human brains, it remained conspicuously absent from anatomical drawings called ‘brain atlases’ throughout history.

This is something of a major oversight, as the VOF is now thought to play a unique and crucial role in how we’re able to process visual information. It maintains several connections between the nearby ‘vision sub-regions’ of the brain, which work together with visual cortex – also in the rear section of the brain – to process what we’re seeing at any given moment.

“I stumbled upon it while studying the visual word form area,” Yeatman told Mo Costandi at The Guardian. “In every subject, I found this large, vertically-oriented fibre bundle terminating in that region of the brain.”

After poring through both contemporary and historic literature for mentions of the region, Yeatman says a colleague remembered having seen something like it in an old medical textbook. So he dipped into the brain atlases of the late 1800s and early 1900s to discover a bizarre squabble between some of the world’s most imminent neuroscientists at the time.

It seems that Wenicke’s superior, German-Austrian neuroanatomist, Theodor Meynert, more or less ignored his student’s discovery, perhaps because it clashed with his own conclusions about the human brain. Meynert, who also taught none other than Sigmund Freud, had proposed a theory that said the neural pathways of the brain ran horizontally from the front of the brain to the back, not vertically, as Wenicke’s new discovery appeared to do.

Or perhaps Wenicke’s discovery was so removed from what Meynert was working on at the time that he ignored the discovery simply because he was focussing on something else. “Meynert’s apparent non-discussion of these fibre systems may simply have reflected his interest and focus,” Jeremy Schmahmann, a neurologist  from the Massachusetts General Hospital and Harvard Medical School who was not involved in the study, told Geggel at LiveScience.

Add the oversight of one of the world’s most respected neuroanatomists to the fact that in many of the brain atlases the VOF did turn up in, it had all kinds of different names, and that it can be very easily missed when you’re dissecting a human brain, and it makes sense how Wenicke’s discovery could have disappeared into obscurity.

Now that they’ve found it, Yeatman’s team has scanned over 70 people to locate and map the VOF properly, and the findings have been published today in the Proceedings of the National Academy of Sciences.

According to Costandi at The Guardian, the team describe the VOF as connecting the ‘upper’ and ‘lower’ streams of the brain’s visual pathway. “The lower stream connects brain regions involved in processes such as object recognition, including the fusiform gyrus, and the upper stream connects the angular gyrus to other areas involved in attention, motion detection, and visually-guided behaviour,” she says.

Yeatman and his team are continuing their research into how learning to read impacts a young person’s brain structure, and he says he thinks there’s a good chance that the newly rediscovered VOF will play a crucial role in that work.

Ospemifene benefited postmenopausal women with vulvar, vaginal atrophy

In postmenopausal women with vulvar and vaginal atrophy, ospemifene showed higher responder rates than placebo in two phase 3 randomized trials and offered relief from symptoms, according to data presented at the 25th annual meeting of The North American Menopause Society.

Responder rates

Rates were better with 60 mg daily than 30 mg daily, and the effect ofospemifene (Osphena, Shionogi Inc.) could be attributed to improvement in vaginal physiology, including maturation value and pH, according to Risa Kagan, MD, of Sutter East Bay Medical Foundation, Berkeley, Calif.

Risa Kagan

Risa Kagan

“Oral ospemifene 60 mg per day demonstrated significantly higher responder rates than placebo in both trials, as did oral ospemifene 30 mg per day, which was only studied in one,” Kagan said.

The analysis was based on two double blind, placebo-controlled trials evaluating the efficacy and safety of ospemifene, approved by the FDA in 2013 for the treatment of dyspareunia in postmenopausal women.

In both studies, women aged 40 to 80 years were diagnosed with vulvar and vaginal atrophy (VVA) based on vaginal pH, maturation index in the vaginal smear and VVA symptoms reported at baseline.

In study A, 826 women were randomly assigned 1:1:1 to ospemifene 30 mg per day, 60 mg per day or placebo and followed for 12 weeks based on most bothersome symptom (MBS). In study B, 919 participants were stratified into two categories by MBS — moderate to severe dyspareunia or vaginal dryness — reported at baseline, then randomly assigned, respectively, 1:1 to ospemifene 60 mg daily or placebo for 12 weeks. Lubricants could be used by all women in both trials.

Kagan and considered objective measures, including the percentage of parabasal cells and vaginal pH, along with subjective measures, including self-reported VVA symptoms, as parameters to assess efficacy.

A responder was defined by: more than 10-unit increase from baseline in maturation value; vaginal pH decrease of at least 0.5 from baseline; and decrease in severity of MBS by at least one point from baseline.

“The criteria of a responder for this specific trial was chosen by the sponsor when designing the phase 3 trials and was agreed to by the US FDA,” Kagan said.

Responder percentage, either at week 12 or last observation carried forward (LOCF), was compared between groups. The researchers used Cochran-Mantel-Haenszel (CMH) general association test, controlling for study center and uterine status, in study A, and CMH row mean score test, controlling for stratum, in study B.

In study A, the responder percentage at week 12/LOCF was 20.6% (58/282) with ospemifene 30 mg and 33.7% (93/276) with 60 mg vs. 3.4% (9/268) with placebo. Both ospemifene groups showed higher responder rates than placebo, with 60 mg better than 30 mg (P<.001 for both).

The researchers conducted an exploratory analysis to assess the percentage of women who met individual criteria in the responder definition; 20.9% in the placebo, 48.9% in the ospemifene 30-mg and 54% in 60-mg groups were maturation value responders, and 32.1% in the placebo, 56.7% in the ospemifene 30-mg and 70.7% in 60-mg groups were vaginal pH responders (P<.001 vs. placebo, for both).

In study B, the responder percentage at week 12/LOCF was significantly higher with ospemifene 60 mg (39.7%, 184/463) than placebo (5.5%, 25/456; P<.0001). The percentage of maturation value responders was 65.7% with ospemifene 60 mg vs. 23% with placebo, and the percentage of pH responders was 70.4% with ospemifene vs. 34.9% with placebo (P<.0001, for both).

“Interpretation of the most bothersome symptom results may be confounded by the use of lubricant in these two trials,” Kagan said.

Subjective symptoms

Besides its effects on objective measures of vaginal epithelium physiology, ospemifene 60 mg daily alleviated subjective VVA symptoms, whether they were reported as MBS, according to Ginger D. Constantine, MD, of EndoRheum consultants, Malvern, Pa.

Ginger Constantine

Ginger D. Constantine

“Oral ospemifene 60 mg per day demonstrated improvements in the severity of the most bothersome symptom of dyspareunia and vaginal dryness,” Constantine said. “In one trial, both symptoms were significantly improved, and in the second trial only dyspareunia was significantly improved.”

Based on the same phase 3 trials, Constantine and colleagues compared women treated with ospemifene 60 mg daily (n=276) vs. placebo (n=278) in study A and study B (n=463 and n=456, respectively) to evaluate subjective endpoints of VVA, looking at both patient-reported MBS and all moderate to severe VVA symptoms.

The trials assessed: vaginal dryness, dyspareunia, vulvar and/or vaginal irritation/itching, difficult and/or painful urination and vaginal bleeding associated with sexual activity. Symptoms were self-reported at baseline, week 4 and week 12; those reported at baseline as moderate to severe were included in the analysis. The researchers used CMH row mean scores test to analyze change in the severity of VVA symptoms from baseline to week 4 or 12.

In study A, ospemifene demonstrated superiority over placebo at week 12 for all endpoints, including mean change in severity of MBS of dyspareunia (–1.19 vs. –0.89; P=.023) or MBS of vaginal dryness (–1.26 vs. –0.84; P=.021). At week 4, the change in severity of MBS dyspareunia or MBS vaginal dryness was numerically but not statistically improved with treatment vs. placebo.

Ospemifene showed superiority compared with placebo in VVA symptoms, regardless of being reported as MBS, including vaginal dryness at week 4 (P<.05) and week 12 (P<.001) and dyspareunia at week 12 (P<.05). Difficult/painful urination was numerically improved with treatment vs. placebo at week 12 (P=.052).

In study B strata, the mean changes in MBS of dyspareunia (n=605) were significantly different between groups at week 12 (P=.0001) and numerically different at week 4 (P=.1698); the mean change in MBS of vaginal dryness was not significant at week 12 (P=.0803) or week 4 (P=.1886).

Ospemifene was better than placebo in reducing the severity of dryness at both weeks 4 and 12 (P<.0001) for VVA symptoms reported as moderate or severe at baseline, regardless of being reported as MBS.

Severity of dyspareunia and vulvar and/or vaginal irritation/itching were significantly reduced with ospemifene (P=.0003) vs. placebo (P=.0421) at week 12. Numerical improvements were seen in severity of dyspareunia at week 4 (P=.2614) and vaginal bleeding associated with sexual activity at week 12 (P=.0691).

“The severity of VVA symptoms, when most bothersome symptom was not a construct, that were reported as moderate to severe at baseline was improved with regard to dyspareunia, vaginal dryness and itching and irritation.” – by Allegra Tiver

Ultraviolet filters linked to reduced male fecundity

Men’s ability to father children in a timely manner may be affected by certain chemicals in sunscreens designed to protect against ultraviolet rays, according to recent study findings published in the American Journal of Epidemiology.

“In our study, male fecundity seems to be more susceptible to these chemicals than female fecundity,” Germaine Louis, PhD, director of the division of intramural population health research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, said in a press release. “The women participants actually had greater exposure to the UV filters overall, but their exposure wasn’t associated with any significant pregnancy delays. Our next step is to figure out how these particular chemicals may be affecting couple fecundity or time to pregnancy — whether it’s by diminishing sperm quality or inhibiting reproduction some other way.”

Germaine Louis

Germaine Louis

Louis and colleagues evaluated 501 couples (women aged 18 to 44 years; men aged ≥18 years) trying to conceive a child to determine if benzophenone (BP)-type UV filters affectedfertility.

Participants were followed until pregnancy or 1 year of trying to determine how long it took women to get pregnant. Urine samples were also tested to measure concentrations of five UV filters including 2,4-dihydroxybenzophenone (BP-1), 2,2,’4,4’-tetrahydroxybenzophenone (BP-2), 2-hydroxy-4-methoxybenzophenone (BP-3) 2-2’-dihydroxy-4-methoxybenzophenone (BP-8) and 4-hydroxybenzophenone; all are associated with endocrine-disrupting activity.

Researchers found that BP-2 (fecundability OR=0.69; 95% CI, 0.5-0.95) and 4-hydroxybenzophenone (FOR=0.74; 95% CI, 0.54-1) were associated with reduced fecundity in males.

Following adjustment for the couples’ concentrations, male BP-2 concentration was still associated with reduced fecundity (FOR=0.69; 95% CI, 0.49-0.97).

“The skin is the body’s largest organ, and how we care for skin matters in more ways than one,” Louis said. “Sunscreen is important for sun protection, and we definitely encourage people to continue using sunscreen to avoid skin cancer. But men who are concerned about fertility may be interested in other ways to reduce their exposure to benzophenone UV filters — whether by cutting back on other products that contain the UV filters or by washing after returning indoors.”

Antibiotics in Children Increase Risk for Juvenile Arthritis

Exposure to antibiotics during childhood significantly increases the risk for juvenile idiopathic arthritis in a dose-dependent manner, say investigators reporting at the American College of Rheumatology 2014 Annual Meeting in Boston.

They suggest that alterations in the human microbiome might be implicated in the development of the disease.

“The more we learn about the microbiome, the more it appears that it plays an important role in a variety of different diseases, such as autoimmune diseases — and that includes inflammatory bowel disease and rheumatoid arthritis and perhaps psoriatic arthritis — all of which have some common features with juvenile arthritis,” said Daniel Horton, MD, from the University of Pennsylvania in Philadelphia.

“We found that antibiotic exposure was associated with an increased risk of developing juvenile arthritis, at an adjusted odds ratio of 2.6, and that the risk increased with each additional prescription,” he told Medscape Medical News.

The nested case–control study “adds to a growing literature on the potential harms of antibiotic use in children,” Dr Horton reported.

Investigators used the Health Improvement Network, a population-based medical records database in the United Kingdom that contains comprehensive diagnostic and outpatient prescription data, to identify people younger than 16 years of age who were newly diagnosed with arthritis.

The 153 children with juvenile arthritis were matched, for age and sex, with 1530 control subjects from general practices in the United Kingdom.

The risk increased with each additional prescription.

On conditional logistic regression, the risk of developing arthritis was found to increase as exposure to antibiotics increased.

For children exposed to 1 or 2 courses of antibiotics, compared with no exposure, the odds ratio for arthritis was 3.1. For children exposed to 3 to 5 courses of antibiotics, the odds ratio was 3.8.

The association between antibiotic exposure in childhood and newly diagnosed juvenile arthritis was similar for different classes of antibiotics. However, there was no association between the development of arthritis and exposure to nonbacterial antimicrobial agents, including antifungal and antiviral drugs.

After adjustment for the number and type of infections children had, the associations did not change significantly. The age at which children were exposed to antibiotics also had no significant effect on the associations.

The fact that antimicrobial agents had a smaller effect on the development of arthritis could be because fungi and viruses are part of the human microbiome, Dr Horton told Medscape Medical News.

“This could support the hypothesis that it’s the antibacterial drugs that are contributing to the development of disease,” he explained.

However, Dr Horton pointed out that they couldn’t rule out the possibility that the infection itself might have contributed to the development of disease, or that children who developed it early in life have a higher risk for infection, or at least more severe infection.

Another Reason to Avoid Antibiotics?

“It’s always good to find another reason not to prescribe antibiotics inappropriately to children, but the fact is that antibiotics can be very useful drugs in certain situations,” Dr Horton said.

Still, the reasons certain children develop arthritis remain poorly understood, he observed, and genetics explains less than half of the cases that do occur.

“If the link between antibiotics and juvenile arthritis can be confirmed, antibiotic avoidance in the right clinical situation might be one of the few ways we have to prevent this life-changing disease,” Dr Horton said.

Alterations in the gut microbiota caused by antibiotic use is a plausible contributor to the development of juvenile arthritis, said Matthew Stoll, MD, from the University of Alabama at Birmingham, who was not involved in the study.

“If you have altered microbiota, there are some bacteria that appear to have proinflammatory effects, while others have anti-inflammatory effects. If you are changing the nature of the microbiota to the point where you have a lot more proinflammatory bacteria, that could potentially lead to arthritis and other autoimmune diseases,” Dr Stoll told Medscape Medical News.

He said he agrees with Dr Horton that there is every reason to be cautious about prescribing antibiotics to children.

“There were reasons to be cautious about prescribing antibiotics to children even before this study came out. If a child doesn’t have a bacterial infection and you give an antibiotic, you are exposing the child to unnecessary medicines. And there is a higher risk of generating antibiotic resistance when you do this,” Dr Stoll said.

“Now there are potentially other reasons to be cautious about giving antibiotics to children, and this is another good one,” he said.

This study is based on the Health Improvement Network in the United Kingdom. Dr Horton and Dr Stoll have disclosed no relevant financial relationships.

Low-Dose Aspirin Fails in Primary Prevention

A new trial shows no benefit of low-dose, once-daily aspirin in the primary prevention of cardiovascular events in patients with multiple risk factors, including hypertension, diabetes, and dyslipidemia.

No benefit was seen for the composite endpoint of nonfatal myocardial infarction (MI), nonfatal stroke, or death from cardiovascular causes. There were significant reductions in MI and in transient ischemic attack (TIA), but a significant increase in serious extracranial hemorrhage meant the net benefit was questionable.

The overall rate of events was much lower than anticipated in this study, and it did not reach statistical significance, said study coauthor Kazuyuki Shimada, MD, Department of Cardiology, Shin-Oyama City Hospital, Tochigi, Japan. “Therefore, the possibility that aspirin does have a beneficial effect in this population cannot be excluded.”

Still, the clinical importance of aspirin for primary prevention was “less than originally anticipated in this population,” he concluded, and further analyses are planned to see whether they can identify patients who may benefit most from aspirin.

“Lastly, it will be interesting to see if the ongoing studies ARRIVE, ASCEND, ASPREE and ACCEPT-D, which are assessing primary prevention in predominantly Western populations, have different outcomes to our study in Japanese patients,” Dr Shimada said.

The results of the Japanese Primary Prevention Project (JPPP) were published online November 17 in JAMA to coincide with presentation here at the American Heart Association 2014 Scientific Sessions.

Primary Prevention

Dr Kazuyuki Shimada

For the last several years, the benefits and risks of aspirin for primary prevention of cardiovascular events for those at moderately increased risk have been “hotly debated,” Dr Shimada said. “Recently the FDA [Food and Drug Administration] cautioned against the general use of aspirin for the primary prevention of heart attacks and strokes,” he noted. An FDA release on May 5 concluded that after a review of the literature, the evidence does not support the use of aspirin for primary prevention.

“In order to inform our decision-making in Japan and to develop country-specific recommendations, we conducted the Japanese Primary Prevention Project study, which prospectively evaluated daily, low-dose aspirin in the primary prevention of CV [cardiovascular] events in elderly Japanese patients with cardiovascular risk factors,” Dr Shimada said.

The Japanese Primary Prevention Project (JPPP) was a multicenter, open-label, randomized, parallel-group trial. Using a Prospective Randomized Open Blinded Endpoint (PROBE) study design, patients with hypertension, dyslipidemia, and/or diabetes mellitus without a history of cardiovascular disease were enrolled during routine visits to their primary care provider at one of 1007 clinics in Japan between March 2005 and June 2007.

A total of 14,658 patients were randomly assigned to receive 100 mg of enteric-coated aspirin per day or no aspirin, along with continuous management of their other risk factors. Patients were to be followed for up to 6.5 years, with last follow-up in May 2012. Study outcomes were adjudicated by an expert panel blinded to treatment assignments.

“At the time of the second interim analysis in May 2011, the independent data monitoring committee recommended that the study was to be discontinued at the next annual study assessment due to futility and to avoid unnecessary risk of adverse events,” he said. At the time of study discontinuation, patients had been followed up for a median of 5.02 years (interquartile range, 4.55 to 5.33 years).

The primary outcome was a composite of death from cardiovascular causes (MI, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or hemorrhagic, including undefined cerebrovascular events), and nonfatal MI. Secondary outcomes included those events plus TIA, angina pectoris, and atherosclerotic disease requiring surgery or intervention, as well as each individual outcome.

A total of 56 fatal events occurred in each group. Nonfatal stroke occurred in 114 patients in the aspirin group and 108 in the no-aspirin group. Nonfatal MI was seen in 20 patients taking aspirin vs 38 in the no-aspirin group, and undefined cerebrovascular events occurred in three patients receiving aspirin vs five patients not receiving aspirin.

“There was no statistically significant difference between the two groups in time to the primary endpoint,” Dr Shimada reported. “The hazard ratio indicates that there was an insignificant 6% reduction in the risk of a primary endpoint event in the aspirin group vs the no aspirin group.”

Table. JPPP: Main Outcomes

Endpoint Aspirin No Aspirin Hazard Ratio (95% Confidence Interval) PValue
5-year cumulative event rate (%) 2.77 (2.40- 3.20) 2.96 (2.58 – 3.40) 0.94 (0.77 – 1.15) .54
Nonfatal MI 0.30 (0.19 – 0.47) 0.58 (0.42 – 0.81) 0.53 (0.31 – 0.91) .02
TIA 0.26 (0.16 – 0.42) 0.49 (0.35 – 0.69) 0.57 (0.32 – 0.99) .04
Extracranial hemorrhage requiring transfusion or hospitalization 0.86 (0.67 – 1.11) 0.51 (0.37 – 0.72) 1.85 (1.22 – 2.81) .004


The risk of a primary endpoint event did not differ significantly for aspirin vs no aspirin in any of the disease risk factor subgroups assessed, including hypertension vs no hypertension, dyslipidemia vs no dyslipidemia, diabetes vs no diabetes, and family history vs no family history, or by demographic factors such as age and sex.

For most secondary endpoints, there was no significant difference between the treatment groups. However, nonfatal MI was significantly reduced by 47% with aspirin vs no aspirin, and TIA was reduced by a significant 43%, Dr Shimada said.

“Conversely, there was a significant increase in serious extracranial hemorrhage in the aspirin group — the hazard ratio indicates an 85% increase in such events,” he said. “Therefore, any benefits of aspirin in terms of the reduced risk of nonfatal MI and TIA must be counterbalanced with consideration of the significantly increased risk of serious extracranial hemorrhage.”

Finally, there was a prespecified analysis of gastrointestinal (GI) adverse events in the randomized population. “The results clearly indicate that aspirin is associated with an increased incidence of these GI events, the known side-effect profile of aspirin, although the study was unblinded and these were not primary or secondary analyses,” he said.

In an accompanying editorial, J. Michael Gaziano, MD, MPH, Veterans Affairs Boston Healthcare System, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and associate editor, JAMA, and Philip Greenland, MD, Departments of Preventive Medicine and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, and senior editor, JAMA, point to the lower than expected event rate in this study, “leading to a study with less power to detect differences in the primary outcome than anticipated.”

Aspirin primary prevention trials have “become increasingly challenging to conduct,” they write. “There is wider use of a number of prevention medications such as antihypertensive agents and lipid-lowering drugs, as well as other preventive measures that collectively result in fewer events than expected, as seen in JPPP.”

The findings add to the “body of evidence that helps refine the answer to the question of when aspirin should be used to prevent vascular events,” they say. “Decision making involves an assessment of individual risk-to-benefit that should be discussed between clinician and patient.”

In some situations the benefit of aspirin is clear, such as those at high short-term risk after an acute vascular event, or those undergoing certain vascular procedures, they add. “On the other hand, patients at very low risk of vascular events should not take aspirin for prevention of vascular events, even at low dose.”

In the middle are those without overt vascular disease but risk levels approaching those with cardiovascular disease. “It remains likely that there is some level of risk of CVD [cardiovascular disease] events that would result in a positive trade-off of benefit and risk for the use of aspirin, but the precise level of risk is uncertain. This is in part because most populations studied have been at very low risk.”

The editorialists also point to the ongoing ASCEND, ARRIVE, and ASPREE studies to help refine guidelines in higher-risk patients.

“Findings from these studies, with additional data about risks and other potential long-term benefits, such as reducing the risk of colorectal and other cancers, will prove helpful for clinical decision making involving the role of aspirin for primary prevention,” Dr Gaziano and Dr Greenland conclude.

End of the Road?

At the meeting here, Dorairaj Prabhakaran, DM, vice president and professor of epidemiology, Public Health Foundation of India, and professor of epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom, was the invited discussant for this trial. He considered the question of whether these findings spell the “end of the road for aspirin in primary prevention.”

Among the reasons the trial was negative were the lack of power due to early termination, he said, and the fact that aspirin on a background of widespread statin use may make it difficult to show a benefit.

“Benefit is very unlikely in low-risk populations such as those with less than 1% events per year,” Dr Prabhakaran said. “There could be a role in special groups, particularly younger populations that are not being evaluated well from low-/middle-income countries like India, where the risk of coronary artery disease is extremely high.”

Risk scores are needed for these countries to identify high-risk people, he added, and “we also await the results of other studies in primary prevention,” such as the TIPS-2 trial in India that combines a “polypill” with aspirin, he noted.

If risk is less than 10%, benefit is unlikely, but there is a “gray area” between 10% and 20% where benefit may yet be seen with aspirin for primary prevention, he said (J Am Coll Cardiol. 2014;64:319-327).

He quoted Sir Richard Doll, who once said, “Death is inevitable, but premature death is not.”

“In reducing premature death, aspirin is the most inexpensive option and we should pursue with vigor in identifying individuals and populations who may benefit,” Dr Prabhakaran concluded.

During a discussion after the presentation, Christopher Cannon, MD, Harvard Medical School, pointed out that in his practice, many patients arrive having already started aspirin therapy on their own, “whereas we’re seeing there’s an active decision of benefit and risk that needs to be taken.

“It’s a serious decision whether to start aspirin, so this is a terrific reminder that we really need to calculate based on risk and see could this be of benefit, or would there be more harm?” he added.

Even Well-Controlled Type 1 Diabetes Associated with Increased Mortality Risk

Patients with type 1 diabetes who have good glycemic control still have about twice the mortality risk as the general population, according to a case-control study in the New England Journal of Medicine.

Using Swedish registries, researchers matched 34,000 adults with type 1 diabetes to roughly 170,000 adults without type 1 diabetes (mean age, 36). All patients with diabetes were at elevated risk for all-cause mortality, even those with well-controlled mean glycated hemoglobin levels (5.4% for patients with hemoglobin A1c levels of 6.9% or below vs. 2.9% mortality rate for controls during 8 years’ follow-up). In that same period, mortality increased with increasing levels of glycated hemoglobin (12% for HbA1c of 9.7% or higher).

There were similar trends in cardiovascular and diabetes mortality, which accounted for much of the excess overall mortality risk.