"People who do puzzles and crosswords may stave off dementia longer,” according to BBC News. The website said that mentally stimulating activities may protect the brain from memory loss but also speed up mental decline once dementia takes hold.

The story is based on research that followed 1,157 elderly people to examine how mentally stimulating activity in old age affects the development of dementia. The results suggest that being mentally active slows down cognitive decline before the onset of dementia but leads to faster decline after dementia has set in. The authors suggest that mental activity may somehow allow the brain to initially tolerate the brain changes associated with Alzheimer’s, but that decline is swifter once brain changes reach a more advanced stage.

While it is interesting, the authors’ theory was not conclusively proven by this study and will need further testing. Mental activity is only one factor that may contribute to the risk of dementia, along with genetics, environment and education. The study did not specifically test brain-training games or puzzles, as some newspapers suggested.

Where did the story come from?

The study was carried out by researchers from Rush University Medical Center, Chicago, and was funded by the US National Institutes of Health.

The study was published in the peer-reviewed journal Neurology. It was widely reported by the media, whose coverage was generally fair but uncritical. Some newspapers focussed on the delays in dementia symptoms seen in people who were most mentally active, while others concentrated on the swifter mental decline they exhibited once dementia eventually began.

The Daily Mirror’s claim that “thinking too hard may actually damage the brain of some older people” is misleading. The study did not specifically test the impact of brain-training games or mental puzzles, both of which were mentioned in press coverage.

What kind of research was this?

The researchers point out that more frequent cognitive activity has been associated with a reduced risk of cognitive decline and symptoms of dementia. However, it has not been associated with any reduction in the development of brain lesions associated with the condition.

Given that greater mental activity appears to protect brain function but not biology, the researchers argue that if cognitive activity before dementia were truly protective, it would also be associated with more rapid decline after the onset of dementia. In this cohort study, they tested the hypothesis that by delaying the onset of dementia, greater cognitive activity would “compress” the illness once it began, with the condition progressing more rapidly over a shorter time.

What did the research involve?

The researchers recruited 1,157 people aged over 65 who did not have dementia at the time of enrolment. Participants were selected at random from a larger study looking at risk factors for dementia. At their initial interview, they were asked to rate how frequently they took part in seven activities in which information processing plays a central role. These included watching TV, reading, doing crosswords and visiting museums. Frequency was estimated using a five-point scale, ranging from every day (5 points) to once a year or less (1 point).

The researchers used these ratings to make an overall estimate of how often people participated in mentally stimulating activities. Participants were also given four validated cognitive performance tests to assess their cognitive abilities.

The participants were followed up for an average of 12 years. Every three years, different samples of the group underwent a comprehensive clinical evaluation, in which they were classified as having no cognitive impairment, mild cognitive impairment or Alzheimer’s disease. Participants underwent further brief cognitive testing at three-yearly intervals to assess cognitive function. (Three waves of clinical evaluation were included in this ongoing study. The fifth wave is still underway.)

The researchers used validated statistical methods to look at the possible associations between people’s levels of cognitive activity and their cognitive function and clinical outcomes.

What were the basic results?

Clinical evaluation over the course of the study found that 614 people had no cognitive impairment, 395 had mild cognitive impairment and 148 had Alzheimer’s disease. When the researchers analysed the data, they found that:

• In the group without cognitive impairment, the annual rate of cognitive decline was reduced by 52% for each additional point on the cognitive activity scale.
• In the group with mild cognitive impairment, the rate of cognitive decline was not associated with cognitive activity level.
• In the group with Alzheimer’s disease, the average annual rate of cognitive decline increased by 42% for each point of the cognitive activity scale.

Together, these results associate greater cognitive activity with slower decline in people without cognitive impairment and faster decline in those with Alzheimer’s disease.

How did the researchers interpret the results?

The researchers said their results suggest that cognitive activity enhances the brain’s ability to maintain relatively normal function despite neurological degeneration. This means that after the onset of dementia, the resulting decline is more rapid. They said that the benefit of delaying the initial appearance of cognitive impairment comes at the cost of a more rapid progression of dementia when it eventually arrives.

The researchers concluded that any mentally enriching interventions, such as puzzles or acting classes, may need to be started before the development of cognitive impairment, because many people with mild cognitive impairment already have substantial physiological signs of Alzheimer’s disease in the brain.

Conclusion

This study has some strengths, including the large number of patients followed and the long follow-up period. Furthermore, its clinical evaluations and assessments of cognitive function were based on validated measures. The participants also represent a broad spectrum of cognitive function, ranging from no impairment to dementia.

However, the study also has limitations.

• It did not make adjustments for other factors (called confounders) which might contribute to the development of Alzheiner’s. For example, certain educational, social and genetic factors may have differed between the groups, which were not accounted for in the researchers’ analyses.
• Importantly, the assessment of cognitive activity was based on a composite measure. Since only seven cognitive activities were assessed, they may not reflect people’s true levels of cognitive activity. The use of composite measures to assess cognitive function also means that specific deficits in memory, for example, were not tested for by themselves.
• Only two to three observations were recorded for each individual in the study. Therefore, when graphed, the rate of decline in cognitive function tended to appear as a straight line, whereas a more complex pattern may have been revealed if more than three data points had been available.

Overall, this study supports the authors’ theories about the development of Alzheimer’s. However, further research that adjusts for other known risk factors is needed before any practical recommendations can be made from the results.

Links To The Headlines

Doing puzzles 'could speed up dementia'. Daily Mirror, September 2 2010

Brain teasers accelerate dementia - pick up a book instead. The Independent, September 2 2010

Keeping the mind active staves off dementia at first but speeds it up later. The Daily Telegraph, September 2 2010

Puzzles and crosswords may delay dementia, study suggests. BBC News, September 2 2010

Links To Science

Wilson RS, Barnes LL, Aggarwal NT et al. Cognitive activity and the cognitive morbidity of Alzheimer disease. Neurology, September 1 2010 (published online before print)

“Newborn babies should not be given sugar as pain relief,” read the headline in The Guardian. The newspaper said the routine use of tiny amounts of sugar before minor medical procedures is common practice but “it does not work and may damage their brains”.

Current medical guidelines recommend that babies swallow sucrose (sugar) solution before minor hospital procedures, such as the newborn heel prick blood test, as sugar solution is safe and effective at reducing pain they will feel.

The conclusions of this small study (44 babies analysed from 59 recruited for the study) directly challenge existing medical practice, with the finding that sugar did not reduce pain measured by looking at brain activity in response to a heel prick. Previous studies had all looked for a change in the baby's facial expression to know when the baby was in pain, rather than looking directly at brain activity. This method of measuring pain in babies may be more objective than interpretations of facial expressions, but more research is needed to prove this.

The study itself did not find that using sugar was associated with any ‘damage to newborn brains’, instead it explained that pain itself may affect a developing brain. If the lack of effect of sugar is confirmed in larger studies, then it can no longer be thought of as an effective pain relief drug for small babies.

Where did the story come from?

The study was carried out by a researcher from the Nuffield Department of Anaesthetics at the University of Oxford, along with colleagues from University College London and Great Ormond Street Hospital for Children all in the UK. The study was supported by the Medical Research Council and published in the peer-reviewed medical journal The Lancet.

Several other newspapers including the Mail and the Mirror also covered this story and reported it fairly. They focused on the fact that pain may cause short or long-term adverse effects on the development of the infant brain and suggested that if sugar is merely a distraction, then hugs or breastfeeding may work just as well.

What kind of research was this?

All babies have a heel prick blood test before they are eight days old to test for a variety of conditions. Currently, it is recommended that babies swallow sucrose (sugar) solution before the test to reduce any pain they may feel. Previous studies, including a systematic review of 44 studies, have suggested that sugar solution is safe and effective for reducing pain from minor hospital procedures.

In this double-blind, randomised controlled trial, the researchers wanted to find out if the sugar solution was actually reducing pain in the babies. The researchers explain that trials of pain relief in small babies are a challenge as the usual ways of reporting pain in clinical trials, such as asking for a description of the pain or using pain relief charts, cannot be used in babies. Usually in studies with babies, an observational pain score (premature infant pain profile - PIPP) is used. This combines video recordings made of the babies facial expressions (grimacing), as well as behavioural and physiological measures, such as oxygen use.

This study used an electroencephalography (EEG) cap to measure the electrical activity in the brain in response to pain as well as the usual PIPP response. The researchers monitored the brain activity of the babies during the heel prick test to look for a particular pattern of pain-specific brain activity, to see if the sugar solution caused a reduction in the pain response.

Care was taken to ensure no one involved in the study knew which babies had received which intervention.

What did the research involve?

The researchers carried out their study from February 2009 to March 2010. The participants were all healthy newborn infants born at 37-43 weeks of pregnancy and were less than eight days old when tested.

The researchers excluded babies from the study if they showed signs of tissue damage on the lower limbs, had previous surgery, serious illness or were born to diabetic mothers or opioid users. The babies were randomly assigned to receive either 0.5mL of 24% of sucrose solution or an equivalent volume of sterile water on the tongue.

A non-painful control stimulus was used first in all babies. The heel prick device was placed on the heel but the blade did not puncture the skin. The solution was then placed on the tongue two minutes before the actual heel prick took place.

Recording electrodes were positioned on the scalp to record the EEG, using the EEG cap. The researchers also used videos to record the behaviour and the facial expressions of the infants along with heart rate and oxygen levels in the blood and reflex movements of the limbs during the heel prick.

The researchers analysed the results on 20 out of 29 from the sucrose group and 24 out of 30 allocated to the sterile water group. The dropouts were mainly due to technical failure of the EEG, for example because of excessive movement. Only one parent withdrew consent in the sterile water group.

What were the basic results?

The measure of brain activity after the painful heel prick did not differ significantly between infants who received sucrose: mean 0.1 (95% Confidence Interval [CI] 0.04 to 0.16) compared with those who received sterile water: mean 0.08 (95% CI 0.04 to 0.12) p=0.46.

The PIPP score, a combined measure of heart rate, oxygen levels and facial expression (grimacing) scored from the video, was significantly lower in infants given sucrose compared with those given sterile water. Furthermore, significantly more infants had no change in facial expression after sucrose administration; 7 of 20 given sterile water (35%) compared with none of 24 given sucrose (p<0.0001).

How did the researchers interpret the results?

The researchers say that oral sucrose does not significantly affect activity in neonatal brain or spinal cord pain circuits, and therefore might not be an effective pain reliever.

They say that the ability of sucrose to reduce the PIPP scores observed in newborn infants after a painful event should not be interpreted as pain relief.

Conclusion

This study has used objective measures of pain in a small sample of infants and used careful blinding and randomisation to reduce bias. There are a few limitations due to the study size, but the conclusions are likely to challenge the currently held belief that sugar is an effective treatment for the pain of minor procedures in infants. The limitations mentioned by the researchers were:

• The small sample size of 44 infants analysed, which could mean that this study was not powered to observe subtle effects that sucrose might have on the brain processes used for pain.
• A measure of pain in infants is necessarily indirect (because they cannot describe the sensation), and so even though the electrophysiological measures reported in this study are more objective it is not clear that they are measuring the conscious pain experience of the newborn infant.
• The significant reduction of PIPP scores with sucrose confirm the results of the systematic review that looked at this as their main outcome. 
• The drop out of 15 infants (25% of those recruited) may have affected the reliability of the results.

The study itself had not identified harms associated with the use of sugar and it is an extrapolation to suggest that the use of sucrose for newborn pain relief ‘may damage their brains’. This may be particularly alarming for parents or doctors to read and is not a finding of this study. There is growing evidence that some newborns’ experience of pain may have lasting adverse effects on their neurodevelopment but to state this in a way that suggests that a study has shown that using sugar causes damage to newborn brains is unhelpful.

The researchers suggest that this single-centre trial should be repeated in a larger sample of infants, and that the new EEG measurement method should be used to test the effect of other known pharmacological analgesic drugs, such as morphine. This seems like sensible advice.

Links To The Headlines

Newborn babies should not be given sugar as pain relief, says study. The Guardian, September 2 2010

Pain relief is not so sweet for babies. Daily Mirror, September 2 2010

A hug, the sugar-free way to ease baby's pain. Daily Mail, September 2 2010

Links To Science

Slater R, Cornelissen L, Fabrizi L et al. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. The Lancet, [Early Online Publication] September 1 2010

Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database of Systematic Reviews 2010, Issue 1

Shah PS, Aliwalas LL, Shah VS. Breastfeeding or breast milk for procedural pain in neonates. Cochrane Database of Systematic Reviews 2006, Issue 3

Scientists have discovered genes that may be behind migraines, “opening the door to a cure”, reported the Daily Mirror. The newspaper said that these genes normally control the levels of a brain chemical called glutamate, but a variant form of the gene may lead to a build-up of glutamate within the nerve cells. According to the paper, halting this build-up could help stop migraines.

The study behind this story scanned the DNA of several thousand people with and without a history of migraine. It compared their genetics and identified a particular gene variant that was more common in migraine sufferers. The study adds to our understanding of the complex processes that lead to migraines and highlights that there may be genetic causes.

This is important research, but finding genes that are linked to a condition is very different from developing a safe treatment based on this knowledge. Overall, it is premature for newspapers to suggest that this research may soon produce a cure for migraines. Migraine is a complex condition in which the interaction between genes and the environment is likely to be important, meaning there may not be a single cause or cure.

Where did the story come from?

The study was carried out by researchers from the Wellcome Trust Genome Campus in Cambridge and from research groups across the world. The work was supported by several groups, including the Wellcome Trust, and was published in the peer-reviewed medical journal Nature Genetics.

Some newspapers optimistically announced that this study may lead to a cure for migraines, but a great deal of further research is needed before we know if this genetic discovery can improve the diagnosis or treatment of migraines.

What kind of research was this?

Migraine is an episodic headache disorder that is more common in women. The cause is thought to be related to changes in levels of particular chemicals in the brain and many potential triggers have been identified. These include dietary factors, physical triggers such as poor posture and tiredness, emotional triggers including stress, anxiety and depression, and environmental triggers. Some people also experience migraines after taking certain medications.

This was a genome-wide association (GWA) study which scanned people’s DNA to look for genetic factors that may be involved in migraines. GWA studies are commonly used to investigate whether particular genetic variants (such as mutations in DNA) are associated with certain conditions. The general approach is to assess the DNA sequences of a group of individuals with a condition and compare them to the DNA sequences in a group of unaffected individuals. In this study, researchers set out to identify genetic variants associated with the most common forms of migraine.

What did the research involve?

The researchers enrolled 3,279 people who suffered from migraines (cases) and 10,747 people who did not have the condition (controls). People were mainly recruited from headache clinics across Europe. Migraine was diagnosed by clinical experts through questionnaires and interviews.

As is common with this type of study, researchers then performed a “replication phase” to verify their initial findings in a separate, independent population. The replication phase examined separate samples of people from Denmark, Iceland, the Netherlands and Germany, plus a sample that combined all of these. In total, these replication tests examined a further 3,202 cases and 40,062 matched controls.

Migraine can sometimes be accompanied or preceded by visual distortions, called aura, which resemble bright rings of light. As well as being analysed as a single group, the participants who experienced migraines were further classified into subgroups based on their symptoms. These were a migraine with aura only group, migraine with and without aura group, and migraine without aura only group.

The researchers then assessed and discussed literature to identify the biological mechanisms that may be affected by the genetic variants identified.

What were the basic results?

The researchers identified one variant, called rs1835740, that was associated with migraine in both the initial and replication samples. People possessing the variant were about 1.5 to 1.8 times more likely to experience migraines than those without the variant. The researchers discussed what is known about the variant and its positioning within the DNA. They said that it is positioned between two genes that are involved in the body’s production of glutamate, a chemical in the brain that is involved in transmitting messages between nerve cells.

How did the researchers interpret the results?

The researchers concluded that their study has established a particular genetic variant (rs1835740) as a genetic risk factor for migraine. They say that, to their knowledge, this is the first time a study has done this.

Conclusion

This was a well-conducted and well-described genetic study that followed a recognised approach for studies in this field. There are some points to consider:

• One proposed cause of neurological disorders is a problem with ion channels (pores in the nerve cell walls that aid the transmission of nerve signals). The researchers say that in their study, they did not identify any associations between known ion channel genes and migraine.
• Possessing the rs1835740 genetic variant put people at an increased risk of migraine, but not all people with the variant experienced migraine. Conversely, some people without the variant experienced migraine, illustrating that other factors are also behind migraine.
• Despite speculation by newspapers, there is still more work to be done in this field and it is too soon to claim that a cure for migraine is on the way. While a particular genetic variant has been associated with migraine, it is unclear how this could lead to a cure as there is not yet any way to remove a variant from a person’s DNA. Drugs that block its action may one day be developed.
• The researchers note that the majority of their samples are from headache clinics and that their study needs replication in population-based samples.

The findings of this research increase our understanding of the biochemistry of neurological disorders, and this important study will pave the way for future research. These next research steps should also examine how genetics interact with the environment, as environmental triggers also play a part in the development of migraine.

The developing and testing of drugs can be a long and complicated process. If future studies result in improvements in the treatment of migraine, they are likely to be some way off.

Links To The Headlines

Revolutionary new scan shows key to migraines is in the genes. The Independent, August 30 2010

Found, migraine gene that could lead to a cure. Daily Mail, August 30 2010

Genes associated with migraine risk pinpointed. The Daily Telegraph, August 30 2010

Migraine gene sparks cure hope. Daily Mirror, August 30 2010

Links To Science

Anttila V, Stefansson H, Kallela M et al. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nature Genetics, 29 August 2010

A diet combining fruit and vegetables with foods such as fish, poultry and nuts “can protect you against heart attack”, reported The Independent.

The news is based on a well-conducted trial which tested the DASH diet, a diet high in fruit and vegetables but low in saturated fat that is recommended by the US government. The study enrolled 459 healthy people with slightly high blood pressure and randomly assigned them to follow the DASH diet, a high-fat “American” diet or an American diet supplemented with more fruit and vegetables. After eight weeks, the DASH diet lowered blood pressure and cholesterol, and decreased the participants’ risk of developing heart disease in the next 10 years more than the other diets.

This study has numerous strengths, but it only estimated future heart disease risk rather than monitoring participants over 10 years. Additionally, the risk of heart disease at the start of this study was very low at only 1%, and the DASH diet reduced this risk by only a minimal amount. Despite these small limitations, this study demonstrates the importance of blood pressure as a risk factor for coronary heart disease and the role a balanced diet might play in reducing this risk.

Where did the story come from?

This study was carried out by researchers from Johns Hopkins University, Baltimore. This particular trial was funded by the US National Center for Research Resources, and individual researchers received various other grants and research awards. The trial used data from a previous study, the DASH trial, which was sponsored by the US National Heart, Lung and Blood Institute. The study was published in the peer-reviewed medical journal Circulation.

In general, The Independent accurately reflected the findings of this well-conducted study, but did not mention some important limitations.

What kind of research was this?

This randomised controlled trial investigated the effects of dietary pattern on the 10-year risk of coronary heart disease (CHD). A randomised controlled trail is the best way of investigating a treatment’s ‘efficacy’, i.e. its effectiveness under ideal test conditions.

Dietary studies frequently have an inherent limitation in that it is difficult to accurately control how well a person adheres to the experimental diet being tested. However, this trial had the benefit of providing all the participants’ meals.

What did the research involve?

The researchers analysed findings of the Dietary Approaches to Stop Hypertension (DASH) trial, a previous study that assessed how various short-term dietary interventions affected high blood pressure. The trial had enrolled 459 healthy people with an average age of 45 and blood pressure that was on the high side of normal (average 131/85 mmHg) but not yet considered to be high. The researchers excluded participants with any significant illness, high cholesterol, any cardiovascular event in the previous six months or a BMI higher than 35kg/m2 (a BMI over 25kg/m2 is above ideal weight).

Participants were randomly assigned to follow one of three dietary patterns for eight weeks:

• a control diet: a “typical American diet”, high in saturated fat and cholesterol, low in minerals such as calcium and magnesium
• the F/V diet: rich in fruit and vegetables but otherwise similar to the control diet
• the DASH diet: rich in fruit, vegetables and low-fat dairy, and with a higher ratio of polyunsaturated fat to saturated fat than the other diets

Diets were reportedly prepared in research kitchens, with lunch and dinner prepared on site and breakfast provided for participants in a cooler to be eaten at home. Participants were also asked to record any additional items they consumed, including drinks and added salt. Blood pressure was measured on five occasions during the last two weeks of the study and the average measure was calculated. Cholesterol was also checked.

This subsequent study took the data from the DASH trial and applied the Framingham heart risk tool, a recognised method for predicting an individual’s risk of developing coronary heart disease (CHD). The researchers estimated the 10-year CHD risk of each participant at the beginning of the study and after eight weeks of their assigned diet. This heart risk calculation method takes into account several factors that can contribute to CHD risk, including gender, age, blood pressure, smoking status and diabetes.

What were the basic results?

At the start of the study, all participants had a low risk of developing CHD within the next 10 years (0.98% on average). The researchers found that, compared with the control diet, following the DASH diet for eight weeks:

• lowered blood pressure
• lowered total cholesterol
• lowered LDL (“bad” cholesterol)
• lowered HDL (“good” cholesterol)

At the end of the eight-week study period, there was no significant difference in 10-year CHD risk between the control and F/V diet groups. However, the DASH group had a significantly greater decrease in their 10-year CHD risk compared to the control group and the F/V group.

Over the course of the trial, participants in the DASH group had:

• an 18% decrease in their CHD risk compared to those in the control group (relative risk [RR] 0.82, 95% confidence interval [CI] 0.75 to 0.90)
• an 11% decreased risk compared to those in the F/V group (RR 0.89, 95% CI 0.81 to 0.97)

How did the researchers interpret the results?

The researchers concluded that the DASH diet, which was low in saturated fat and high in fruit and vegetables, decreased the 10-year CHD risk more than a diet high in fruit and vegetables alone or a typically American control diet that was high in saturated fat.

Conclusion

This well-conducted trial benefits from its relatively large size, accurate provision of the three randomised diets and high study completion rates (95%). It also featured a reliable study outcome by using the average of a series of blood pressure measures, which is preferable to relying on a single blood pressure reading.

The study found that eight weeks of the DASH diet, which was rich in fruit and vegetables and low in saturated fat, lowered blood pressure and cholesterol. This contributed to a decrease in predicted 10-year CHD risk. The DASH diet reduced this risk by 18% compared to a high-saturated fat “American” diet and by 11% compared to a diet similar to the American diet but with higher intake of fruit and vegetables.

Some points to note when interpreting this study include:

• All participants in this study had a low risk of developing coronary heart disease in the next 10 years (only about 1%). The DASH diet lowered this 1% risk by approximately one-tenth compared with the diet high in fruit and vegetables and by approximately one-fifth compared to the high-fat diet. Therefore, although the DASH diet lowered risk further, the overall risk remained low in all groups and the differences in risk between the groups were small.
• Although the tool used to calculate 10-year CHD is fairly reliable and commonly used, it is still only an estimate. The people were not followed up over 10 years to see whether they developed heart disease.
• This was only a brief eight-week intervention period. The effects of continuing these diets in the long term are unclear.
• The content of these diets is unclear. Although the newspapers reported that a more balanced diet involving nuts, chicken and fish was the most beneficial, the researchers did not describe the particular foods the participants ate, the calorific content or how much fat and cholesterol the diets contained.
• There were some differences between the three dietary groups at the start of the study. Those in the DASH group had a lower starting cholesterol level than participants in the F/V and control groups. This is an important difference as it could affect blood pressure.
• 60% of the participants in the trial were of African-American ethnicity, 35% were white and the remainder were of other ethnicity. Subgroup analysis also demonstrated that there was a greater decrease in CHD-risk in African-American participants. Therefore, it seems that these results are most applicable to this population group, which should be taken into account when generalising results to all ethnic populations.
• As the researchers acknowledge, this study was too small to reliably predict how the diets tested may affect other population subgroups, such as postmenopausal women, people with higher CHD risk or people with existing CHD.

Overall, this well-conducted study demonstrates the importance of blood pressure as a risk factor for coronary heart disease. It also supports the benefits of fruit and vegetables and low saturated fat as part of a healthy lifestyle to further modify the risk of heart disease.

Links To The Headlines

Revealed: the diet that can protect you against heart attacks. The Independent, August 31 2010

Links To Science

Chen ST, Maruthur NM, Appel LJ. The Effect of Dietary Patterns on Estimated Coronary Heart Disease Risk: Results from the Dietary Approaches to Stop Hypertension (DASH) Trial. Circulation: Cardiovascular Quality and Outcomes. August 31 2010 (published online before print)