Key messages

• In people with alpha 1 antitrypsin deficiency, delivering additional alpha 1 antitrypsin through a drip into a vein (intravenous augmentation therapy) may lead to a slight increase in the number of exacerbations (worsening of lung disease) people experience each year, but may have little or no effect on the number of people who die. We are unsure whether intravenous augmentation therapy has any effect on the number of people who have serious unwanted events like hospitalisation or permanent damage. Delivering additional alpha 1 antitrypsin through a breathing mask (inhaled augmentation therapy) may have little or no effect on the number of people who have serious unwanted events, and we are unsure whether this treatment has any effect on exacerbations.

• Our review included few studies, and we have little confidence in the evidence.

What is alpha 1 antitrypsin deficiency (AATD)?

Alpha 1 antitrypsin (AAT) is a protein that helps protect our organs against damage from our body's own enzymes. AAT deficiency (AATD) is a genetic disease where people do not produce enough AAT. It can lead to lung damage and chronic obstructive pulmonary disease (COPD; a long-term condition that makes it hard to breathe). Symptoms of AATD include shortness of breath, cough, and wheeze. Smokers with AATD have a higher risk of developing severe lung disease. AATD can also lead to liver problems. Some people with AATD can stay healthy throughout their lives.

What is alpha 1 antitrypsin augmentation therapy?

AAT augmentation therapy aims to raise AAT levels in the bloodstream and lungs using AAT protein taken from the blood of healthy donors. AAT augmentation therapy may help protect lung tissue from damage and slow lung disease progression. It can be given through a drip into a vein (intravenous), injected under the skin (subcutaneous), or inhaled through a breathing mask.

What did we want to find out?

We wanted to find out if topping up AAT levels in people with AATD could reduce the number of exacerbations (worsening of the disease), the number of people who die, and the number of people who have serious unwanted events like hospitalisation or permanent damage. Our review focused on the results that were most important to people with the disease.

What did we do?

We searched for studies that compared AAT augmentation therapy given by any route (intravenous, subcutaneous, or inhaled) against AAT augmentation therapy delivered by another route, a dummy treatment (placebo), or no treatment. We compared and summarised the results and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We found six studies with 524 participants. Four studies looked at intravenous AAT augmentation therapy, and the other two looked at inhaled AAT augmentation therapy. All six compared AAT augmentation therapy with placebo. The studies were conducted in high-income countries across Europe, North America, and Australia. The smallest study had five participants, and the largest had 180 participants.

Main results

Intravenous AAT augmentation therapy versus placebo

• Intravenous AAT augmentation therapy may lead to a slight increase in the number of exacerbations people experience each year. The evidence shows a rate of 1710 yearly exacerbations for every 1000 people receiving intravenous AAT augmentation therapy, compared with 1420 yearly exacerbations for every 1000 people receiving placebo (290 more exacerbations in the AAT group).

• Intravenous AAT augmentation therapy may have little or no effect on the number of people who die compared with placebo.

• We do not know whether people who receive intravenous AAT augmentation therapy are any more likely to have one or more serious unwanted events than those who receive placebo.

Inhaled AAT augmentation therapy versus placebo

• We do not know whether inhaled AAT augmentation therapy has any effect on the number of exacerbations people experience each year compared with placebo.

• No studies reported deaths.

• Inhaled AAT augmentation therapy may make little or no difference to the number of people who have one or more serious unwanted events compared with placebo.

What are the limitations of the evidence?

We have little confidence in the evidence because few studies were available, the studies we found included few participants, and the results only covered some of the people we were interested in.

How up to date is this evidence?

We included evidence published up to August 2025.

Key messages

• Brain–computer interface (BCI) training may slightly improve arm movement, but may make little to no difference to leg movement. We are very uncertain whether it helps with everyday activities.

• Compared with a 'sham' (fake) BCI, BCI training may make little to no difference to movement or everyday activities.

• Larger, well-designed studies are needed to confirm the true benefits and harms of BCI training.

What is a brain-computer interface (BCI)?

A brain–computer interface (BCI) is a technology that creates a direct link between the brain and an external device. It usually uses sensors placed on the scalp to detect brain signals when a person imagines or attempts a movement.

How is BCI used after stroke?

After a stroke, people often experience muscle weakness or loss of movement. BCI training reads the brain signals produced when a person intends to move, and turns them into real-time feedback. For example, when the patient thinks about moving their hand, the BCI detects this and triggers a robotic glove to move their hand, or delivers electrical stimulation to the muscles. This feedback happens at the same moment as the person's effort, which is thought to help "rewire" the brain and promote recovery of movement.

What did we want to find out?

We wanted to find out whether BCI training is better than conventional therapy, other active treatments, or a sham (fake) BCI at improving arm and leg movement, and the ability to carry out everyday activities in people with stroke. We also wanted to find out if BCI training is linked to any unwanted effects.

What did we do?

We searched for studies looking at the effects of BCI training in adults who had had a stroke and had difficulty moving as a result. The people in these studies had had either type of stroke (one caused by a blocked blood vessel or one caused by bleeding in the brain), and most were in the months following their stroke, once their condition had stabilised. We then compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as the methods used and the number of people studied.

What did we find?

We found 43 studies involving 1628 adults who had had a stroke. Here is what the evidence suggests:

• When BCI training was compared with conventional therapy, it may give arm movement a small boost (10 studies, 611 people), but may make little to no difference to leg movement (1 study, 64 people). We cannot tell whether it helps with everyday activities (5 studies, 282 people), as the evidence is very uncertain.

• When compared with other active treatments, BCI training may give balance a small boost (6 studies, 165 people), but may make little to no difference to leg movement (4 studies, 130 people). For arm movement (14 studies, 331 people) and everyday activities (5 studies, 163 people), we are not confident enough to say either way.

• When it was compared with a fake or 'sham' BCI, which looks and feels like the real thing but does not give genuine brain-signal feedback, BCI training did not seem to make much difference to arm (9 studies, 279 people) or leg movement (3 studies, 106 people), or to everyday activities (1 study, 28 people).

We also looked at a few other things, such as muscle tightness, muscle strength, and overall recovery of the nervous system. The evidence on these was too uncertain for us to draw conclusions.

We also wanted to know about unwanted effects, but many studies simply did not mention them. In the studies that did, the effects were usually mild, such as sore muscles or feeling tired. Because so few studies reported this properly, we cannot be sure whether BCI training carries any extra risk.

What are the limitations of this evidence?

We have little to very little confidence in the evidence, for several reasons:

• Most of the studies were small and involved only a few people.

• Many were carried out in ways that could have influenced their results. For example, the people taking part often knew which treatment they were receiving.

• The findings also varied widely from one study to another.

• Finally, some studies that found no benefit may not have been published, which could make BCI training appear more helpful than it really is.

How up to date is this evidence?

The evidence is up to date to October 2025.

Key messages

• Only one study looked at whether giving medicines that stimulate breathing, like caffeine, to babies born a few weeks early can help prevent or reduce problems with low oxygen levels or breathing. This means that we have very little evidence about their use.

• Caffeine may help reduce the number of times late preterm babies have low oxygen levels, but we do not know if it reduces the need for breathing (respiratory) support (such as ventilators); and we are not sure if caffeine causes unwanted effects.

• More research is needed to know if medicines that stimulate breathing are helpful and safe for babies born a few weeks early. We found some studies that will be published soon that will help to update the evidence.

How old are late preterm babies?

Babies born a few weeks early, between 34 and 36 weeks of pregnancy, are called ‘late preterm’. These babies are not as fully developed as babies born at full term (after 37 weeks, or 8.5 months), and their lungs and other organs may be weaker.

What is intermittent hypoxemia?

Sometimes, a person's oxygen levels can drop for short periods of time (a condition called intermittent hypoxia). When this happens, it is difficult to breathe. Breathing difficulties can cause long-term problems by damaging the brain.

What are methylxanthines?

Methylxanthines are medicines which make breathing easier by relaxing the muscles we use to breathe. Caffeine is the most commonly used type of methylxanthine because it has fewer unwanted effects than other types.

What did we want to find out?

Although methylxanthines like caffeine are often used, successfully, to treat breathing problems in very early (premature) babies (born before 32 weeks of pregnancy), they are used less often in late preterm babies, and it is not clear if this treatment can help them. We wanted to know if methylxanthines are better than no treatment or a dummy treatment (placebo) for preventing or treating problems with low oxygen levels or breathing in late preterm babies. We also wanted to know if these medicines cause any unwanted effects.

What did we do?

We searched for studies that compared methylxanthines with placebo or no treatment in late preterm babies. We looked for studies that measured:

• how often babies had low oxygen levels;

• whether they needed help to breathe;

• how long they stayed in the hospital;

• if the treatment had any unwanted effects;

• if the babies survived until leaving the hospital.

We looked at the results of the only study we found. We summarized the results, and rated our confidence in the evidence based on factors such as the number of babies in the study (study size), and methods used when conducting the study.

What did we find?

We found one study from New Zealand with 132 late preterm babies. The study compared different doses of caffeine with a placebo and had the following results.

• Caffeine may reduce the number of times babies have low oxygen levels over one week from starting treatment.

• It is not clear if caffeine helps with other problems, like needing help to breathe, or improves the chances of being able to leave hospital earlier or surviving until leaving the hospital.

• It is not clear if caffeine causes unwanted effects.

• The study did not report on other important outcomes, like long-term development or the number of times a baby stopped breathing (apnea).

We found no studies that looked at using methylxanthines to treat, rather than prevent, breathing problems in these babies.

What are the limitations of the evidence?

The biggest limitation is that we only found one study. This means we cannot be sure about the results. The study did not report on all the outcomes we wanted to know about, and some results were not clear. Our confidence in these findings is very low because they are based on only one small study, and we had some concerns about how the study was carried out and reported. Future research may change these results.

How up to date is this evidence?

The evidence is current to December 2025. There are five studies in progress and when they are complete, their results may help us better understand if methylxanthines are helpful and safe for late preterm babies.

What are the long-term benefits and risks of different types of weight loss surgery (also called metabolic and bariatric surgery) to treat obesity and type 2 diabetes in adults?Key messages

• In people with obesity and type 2 diabetes, gastric (stomach) bypass (i.e. Roux-en-Y gastric bypass and one-anastomosis gastric bypass) may be most beneficial for improving body weight, waist circumference, type 2 diabetes status and long-term blood sugar levels at least five years after surgery, but for one-anastomosis gastric bypass, we are very uncertain about the results.

• It is unclear whether the different surgical procedures have an effect on risks such as serious unwanted health effects and death from any cause at least five years after surgery.

• Larger and well-designed studies may help reduce the existing uncertainties and increase our confidence in the findings.

What are obesity and type 2 diabetes?
Obesity is a condition with too many fat deposits that can damage health. In type 2 diabetes, the body has difficulty controlling blood sugar levels because the hormone insulin does not work properly. Type 2 diabetes often occurs in people with obesity, and both conditions increase the risk of premature death and other health problems, such as cardiovascular disease.

How are obesity and type 2 diabetes treated?

Lifestyle interventions such as nutrition, exercise, and behavioural programmes, along with medicines, are often used first for weight loss and improvement of diabetes status. When these do not work well, metabolic and bariatric surgery may be considered as an additional treatment option. There are a number of different types of bariatric surgery:

• gastric (stomach) banding;

• gastric sleeve (removal of a part of the stomach);

• Roux-en-Y gastric bypass (RYGB);

• one-anastomosis gastric bypass, or mini-gastric bypass;

• gastric plication (folding to make the stomach smaller);

• biliopancreatic diversion with duodenal switch.

What did we want to find out?

• Which of the different types of surgery are the safest and most beneficial ones by comparing them with each other and with lifestyle and medication therapy regarding their long-term (at least 5 years follow-up) benefits and risks.

• Whether these surgical procedures improve body weight, waist circumference, type 2 diabetes status, long-term blood sugar levels, and quality of life at least five years after surgery.

• Whether surgery affects serious unwanted health effects, death from any cause, and type 2 diabetes complications over this period.

What did we do?
We searched for studies involving people with obesity and type 2 diabetes. We included studies that compared at least two different surgical procedures, or surgery with lifestyle and medication treatment. We summarised and compared all treatments using a method called network meta-analysis, and we rated our confidence in the results based on factors such as study methods and sample size.

What did we find?
We found 18 studies, including 15,282 people with obesity and type 2 diabetes. In 13 of these studies (including 911 people), participants were assigned randomly to two or more treatment groups. This is the best way to ensure that groups of people are similar. Five studies (with 14,371 people) used ‘real-life’ observational data. The studies investigated surgical procedures such as gastric band, gastric sleeve, Roux-en-Y gastric bypass, one-anastomosis gastric bypass, and gastric plication. We found that:

• Roux-en-Y gastric bypass, may improve body weight and likely reduce waist circumference compared with lifestyle and medication treatment in the long term.

• One-anastomosis gastric bypass and, to a lesser extent, gastric sleeve, may also improve body weight and waist circumference, but we are very uncertain about the results.

• Roux-en-Y gastric bypass, one-anastomosis gastric bypass, gastric sleeve, and gastric band may improve type 2 diabetes status, but we are very uncertain about the results.

• It is unclear whether the types of surgery have an effect on serious unwanted health effects or death from any cause.

• Roux-en-Y gastric bypass may reduce type 2 diabetes complications in the long term compared to non-surgical treatments, but we are very uncertain about the results.

• Roux-en-Y gastric bypass may improve blood sugar levels compared to non-surgical treatments.

• One-anastomosis gastric bypass and gastric sleeve may also improve blood sugar levels, but we are very uncertain about the results.

• RYGB and SG may lead to a greater increase in health-related quality of life than non-surgical treatments, but again, we are very uncertain about the results.

What are the limitations of the evidence?
Our confidence in the evidence is often low to very low because the studies included only small numbers of people, and the results for some outcomes, especially serious unwanted health effects, death from any cause, and type 2 diabetes complications, were based on very few events. Moreover, for several surgical procedures, there were not enough studies to be certain about the outcomes. It is important to note that rating our confidence in findings was based only on studies in which participants were randomly assigned to groups and did not include observational studies.

How up to date is this evidence?
This evidence is up to date as of June 2024.

Key messages

• Any type of physical activity may slightly reduce body weight, waist size, and body fat percentage in adolescents with obesity, compared to no physical activity.

• We do not know if physical activity has an effect on other measures of weight, body size, or health problems due to obesity, compared to no physical activity.

• We need larger, longer-lasting, and better-quality studies to be more certain about the effects of physical activity on adolescents with obesity.

What is obesity?

Obesity is when a person has too much body fat, which can harm their health. Worldwide, obesity amongst adolescents (aged 10 to 19 years) has tripled since 1990, and more than 300 million children and adolescents may be living with obesity by 2050.

Obesity during childhood and adolescence can negatively affect physical and mental health, and may increase the risk of having cancer, liver disease, or kidney disease in adulthood.

Weight loss is the best way to reduce the health risks caused by obesity. This is usually done through lifestyle changes such as doing more physical activity (e.g. swimming, running, weight-lifting) and eating healthier foods, or with surgery or medication.

What did we want to find out?

We wanted to find out if, compared to no physical activity, physical activity helps adolescents with obesity:

• lose weight and reduce their BMI (the 'body mass index' is used to check if someone is a healthy weight; their weight is divided by their height multiplied by itself), BMI z-score (how someone's BMI compares to BMIs of others of the same age and sex), waist size, and body fat percentage;

• lower their blood sugar levels and insulin resistance (insulin is a hormone that helps to control blood sugar levels).

We also wanted to find out if one type of physical activity was better than another type at producing these effects, and if the physical activity programmes led to any unwanted, harmful events.

What did we do?

We searched for studies that compared participating in physical activity (such as doing aerobic exercise, weight-lifting, or playing football) to:

• no physical activity;

• another type of physical activity (for example, high-intensity exercise compared to moderate-intensity exercise).

The adolescents needed to do the physical activities for at least 12 weeks. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and number of participants.

What did we find?

We found 30 studies including 1508 adolescents. The studies were small: the smallest included only 21 adolescents and the largest, 106. Just under half of the adolescents involved were female (46%). Their average age ranged from 10 years to nearly 17 years. The studies took place in 15 countries: 5 in Tunisia; 4 each in China and Iran; 3 in Brazil; 2 each in Canada, Spain, and the USA; and 1 each in Australia, Estonia, India, Mexico, South Korea, Sweden, Taiwan, and Thailand.

Most studies lasted 12 or 13 weeks; the longest study lasted 32 weeks.

We organised the studies' results into two broad comparisons:

• any type of physical activity (e.g. aerobic exercise, active video-gaming) compared to no physical activity (22 studies);

• one type of physical activity compared to another type (17 studies).

Main resultsPhysical activity versus no physical activity

Compared to no physical activity, any type of physical activity may slightly reduce:

• body weight: adolescents in the active groups weighed on average 1.88 kg less (17 studies, 749 adolescents);

• waist size: in the active groups, adolescents' average waist size was 2.88 cm smaller (10 studies, 476 adolescents);

• body fat percentage: in the active groups, adolescents' average body fat percentage was 2.96% lower (9 studies, 313 adolescents).

We are very uncertain about the effect of any type of physical activity on:

• BMI;

• BMI z-score;

• blood sugar levels;

• insulin resistance;

• unwanted, harmful events.

One type of physical activity versus another type

We are very uncertain about the effect of one type of physical activity compared with another on any of the points we were interested in.

What are the limitations of the evidence?

We have limited confidence in the evidence because:

• the studies were small;

• the types of physical activities varied;

• the studies' reporting of their methods and findings was poor;

• some studies did not report all their results;

• no studies reported on unwanted, harmful events.

The studies comparing two different types of physical activity were quite varied, which meant we were mostly unable to combine their results to produce strong evidence. Therefore, we do not know whether one type of physical activity is better than another.

How up to date is this evidence?

This evidence is current to December 2025.

Key messages

• This updated review assessed special solutions (culture media) that are important for helping embryos develop in assisted reproduction technology (ART) treatments used for women who cannot get pregnant naturally. Currently, we do not know which culture medium gives the best chance of giving birth to a live baby. One study showed that an embryo culture medium called G5 probably leads to more live births than one called HTF, but the other studies did not show clear differences in success rates between different culture media.

• The evidence is limited because the studies tested different culture media and their results could not be combined. Many studies had weaknesses, such as small numbers of people taking part. More, well-designed studies are needed to find out which embryo culture medium works best.

What is an embryo culture medium?

A woman who cannot get pregnant naturally may use assisted reproductive technology (ART) treatments, such as IVF (in vitro fertilization), in which eggs are fertilized by sperm outside the body. Supporting the embryo this creates to develop (culture) is a very important part of IVF treatment. The embryo is placed in a special solution called an embryo culture medium. This medium provides nutrients and helps the embryo grow in the laboratory until it is transferred to the womb (uterus) or frozen for later use. There are many different embryo culture media.

Why is there no agreement about which culture medium works best?

There is currently no clear agreement on which type of embryo culture medium gives the best chances of having a live baby. The available research does not give enough reliable information to clearly choose one culture medium over another. This makes it difficult for doctors and patients to know which option to use.

What did we want to find out?

We wanted to know whether different types of human embryo culture media affect the chances of having a baby or an ongoing pregnancy (pregnancy confirmed by heartbeat on ultrasound) for women undergoing IVF treatments.

What did we do?

We searched for studies that compared different embryo culture media available for use during IVF treatments. We looked at the results of studies for all the measurements we think are important. We considered the reliability of each study based on how it was designed and conducted. We made a judgement about how certain we were about the evidence for each important measure.

What did we find?

We found 26 relevant studies, eight of which evaluated the most important measures, such as live birth or ongoing pregnancy. Another five studies are in progress, and there are 60 studies that we have not been able to include because they are only published as short summaries without enough information. It was not possible to combine any of the studies' results because no two studies compared the same culture media.

Main results

Eight studies (3315 women) of the 26 studies included in the review reported live birth or ongoing pregnancy.

Most studies did not find a clear difference between the culture media they compared. However, the two largest studies did find some differences that could be important.

One study showed that there was probably a 6% higher chance of having a live birth with G5 compared to HTF (836 women). Another study showed that there may be a 6% higher chance of having a live birth with EmbryoAssist plus GM-CSF (with low HSA (a low concentration of a protein in the blood called albumin)) compared to a version of EmbyroAssist without the GM-CSF (743 women), but we are very uncertain about this result, especially because the treatment was changed during the study.

The same studies found differences in ongoing pregnancy rates. One suggested that G5 probably increases the chance of ongoing pregnancy compared with HTF (836 women). The other suggested that EmbryoAssist plus GM-CSF (low HSA) may increase the chance of ongoing pregnancy compared with EmbryoAssist without GM-CSF (743 women), but we are very uncertain about this result.

The evidence is very limited and unclear, and we could not combine results from different studies. Further well-designed studies are needed to confirm the findings and determine if any specific culture medium improves treatment success.

What are the limitations of the evidence?

• Many studies included only a small number of women.

• Some studies had problems with how they were designed.

• A few studies assigned eggs or embryos (rather than women) to the groups being compared, or transferred embryos from different study groups to the same woman.

• Most studies did not clearly describe the ingredients in the culture media.

• Many studies did not report all important measures.

Overall, the evidence was mostly very uncertain because:

• the studies could not be combined with each other;

• the studies' results were not precise; and

• the studies' results were not always worked out in the right way.

How up to date is the evidence?

This review updates one published in 2015. The evidence is current to 28 August 2025.

Key messages

• Given as maintenance treatment (long-term treatment to keep symptoms under control) in people with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), subcutaneous immunoglobulin (SCIg) compared to placebo (dummy treatment) probably reduces the number of people who experience a worsening in disability. In addition, the average loss of grip strength and average worsening in disability score are probably lower among people receiving SCIg maintenance treatment compared with those receiving placebo. There is probably a higher risk of local side effects (affecting the injection site), but no difference in systemic side effects (affecting other parts of the body), in people treated with SCIg compared to those treated with placebo.
• We need more and better studies to investigate the benefits of SCIg given as induction treatment (short-term therapy) or maintenance treatment. In particular, there is a need for studies comparing SCIg maintenance treatment with other medicines, such as intravenous immunoglobulin (antibodies given through a vein).

What is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)?

CIDP is a rare disorder of the nerves that leads to gradually progressive sensory symptoms and weakness in arms and legs. CIDP is a disorder in which the body's own immune system presumably attacks the nerves (an autoimmune disease). If left untreated, people with CIDP can become severely disabled.

How is CIDP treated?

Treatment for CIDP can be divided into short-term (induction) treatment and long-term (maintenance) treatment. Most people with CIDP will require long-term treatment. The aim of induction treatment is to improve disability, whereas the goal of maintenance treatment is to keep the condition stable and prevent disability from worsening. One of the preferred treatments for both induction and maintenance treatment is intravenous immunoglobulins (IVIg). This treatment consists of purified antibodies collected from donated blood and given through a drip into a vein. Immunoglobulins can also be given by injection directly under the skin (subcutaneously). Unlike IVIg, subcutaneous immunoglobulin (SCIg) treatment does not require hospitalisation or an intravenous line.

What did we want to find out?

We wanted to know if SCIg induction treatment is better for increasing the probability of an improvement in disability, and if SCIg maintenance treatment is better for reducing the risk of worsening in disability, compared with placebo (dummy treatment) or other treatments (such as IVIg). We also wanted to know if SCIg treatment is better than placebo or other treatments for improving change in grip strength and change in disability score, and whether SCIg treatment has any side effects.

What did we do?

We searched for studies that evaluated SCIg as induction treatment or maintenance treatment compared with placebo or other treatments. We compared and summarised the results of the studies for both the induction and maintenance treatment groups, and rated our confidence in the evidence.

What did we find?

We found four studies that involved 360 people with CIDP. Most participants were men (62%), and the average age was 55 years. The studies involved people from all over the world. The smallest study involved 20 people and the largest 172. One study compared SCIg to IVIg as induction treatment. The other three compared SCIg with placebo as maintenance treatment. Studies lasted from 10 weeks to 26 weeks. All studies were partly or entirely funded by pharmaceutical companies.

Main results

We found no studies comparing SCIg to placebo as induction treatment.

The study comparing SCIg to IVIg provided very few data. There may be no difference in change in disability score after five weeks in people who receive SCIg induction treatment and those who receive IVIg induction treatment.

Compared with placebo, SCIg maintenance treatment probably reduces the number of people who experience a worsening in disability. In addition, the average loss of grip strength and average worsening in disability score are probably lower in people receiving SCIg maintenance treatment compared with those receiving placebo. SCIg maintenance treatment probably leads to more local side effects (affecting the injection site) than placebo treatment. There is probably no difference in systemic side effects (affecting other parts of the body) with SCIg maintenance treatment compared to placebo. Side effects were mostly mild in the studies, but some were more serious.

We found no studies comparing SCIg maintenance treatment to other treatments.

What are the limitations of the evidence?

In the induction treatment group, we have little confidence in the evidence because the study enroled few participants, and they were aware of the treatment they received. In the maintenance treatment group, we are only moderately confident in the evidence, because the number of included participants was relatively small.

How up to date is this evidence?

The evidence is up-to-date to July 2025.

Key messages

• Some immune-checkpoint inhibitor combinations help people with extensive-stage SCLC live longer than standard chemotherapy alone.

• Not all combinations of immunotherapy are equally effective or safe.

• More research is needed on quality of life and long-term treatment effects, and several immune-checkpoint inhibitor combinations are now important first-line treatment options.

This summary is written for people living with extensive-stage small cell lung cancer (SCLC), their families, caregivers, and anyone looking for clear and accessible information about treatment options.

What is extensive-stage small cell lung cancer (extensive-stage SCLC)?

SCLC is a fast-growing type of lung cancer. It is usually divided into two stages: limited and extensive. In extensive-stage disease, cancer has already spread widely in the lungs or to other parts of the body. Most people with extensive-stage SCLC are treated with a combination of chemotherapy drugs, usually platinum and etoposide, often referred to as 'PE chemotherapy'. But cancer often comes back quickly.

Immune-checkpoint inhibitors are a type of cancer treatment that helps the immune system recognise and attack cancer cells. They work differently from chemotherapy and have become important in treating several types of cancer.

What did we want to find out?

We wanted to find out whether combining immune-checkpoint inhibitors with standard chemotherapy improves survival and other outcomes for people with extensive-stage SCLC. We also wanted to know how safe these treatments are and whether they affect quality of life.

What did we do?

We looked for high-quality studies that compared different immune-checkpoint inhibitor treatments with chemotherapy alone in people with extensive-stage SCLC. We combined the results using a method called network meta-analysis (NMA). This method lets us compare many treatments at the same time, even when some treatments were not directly compared in the same study. NMA works by linking results across different trials. For example, if Study 1 compared Treatment A with Treatment B, and Study 2 compared Treatment B with Treatment C, we can estimate how Treatment A might compare with Treatment C — even though they were never tested against each other. This approach helps build a more complete picture of how all treatments compare overall and which options may be more helpful.

What did we find?

We found 14 studies, with 7541 people contributing data on overall survival, the main outcome of interest. Most of the studies tested whether adding immune-checkpoint inhibitors to platinum-etoposide chemotherapy could improve outcomes.

• Among the evaluated regimens, we found the lowest estimated risk of death with platinum-etoposide chemotherapy combined with benmelstobart plus anlotinib or serplulimab, and we also found improvements in survival with durvalumab or adebrelimab.

• Other combinations, such as those including ipilimumab, probably do not improve survival and may increase side effects. Some treatments, including serplulimab or certain combination immunotherapies, were also linked with more side effects than standard chemotherapy.

• For progression-free survival (the time before the cancer gets worse), some treatments delayed cancer worsening, but these effects did not always match improvements in overall survival.

• Only a few treatments improved response rates (shrinking or eliminating tumours), and this did not always match the improvements in survival.

• There was not enough useful information about quality of life to help people and clinicians make informed decisions.

What are the limitations of the evidence?

Some studies included only a small number of people or were conducted in limited regions, which may affect how well the results apply to everyone. Also, not all studies reported results in the same manner. Few studies reported on patient experiences or long-term effects. Because few studies directly compared different immune-checkpoint inhibitor combinations with each other, we need more head-to-head trials to be certain about which treatments work best. People may wish to discuss with their healthcare team how these results apply to their own situation, including side effects, expected benefits, and how treatment may affect day-to-day quality of life.

How up to date is this evidence?

This review includes evidence available up to December 2025.

Review question

We aimed to find out if it is effective and safe to stop antidepressants for people with depression or anxiety who have been taking them for six months or longer.

We compared different approaches for stopping long-term antidepressants versus continuation. We looked at benefits (e.g. successful discontinuation rate) and harms, such as return of the depressive or anxiety episode (relapse), side effects, and withdrawal symptoms (i.e. symptoms people experience when stopping an antidepressant).

Background

Antidepressants are widely used for depression and anxiety. Guidelines recommend that an antidepressant should be continued for at least six months after people start to feel better, and for at least two years if they have had two or more periods of depression. Many people take antidepressants for much longer, and as they can cause unpleasant side effects, long-term use puts people at risk of harm that may outweigh the benefits.

Study characteristics

Our search up until January 2020 found 33 studies, which included 4995 adult participants. Most people in these studies had recurrent depression (two or more episodes of depression before stopping antidepressants), and most were recruited from specialist mental healthcare services. In 13 studies, the antidepressant was stopped abruptly; in 18 studies, the antidepressant was stopped gradually over several weeks ("tapering"); in four studies, psychological therapy support was also offered; and in one study, stopping was prompted by a letter to the GP with guidance on tapering. Most tapering schemes lasted four weeks or less.

Key results

We found very low-certainty evidence suggesting that abrupt stopping may lead to higher risk of relapse and there was insufficient evidence of its effect on occurrence of side effects compared to continuation of the antidepressant.

We found very low-certainty evidence suggesting that "tapering" over a few weeks may lead to higher risk of a return and again may have little or no effect on side effects compared to continuation.

We found evidence of very low to low certainty to suggest that stopping the antidepressant in combination with providing preventive cognitive therapy (PCT), or MBCT, was possible for 40% to 75% of participants in the group tapering the antidepressant and may show no difference in effects on relapse.

We found low-certainty evidence suggesting that a prompt letter and guidance on tapering sent to the GP may have no effect on the number of people who stop their antidepressant.

We were unable to draw conclusions about withdrawal symptoms after abrupt or gradual stopping of an antidepressant, as this generally was not assessed.

None of the studies used very slow tapering schemes beyond a few weeks, tapered liquid forms of antidepressants, or used tapering strips (to allow tapering with very low doses).

None of the identified studies investigated stopping combined with providing supportive therapy such as online support or self-help therapy.

Certainty of evidence

Overall, the certainty of evidence was low to very low. This means we have limited or little confidence in the results, and new research is likely to change our conclusions. The main reasons for this assessment of evidence certainty were that trials did not distinguish between symptoms of relapse of depression and symptoms of withdrawal. Also, most studies used no tapering or very "rapid" tapering schedules (four weeks or less), and nearly all studies included people with recurrent depression (more than two episodes).

Conclusions

We found few studies that examined stopping long-term antidepressants. We are uncertain if the approaches for stopping long-term antidepressants studied to date are effective and safe in people with recurrent depression. People should discuss with their doctor when they want to stop their antidepressant.

Future studies should include people in primary care with only one or no earlier episodes of depression, older people, and people taking antidepressants for anxiety. Studies should taper antidepressants slowly while taking care to distinguish withdrawal symptoms from relapse.

Key messages

- Using balloons that coat the inside of blood vessels with medicines (drug-eluting) to treat peripheral arterial disease led to better results in terms of whether a person received more than one treatment for the same artery during the study (target lesion revascularization), whether a treated artery became narrowed again (binary restenosis), and the difference in millimeters between the treated segment and how narrow it was on follow-up (late lumen loss).

- There was no difference between drug-eluting balloons and uncoated, plain balloon angioplasty in amputation, amputation-free survival, death, change in a way of measuring disease severity (the ankle-brachial index), quality of life scores, or walking ability.

What is peripheral arterial disease of the lower legs, and what are drug-eluting balloons?

Peripheral arterial disease of the lower legs is a condition where blood supply to the lower legs is not as good as it should be because of blockages in the blood vessels (tubes that carry blood around the body). It affects many people. In its most serious form, it can lead to pain, infections, and amputation due to poor blood flow. People with peripheral arterial disease are usually first treated with medicines and habit changes, including strategies to stop smoking and a walking program to improve their general health, which in turn can improve their condition. However, medicines and habit changes do not work for all people, and some may need an operation. This operation can be traditional open surgery or a less invasive procedure known as angioplasty, which uses a balloon to open the blockages in the arteries. A new type of angioplasty, known as drug-eluting balloon angioplasty, is a promising alternative to traditional balloon angioplasty for treating peripheral arterial disease. Unlike traditional plain balloons, drug-eluting balloons also coat the inside of the blood vessels with medicines that are used to treat cancer (chemotherapy), such as paclitaxel, in hopes of stopping the worsening of peripheral arterial disease even after surgery and preventing or delaying its complications.

What did we want to find out?

The goal of this review was to find out how drug-eluting balloon angioplasty compares with plain balloon angioplasty for treating peripheral arterial disease of the lower legs.

What did we do?

We combined 31 studies (clinical trials) that randomly assigned 5292 participants having an angioplasty for peripheral arterial disease to either receive drug-eluting balloon angioplasty or plain balloon angioplasty. The studies included thigh and leg arteries above and below the knee. The studies were carried out in Europe, the USA, China, Singapore, Jordan, Japan, and New Zealand, and all used drug-eluting balloons with the drug paclitaxel. Participants were followed up for up to five years after surgery.

What did we find?

At up to five years, there were better results for drug-eluting balloons based on an indicator of whether a person received more than one treatment to the same artery during the period covered by the study (target lesion revascularization). At up to two years, there were also better results for binary restenosis, which happens when a treated artery becomes narrowed again after being previously treated. At up to six months, there were better results in terms of the difference in millimeters between the treated segment and how narrow it was on follow-up (late lumen loss). There was no evidence of a difference between drug-eluting balloon and uncoated angioplasty in amputation, amputation-free survival, death, change in the ankle-brachial index (a measure of disease severity), quality of life scores, or walking ability.

What are the limitations of the evidence?

There were differences in the way that participants were given anti-clotting medication to be taken by mouth after surgery. Other concerns included various studies reporting results for the same outcome that differed more than would be expected, and results that showed both an important difference as well as no difference between treatments. This meant that we had to lower our confidence in the evidence. Our confidence in the evidence was low for the outcome target lesion revascularization and moderate for amputation, binary restenosis, death, and change in the ankle-brachial index.

How up to date is this evidence?

This review updates our previous review from 2016. The evidence is up to date to March 2023.

Key messages

• Swallowing therapy may improve swallowing in stroke survivors following a recent stroke, but no one therapy is effective overall.

• Severity of swallowing problems is probably improved by electrical stimulation of the outside of the neck and brain, nerve stimulation and combined therapies. Acupuncture probably reduces swallowing problems at the end of the trial and increases swallowing safety; medication probably reduces chest infections; and electrical stimulation of the inside of the neck probably reduces the number of people needing a breathing tube at the end of the study.

• Future studies should be larger and of better quality.

Why do people who have had a stroke need swallowing therapy?

People who have had a stroke often have difficulty chewing and swallowing saliva, and food and drink (called 'dysphagia'). It can affect up to 80% of stroke survivors and can lead to:

• choking and chest infections, due to inhaling not swallowing saliva and food;

• malnutrition and weight loss, which might mean slower recovery;

• poor quality of life;

• long stays in hospital; and

• increased risk of death or being sent to a care home.

Many people's swallowing improves without treatment, but between 15% and 51% of people will still have problems swallowing around two weeks after their stroke.

What is swallowing therapy?

Swallowing therapy aims to speed up recovery of swallowing function and reduce the negative effects of swallowing problems on health and well-being.

There are many types of swallowing therapy; we looked at the following:

• acupuncture;

• swallowing exercises;

• medication;

• stimulating the neck with electrical pulses (NMES: outside; PES: inside), or the brain with electrical (tDCS) or magnetic pulses (TMS, TBS);

• physical stimulation with cold, sour flavours or fizzy drinks;

• nerve stimulation; and

• combinations of these therapies.

What did we want to find out?

We wanted to assess the effectiveness of swallowing therapies to improve swallowing in stroke survivors up to six months after their stroke. We were interested in:

• how bad (severity) their swallowing problems were after treatment;

• the number of people who had swallowing problems at the end of the trial;

• how safe their swallowing was;

• whether chest infections or pneumonia were reduced due to improved swallowing; and

• the number of people dependent on a breathing tube.

What did we do?

We searched for studies that investigated different swallowing therapies for adults with swallowing problems after a stroke. Studies had to compare a therapy with usual care, no treatment, or a placebo treatment (that is, an inactive treatment that seems like a real treatment). Usual care could be any treatments or combinations of treatments, but had to be the same for all the people in the studies.

We read the studies carefully and recorded what they found. We also judged how much we could trust the results by looking at how big the trials were and how well they were done.

What did we find?

We found 181 studies with 11,500 people.

• Severity of swallowing problems after treatment: acupuncture, swallowing exercises and medication may reduce swallowing problems but the evidence is very uncertain. Physical stimulation and magnetic brain stimulation (TBS, TMS) may reduce, and NMES, tDCS, nerve stimulation and combined therapies probably reduce swallowing problems. PES may make little to no difference.

• Number of people with swallowing problems at the end of treatment: acupuncture probably results, and physical stimulation and tDCS may result in fewer people with swallowing problems at the end of treatment. We are not sure about the effects of swallowing exercises and NMES. Medication may, and PES and combined therapies probably make little to no difference.

• Safety of swallowing: acupuncture and TMS probably improve, and swallowing exercises and PES may improve swallowing safety. TBS may improve swallowing safety, and NMES and tDCS may have little to no effect on swallowing safety, but the evidence is very uncertain.

• Chest infections or pneumonia: medications probably reduce, and acupuncture, swallowing exercises, PES and physical stimulation may reduce the number of chest infections or pneumonia. We are unsure about the effects of NMES. Combined therapies probably do not reduce the number of chest infections or pneumonia.

• Need for a breathing tube: PES probably reduces the number of people dependent on a breathing tube. We are very uncertain about the effects of swallowing exercises.

What are the limitations of the evidence?

Many of the studies were small and of poor quality. This makes it harder to trust the results. In the future, studies should use more reliable methods, and they should be larger so we can be more confident in the results. Many of the swallowing therapies involved different methods of delivery, so it is still not clear which approach is most effective for each type of therapy.

How up to date is this evidence?

The evidence is current to July 2025. This is an update of the review originally published in 1999 and updated in 2012 and 2018.

Key messages

• Any benefits in terms of pregnancy chances of full bladder, removing mucus from the cervix, or afterloading (loading the embryo into the catheter after it has been placed in the uterus) are unclear, and information on unwanted effects was rarely reported.

• Further larger and well-designed studies are needed to improve our confidence in the evidence on the effects of preparation techniques before embryo transfer.

What is in vitro fertilisation and embryo transfer?

In vitro fertilisation (IVF) is a type of fertility treatment. An egg is fertilised by sperm in a laboratory, and the resulting embryo is placed in the uterus (womb) to develop as normal. The embryo is transferred through a tube (catheter) that is inserted into the vagina and through the neck of the womb (cervix) into the uterus. This is the last step in the IVF process and is the most likely to go wrong. Only one-third of transfers result in pregnancy.

Clinicians use various techniques to improve the success of embryo transfer. For example, inserting the catheter may be easier if the woman has a full bladder, or if doctors clear away any mucus from the cervix. The type of catheter used, positioning the catheter first and then putting the embryo in the catheter (called ‘afterloading’), or carrying out a practice procedure may also help.

What did we want to find out?

We wanted to find out the effects of preparation techniques before embryo transfer on live birth rate, unwanted effects, pregnancy rate, pregnancy loss rate, and difficulty of transfer.

What did we do?

We searched for studies comparing preparation techniques before embryo transfer with no special preparation techniques in women with infertility having IVF. We compared and summarised the results of the studies and rated our confidence in the evidence using structured methods and standard tools, based on factors such as study methods and sizes.

What did we find?

We found 11 studies involving a total of 2524 women with infertility who were undergoing embryo transfer. The studies were conducted in Canada, the USA, Argentina, Brazil, Belgium, Greece, Italy, the Netherlands, Spain, the UK, Turkey, and Japan. Six of these studies looked at techniques including:

• adjusting bladder fullness;

• cleaning the mucus from the cervix; and

• afterloading.

Main resultsEmbryo transfer under a full bladder versus an empty bladder

We are very uncertain about the effect of a full bladder versus an empty bladder on pregnancy rate, pregnancy loss rate, and difficulty of transfer.

• Live birth rate: not reported

• Pregnancy rate (2 studies, 273 women)

• Pregnancy loss rate (1 study, 131 women)

• Difficulty of transfer (1 study, 142 women)

Removing mucus versus no mucus removal

• Live birth rate: one study reported 52 live births per 220 cycles in the mucus removal group and 42 live births per 205 cycles in the no-mucus removal group.

• Pregnancy rate: there may be little to no difference between groups in pregnancy rate (1 study, 97 women). A second study reported 65 pregnancies per 220 cycles in the mucus removal group and 63 pregnancies per 205 cycles in the no-mucus removal group.

• Pregnancy loss rate: one study reported 15/220 cycles in the mucus removal group and 20/205 cycles in the no-mucus removal group.

• Difficulty of transfer: not reported

Embryo afterloading versus direct embryo transfer

• Live birth rate: not reported

• Pregnancy rate: there may be little to no difference between groups in pregnancy rate (2 studies, 654 women).

• Pregnancy loss rate: there may be little to no difference between groups in pregnancy loss rate (1 study, 352 women).

• Difficulty of transfer: we are very uncertain about the effect of embryo afterloading versus direct embryo transfer on difficulty of transfer: one study reported that afterloading may reduce the difficulty of transfer (352 women), while a second study reported there was no difficulty of transfer for both groups.

What are the limitations of the evidence?

We have little to very low confidence in the evidence. The available research is limited, and most studies were small in size and old. This means we cannot be sure which, if any, of these individual preparation techniques (e.g. full bladder, mucus removal, afterloading) are effective or safe, so the findings should be interpreted with caution. More high-quality research is needed to find out whether any of these preparation techniques truly improve IVF outcomes and to better understand their possible unwanted effects.

How up to date is this evidence?

This review is an update of our previous review published in 2009, with literature searches conducted up to October 2025.

Key messages

• Based on three included studies, we found that checking more often might help people keep their blood sugar under better control over time, although the evidence is very uncertain.

• Future studies are needed looking at the best way for people with type 1 diabetes to check their blood sugar at home, including how often to check, when to check, and what target numbers to aim for, so they and their doctors have clear guidance.

• People wanting to know how often to check their blood sugar should talk to their healthcare provider, as the best choice may depend on the patient's specific needs.

What is type 1 diabetes?

Type 1 diabetes is a lifelong condition that occurs when the body can no longer make insulin. Insulin is a hormone that turns food into energy and manages the level of sugar in your blood. People with type 1 diabetes need to take insulin every day. Many also check their blood sugar regularly, which can help them decide on insulin doses and manage food, exercise, and daily activities more safely. People with type 1 diabetes typically check their blood sugar 4 to 10 times a day.

Guidelines offer different advice about how to check blood sugar. It remains unclear which approach works best, especially where test supplies or other resources are limited.

What did we want to find out?

We wanted to find out what kind of blood sugar checking works best for adults with type 1 diabetes in everyday life. This includes how many times a day people may need to check their blood sugar, what times of day checking is most useful, and what blood sugar range they should try to stay within. We also wanted to know whether different ways of checking blood sugar affect people’s health and daily well-being.

What did we do?

We looked for studies that compared different ways of checking blood sugar in adults aged 18 years and older with type 1 diabetes. This included how often people checked their blood sugar, what times of day they checked it, and the blood sugar levels they were trying to reach. We compared and summarised the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We found three studies involving 16,481 adults with type 1 diabetes. All three studies only looked at how often people checked their blood sugar. No studies provided evidence about the best times of day to check blood sugar or the best blood sugar targets to use.

• In one study (123 people), people who checked their blood sugar more carefully throughout the day may have had slightly lower blood sugar levels after nine months than those receiving usual care according to standard diabetes guidelines, but the evidence is very uncertain.

• In the other two studies (16,358 people), which followed people for up to two years, those who checked their blood sugar more often tended to have better blood sugar control. Those who checked most often had the lowest blood sugar levels. However, this evidence is very uncertain.

The studies we found all pointed in the same direction, suggesting a benefit with more frequent checking.

No study reported effects on:

• low blood sugar events;

• diabetic ketoacidosis, a life-threatening complication of diabetes that can occur when there is a lack of insulin;

• long-term diabetes complications; or

• quality of life

People who are considering how often to check their blood sugar should discuss this with their healthcare provider, as the best choice may depend on individual circumstances.

What are the limitations of the evidence?

We have very low confidence in the evidence. The studies were few, small, or had problems with their methods. Because of this, we still do not know how often adults with type 1 diabetes should check their blood sugar, the best times of day to check it, or what blood sugar levels they should aim for.

How up to date is this evidence?

The evidence is current to January 2026.

What are international travel-related control measures?

International travel control measures are methods to manage international travel to contain the spread of COVID-19. Measures include:

- closing international borders to stop travellers crossing from one country to another;

- restricting travel to and from certain countries, particularly those with high infection levels;

- screening or testing travellers entering or leaving a country if they have symptoms or have been in contact with an infected person;

- quarantining newly-arrived travellers from another country, that is, requiring travellers to stay at home or in a specific place for a certain time.

What did we want to find out?

We wanted to find out how effective international travel-related control measures are in containing the COVID-19 pandemic.

What we did

We searched for studies on the effects of these measures on the spread of COVID-19. Studies had to report how many cases these measures prevented or detected, or whether they changed the course of the pandemic. The studies could include people of any age, anywhere. They could be of any design including those that used ‘real-life’ data (observational studies) or hypothetical data from computer-generated simulations (modelling studies).

This is the first update of our review. This update includes only studies on COVID-19, published up to 13 November 2020.

What we found

We found 62 studies. Most (49 studies) were modelling studies; only 13 used real-life data (observational studies). Studies took place across the world and at different times during the pandemic. Levels of COVID-19 within countries varied.

Most studies compared current travel-related control measures with no travel-related controls. However, some modelling studies also compared current measures against possible measures, for example, to see what might happen if controls were more or less relaxed or were combined with other measures.

Main results

Below we summarise the findings of some outcomes.

Travel restrictions reducing or stopping cross-border travel (31 modelling studies)

Most studies showed that travel restrictions reducing or stopping cross-border travel were beneficial, but this beneficial effect ranged from small to large. Additionally, some studies found no effect. Studies also predicted that these restrictions would delay the outbreak, but the delay ranged from one day to 85 days in different studies.

Screening at borders (13 modelling studies and 13 observational studies)

These studies assessed screening at borders, including screening people with symptoms or who had potentially been exposed to COVID-19, or testing people, before or after they travelled.

For screening based on symptoms or potential exposure to COVID-19, modelling studies found that screening reduced imported or exported cases and delayed outbreaks. Modelling studies predicted that 1% to 53% of cases would be detected. Observational studies reported a wide range of cases detected, from 0% to 100%, with the majority of studies reporting less than 54% of cases detected.

For screening based on testing, studies reported that testing travellers reduced imported or exported cases, and cases detected. Observational studies reported that the proportion of cases detected varied from 58% to 90%. This variation might be due to the timing of testing.

Quarantine (12 modelling studies)

All studies suggested that quarantine may be beneficial, but the size of this effect ranged from small to large in the different studies. Modelling studies, for example, predicted that quarantine could lead to between 450 and over 64,000 fewer cases in the community. Differences in effects may depend on how long people were quarantined for and how well they followed the rules.

Quarantine and screening at borders (7 modelling studies and 4 observational studies)

For quarantine and screening at borders, most studies suggested some benefit, however the size of this effect differed between studies. For example, observational studies reported that between 68% and 92% of cases would be detected. Differences in effects may depend on how long people were quarantined for and how often they were tested while in quarantine.

How reliable are these results?

Our confidence in these results is limited. Most studies were based on mathematical predictions (modelling), so we lack real-life evidence. Further, we were not confident that models used correct assumptions, so our confidence in the evidence on travel restrictions and quarantine, in particular, is very low. Some studies were published quickly online as ‘preprints’. Preprints do not undergo the normal rigorous checks of published studies, so we are not certain how reliable they are. Also, the studies were very different from each other and their results varied according to the specification of each travel measure (e.g. the type of screening approach), how it was put into practice and enforced, the amount of cross-border travel, levels of community transmission and other types of national measures to control the pandemic.

What this means

Overall, international travel-related control measures may help to limit the spread of COVID-19 across national borders. Restricting cross-border travel can be a helpful measure. Screening travellers only for symptoms at borders is likely to miss many cases; testing may be more effective but may also miss cases if only performed upon arrival. Quarantine that lasts at least 10 days can prevent travellers spreading COVID-19 and may be more effective if combined with another measure such as testing, especially if people follow the rules.

Future research needs to be better reported. More studies should focus on real-life evidence, and should assess potential benefits and risks of travel-related control measures to individuals and society as a whole.

Key messages

• Antifibrinolytics help prevent bleeding by stopping blood clots from breaking down too quickly. Tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) are two antifibrinolytic medications.

• Compared to placebo (an inactive 'dummy' medicine), TXA probably makes little or no difference to the number of people with thrombocytopenia and blood disorders who experience moderate or worse than moderate bleeding. It may make little or no difference to the number who experience severe, life-threatening bleeding, or dangerous blood clots in the blood vessels (thromboembolism).

• We do not know if EACA helps because there was a lack of data.

What are haematological disorders?

Haematological (i.e. blood) disorders are conditions that affect the blood and blood-forming organs (such as bone marrow). They disrupt the blood's normal functions of oxygen transport, clotting, and immunity. Some of these blood disorders are not cancer and may cause problems like anaemia or sickle cell anaemia. Others are cancers of the blood, such as leukaemia, lymphoma, and myeloma.

How are haematological disorders treated?

People with haematological (blood) cancers and other blood disorders are frequently at risk of severe or life-threatening bleeding from having low platelet counts (thrombocytopenia). When the number of platelets in the blood is low, the blood does not clot as it should, so people may bruise or bleed more easily. This may be from bone marrow failure due to an underlying blood disorder, but also from the toxic effect of treatment (chemotherapy) on the bone marrow.

People with low platelets may be given platelet transfusions: that is, receive platelets from donated blood to help prevent bleeding. These transfusions carry risks, ranging from mild reactions such as fevers, to more serious or even life-threatening consequences. These include infections transmitted to the patient from the transfused platelets, despite stringent attempts to prevent this.

What did we want to find out?

Clearly, ways to safely prevent bleeding in people with thrombocytopenia whilst also minimising exposure to transfused platelets would be welcome. One possible way of achieving these goals is the use of antifibrinolytics (also known as lysine analogues): tranexamic acid (TXA) and epsilon aminocaproic acid (EACA).

These medications help to stabilise the clots that form after bleeding, therefore reducing the chances of further bleeding as well as the need for transfusing platelets. There may be risks associated with the use of TXA and EACA: the most important is the increased risk of forming unwanted blood clots (such as deep vein thrombosis (DVT)), which could be potentially life-threatening.

We wanted to find out if TXA and EACA are better than placebo (an inactive 'dummy' medicine) or no medication at reducing the number of people who:

• experienced moderate bleeding or worse;

• experienced severe or life-threatening bleeding;

• experienced any type of thromboembolism (dangerous blood clots);

• died.

We also wanted to find out if TXA or EACA caused any serious unwanted, harmful effects.

What did we do?

We searched for studies that compared TXA or EACA with placebo or no treatment in people with haematological (blood) disorders who have a low platelet count and would usually be treated with platelet transfusions. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and the number of participants involved.

What did we find?

We found eight studies with a total of 1041 participants. Six studies compared TXA to placebo, one compared EACA to no EACA, and one compared EACA to standard platelet transfusion. Seven studies were in adults and one was in children. Five studies were funded by governments, universities, or other non-pharmaceutical organisations; one study received funding from a pharmaceutical company; and the remaining two studies did not provide information about funding.

Main results

In people with haematological disorders who have a low platelet count, tranexamic acid (TXA) compared to placebo:

• probably makes little or no difference to the number who experience moderate or worse than moderate bleeding;

• may make little or no difference to the number who experience severe, life-threatening bleeding, or dangerous blood clots in the blood vessels (thromboembolism).

There was not enough evidence to reach conclusions about the effect of TXA on the risk of death or the risk of serious side effects.

The two studies that looked at epsilon aminocaproic acid (EACA) did not report enough information to allow us to analyse their results.

What are the limitations of the evidence?

In general, we have little to no confidence in the evidence because there were too few studies to be certain about the results of our outcomes. In addition, some of the events we were looking for (e.g. death, dangerous blood clots) happened in very few people, which makes the results uncertain. These limitations mean it is difficult to draw firm conclusions about the effectiveness and safety of antifibrinolytic medications.

How current is this evidence?

The evidence is current to January 2025. This is an update of a review last published in 2016.

Background

Some infectious diseases are spread by airborne droplets from coughs and sneezes, which can infect people who touch contaminated skin or surfaces. Washing hands with soap and water may prevent these diseases from spreading. People with no soap may use other materials like ash, mud, soil with or without water, or water alone, to clean their hands. Hand cleaning with ash (the solid remains from cooking stoves and fires) might work by rubbing away or inactivating the virus or bacteria. However, chemicals in the ash could also damage the skin.

If ash is an effective hand cleanser, it could reduce the spread of coronavirus (COVID-19) and other infectious diseases in low-income areas where soap is not widely available.

What did we want to find out?

We wanted to know whether people who use ash for hand cleaning are more or less likely to catch infectious diseases than people who use soap, water, mud or soil, or who do not clean their hands. We also wanted to know whether using ash causes unwanted effects, like sore hands or a rash.

Our methods

We looked for studies that examined hand cleaning with ash compared with soap, mud, soil, water only or no hand cleaning. To answer our questions, the studies could include adults and children and take place anywhere.

COVID-19 is spreading rapidly, so we needed to answer this question quickly. This meant we shortened some steps of the normal Cochrane Review process. We could not find the full texts of five potentially relevant studies, or contact study authors for additional data. Although we searched several databases we may have missed some studies. We plan to include all relevant information in a future version of the review.

Results

We identified 14 studies that assessed ash for hand cleaning. Only one small study directly compared people chosen at random to use ash or soap or other materials (randomised studies produce the best evidence). The studies included people of all ages and mainly took place in low-income, rural communities. Six studies provided information to help answer our question.

One study investigated children who had been to hospital with diarrhoea compared with children who had not. Study authors looked at the hand washing area in the children’s houses to see how they cleaned their hands. They found that families that used ash for hand cleaning made a similar number of hospital visits for children with diarrhoea as those families that used soap.

Another study investigated whether women with unusual vaginal itching or discharge were more likely to clean their hands with ash than women who had not experienced such symptoms. They found that women who used ash and water for hand cleaning were as likely to experience vaginal itching or discharge as those women who used soap.

Four studies measured bacteria on hands after using ash, soap, water, mud or no hand cleaning. We are uncertain about the effect of ash compared with other materials for hand cleaning on bacteria on people’s hands because the studies used unreliable methods and their results were unclear.

None of the studies provided information about the severity of infectious diseases, whether people used ash or another material consistently, the number of deaths, or unwanted effects due to hand cleaning with ash.

Certainty of the evidence

Our certainty (confidence) in the evidence was limited because we found few studies; those we did find had unreliable methods and different kinds of participants, and none of the studies we found reliably examined whether participants got infections.

Conclusion

We are uncertain whether hand cleaning with ash compared with hand cleaning with soap, water, mud, soil or no hand cleaning stops or reduces the spread of viral or bacterial infections. We do not know if hand cleaning with ash causes unwanted effects.

Search date

This review includes evidence published up to 26 March 2020.

Key messages

• Vitamin B12 supplementation reduces the risk of vitamin B12 deficiency, and probably improves vitamin B12 levels in children less than 12 years of age, compared to placebo (a substance that looks the same as the intervention/treatment but does not contain any active ingredient) (that is, children who did not take vitamin B12 supplements).

• Vitamin B12 supplements, with other micronutrients (important vitamins and minerals the body needs in small amounts to function), may result in little to no difference in vitamin B12 deficiency or total vitamin B12 levels, compared to children who received the same supplements without vitamin B12.

• The impact of vitamin B12 supplements on other health outcomes in children is less clear.

What is vitamin B12?

Vitamin B12 is an important nutrient that helps make red blood cells and keep the body's cells and nerves healthy. Vitamin B12 deficiency is an important public health problem, including in children and in resource-poor settings. Lower vitamin B12 levels in children have been linked to anaemia (lower haemoglobin levels), and poorer growth, development, and cognition (a child's ability to gain knowledge through thought, understanding, and the senses).

What did we want to find out?

We wanted to find out if taking vitamin B12 supplements would improve the nutrition and health of children less than 12 years of age.

What did we do?

We searched for studies that looked at the effects of vitamin B12 compared to placebo (a substance that looks the same as the intervention/treatment but does not contain any active ingredient), no intervention, or the same supplements without vitamin B12. We summarised the results of the studies and our confidence in the evidence, based on information such as how the study was done.

What did we find?

We included 16 studies involving 4083 children less than 12 years of age (2 days to 11 years). Nine studies, including 2391 children, had data that we could analyse. The studies were conducted in 10 countries around the world. In most studies, the outcomes were assessed immediately after the intervention from five weeks to 31 months, with one study assessing outcomes after nine years. Vitamin B12 supplements were provided from 28 days to 31 months in amounts from 0.9 to 150 micrograms a day.

Supplementation with vitamin B12 alone versus placebo

There may be little to no difference in height/length, cognition (for example, attention), or development (for example, motor skill development). Children who received vitamin B12 supplements had less vitamin B12 deficiency, and probably had higher vitamin B12 levels, compared to placebo. There may be little to no difference between groups in anaemia. No studies provided data on any unwanted (adverse) effects.

Vitamin B12 alone versus no intervention

The evidence is very uncertain for height/length. No studies reported data we could analyse for other outcomes.

Vitamin B12 and other micronutrients, compared to supplements with the same supplement without vitamin B12

There may be little to no difference between groups for height/length, cognition (for example, attention), or development (for example, motor skill development). Children who received vitamin B12 supplementation (with other nutrients) may have little to no difference in vitamin B12 deficiency, vitamin B12 levels, anaemia, or any unwanted effects.

What are the limitations of the evidence?

The small number and the size of studies were limitations of this review. Few studies reported on health outcomes, including growth, cognition, development, anaemia, or any adverse effects. The different ages of children, and differences in the amount of vitamin B12 and when the outcomes were measured, are also limitations of this review.

How up to date is this evidence?

The evidence is up to date as of 23 September 2025.

Key messages

• We found four breast cancer risk prediction models that had been tested enough times to evaluate in detail. These were the Gail, Tyrer-Cuzick, BOADICEA, and BRCAPRO models.

• The BOADICEA model was one of the more reliable tools for estimating future breast cancer risk in women with a family history of the disease, meaning it may help them and their doctors to decide on treatment.

• Further research is needed to improve the accuracy of existing prediction models in distinguishing between women with a family history of breast cancer who will and will not develop the disease.

Why is it helpful to be able to predict a woman’s risk of breast cancer?

Women who have a history of breast cancer in their family have a higher likelihood of developing breast cancer themselves during their lifetime. In clinics, a woman's chance of developing breast cancer in a given time period is often estimated using statistical tools known as breast cancer risk prediction models.

Being able to estimate the risk of developing breast cancer accurately for a woman with a family history of breast cancer helps doctors and the woman decide how to manage or reduce her risk of breast cancer. Management may include:

• regular imaging with mammograms or magnetic resonance imaging (MRI; a type of scan that creates detailed pictures of the breast tissue) to detect breast cancer at an early stage;

• taking risk-reducing medications; or

• in some cases, surgical removal of both breasts to prevent breast cancer.

Currently, it is not clear which of the available breast cancer risk prediction models works best in women with a family history of breast cancer.

What did we want to find out?

We wanted to:

• identify breast cancer risk prediction models that have been developed or tested (or both) in women with a family history of breast cancer; and

• assess how accurately they predict future risk of developing breast cancer in these women.

What did we do?

We searched for studies that developed or tested these models. We looked at how accurately the models predicted breast cancer risk, focusing on:

• whether the predicted number of breast cancer cases was similar to the number that actually occurred (calibration); and

• whether the model could distinguish between women who did and did not develop breast cancer (discrimination).

When enough studies assessed the same model, we combined their results statistically.

What did we find?

We identified 12 models that estimate future breast cancer risk that had been tested in studies where all or most women had a family history of breast cancer. The models were tested using information from as few as 134 women to as many as 130,058. Most of the women lived in North America, Europe, or Australia, with a small number from Asia.

The studies were funded by governments (25 studies), universities (24), non-profit organisations (21), and industry (3). Six studies did not report funding sources, and some received funding from more than one source.

We were able to combine results from several studies for four models: the Gail, Tyrer-Cuzick, BOADICEA, and BRCAPRO models.

Calibration: was the predicted number of breast cancer cases similar to the actual number?

• The Gail and BOADICEA models accurately estimated the numbers of women in the included studies who would develop breast cancer in a given timeframe:

  • for every 100 breast cancers Gail predicted would occur, about 106 actually occurred in reality;

  • for every 100 breast cancers BOADICEA predicted, about 98 actually occurred.

• The Tyrer-Cuzick model estimated that more women in the studies would develop breast cancer than actually did. For every 100 breast cancers it predicted, only about 86 actually occurred.

• The BRCAPRO model estimated that fewer women in the studies would develop breast cancer than actually did. For every 100 breast cancers it predicted, about 144 actually occurred.

Discrimination: how well did the models distinguish between women who develop and do not develop breast cancer?

• All four models were moderately accurate in distinguishing between women who would and would not develop breast cancer in a given timeframe, but none did a great job.

• The Tyrer-Cuzick (version 8), BOADICEA, and BRCAPRO models correctly distinguished women who would develop breast cancer from those who would not about 64 to 65 times out of 100.

• The Gail model performed slightly less well, correctly distinguishing women who would develop breast cancer 61 times out of 100.

What are the limitations of the evidence?

We rated the quality of most studies included in our review as poor or unclear, which means we cannot be confident that these results are reliable. Our confidence was reduced for several reasons, including:

• in some studies, too few women developed breast cancer, making it harder to judge how accurate the prediction models were;

• not all studies reported the model performance information we sought;

• some studies had missing information or did not explain how they handled missing information.

How up to date is this evidence?
The review includes studies published up to December 2024.

Key messages

• There is little difference in how long women with advanced (stage IIIC/IV) epithelial ovarian cancer (EOC) survive, whether they have chemotherapy or surgery first. There is probably little difference in how long it takes for EOC to return after treatment.

• Giving chemotherapy prior to surgery probably reduces serious risks of surgery; probably halves the risk of needing bowel removal during surgery; and probably results in a large reduction in needing a stoma (where the bowel is diverted through the abdominal wall into a bag to collect the contents).

• Giving chemotherapy prior to surgery is an alternative to surgery followed by chemotherapy in women with advanced EOC. Decisions about which treatment to have first depend on patient preference, how well the woman is at time of diagnosis, the risks of surgery, and the amount and spread of disease.

What is epithelial ovarian cancer, and how is it treated?

Ovarian cancer is the eighth most common cancer worldwide in women. Around 90% of ovarian cancers are epithelial ovarian cancer (EOC), arising from the surface of the ovary or lining of fallopian tubes. Most women with EOC are diagnosed when their cancer is at a late stage, and their disease has spread throughout the abdominal cavity (stage IIIC/IV). Although survival rates have improved over the last 30 years, only four in every 10 women with EOC are alive 10 years after diagnosis.

Treatment for ovarian cancer involves a combination of surgery and chemotherapy. Surgery aims to remove as much visible cancer as possible. However, surgery alone is unlikely to cure EOC, and most women will also need chemotherapy. Chemotherapy uses platinum-based medications to treat cells that cannot be removed by surgery or cannot be seen.

Traditionally, chemotherapy is given after surgery. However, chemotherapy can be given before surgery and then followed by the remaining cycles of chemotherapy, as usual.

Why is this important?

Women with advanced EOC may be too unwell at diagnosis to have surgery, or may require extensive surgery to remove all visible disease. Giving chemotherapy before surgery may shrink the cancer prior to surgery, so that women become well enough to undergo surgery or need less extensive surgery.

What did we want to find out?

We wanted to find out if giving chemotherapy before surgery was better than doing surgery first and then giving chemotherapy. We were interested in how many women with EOC:

• were alive 48 months after diagnosis;

• had no EOC 24 months after treatment;

• died following surgery;

• had unwanted effects due to surgery;

• needed to have their bowel diverted through the abdominal wall into a bag to collect bowel contents (a 'stoma'), or to have part of the bowel removed (a 'bowel resection'); and

• saw an improvement in their quality of life.

What did we do?

We searched for studies that investigated chemotherapy followed by surgery compared with surgery followed by chemotherapy in women diagnosed with advanced EOC. We compared and summarised the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We found seven studies with 2650 women with stage III/IV EOC that compared the effects of giving an initial chemotherapy treatment followed by surgery then chemotherapy as normal, with surgery followed by chemotherapy. Studies took place worldwide, in 20, mainly high-income countries.

Giving chemotherapy before surgery:

• makes little or no difference to the number of women still alive after 48 months (5 studies, 2380 women);

• probably makes little or no difference to the number of women who remained disease-free after 24 months (5 studies, 2380 women);

• reduces deaths due to surgery (5 studies, 2201 women);

• probably reduces the risk of severe unwanted effects of surgery (3 studies, 1094 women);

• probably results in a large reduction in the risk of needing a stoma (3 studies, 1291 women), or a bowel resection (5 studies, 2237 women);

• may slightly improve quality of life 6 months after treatment, but the results are uncertain (3 studies, 559 women).

What are the limitations of the evidence?

We are confident that chemotherapy before surgery makes no difference to overall survival and reduces deaths due to surgery. We are less confident in the rest of the evidence for several reasons. It was clear which treatment women received, which might change the results. Although the studies only enrolled women with advanced EOC (stage IIIC/IV), and many had extensive disease, later studies only enrolled women when the surgeons thought they could remove all of the visible disease with surgery. We could only analyse results from five of the seven studies. We will add results from further studies when they are available.

How up-to-date is the evidence?

The evidence is current to 9 October 2025.

Key messages

• We are unsure about the effects of rocking premature babies to stimulate their inner ear and brain (vestibular stimulation) on death compared to no stimulation; there may be little to no difference in weight gain.

• We identified too few studies to report on the effects of vestibular stimulation on physical or mental development, such as learning difficulties, cerebral palsy, or blindness. No studies compared one type of vestibular stimulation with another, so it is unclear which types of vestibular stimulation are most effective.

• Future studies should be bigger, use more robust methods, and define and report their research more clearly.

What is the vestibular system?

The vestibular system is a sensory system within the inner ear and the brain. It controls balance and physical coordination. It helps us maintain our posture when standing, sitting or walking; it helps our brains to process what we see and hear. It is vital to navigate the day-to-day world. Like other organs and sensory systems, the vestibular system develops while we are in the womb.

What is vestibular stimulation?

Vestibular stimulation involves body movements such as rocking, swinging, rolling, turning and bouncing. In the womb, babies receive this type of stimulation through the mother's movements. After birth, babies receive this type of stimulation when they are held and fed, washed and changed, played with, and moved around onto their tummies or sides. Premature babies, born before nine months of pregnancy, may not receive as much of this type of stimulation as babies born at nine months because they may be quite small and fragile, or ill and in an incubator. This may affect their physical and mental development. For example, they may develop breathing problems, not gain weight, or be deaf or blind.

What did we want to find out?

We wanted to find out if stimulating the vestibular systems of hospitalized, premature babies by gently rocking, repositioning, swinging in a hammock, or laying on a waterbed or on an air mattress could be helpful and safe for their short-term and long-term well-being. Specifically, we wanted to find out if vestibular stimulation might:

• decrease the number of babies who develop physical or mental delays at 18 to 24 months of age;

• increase infants' weight gain;

• reduce death in babies during hospitalization after birth.

What did we do?

We searched for studies set in neonatal intensive care units that compared:

• any type of vestibular stimulation to no vestibular stimulation;

• one type of vestibular stimulation to another. For example, hammock swinging compared to waterbed rocking.

We compared and summarized the results of the studies and rated our confidence in the evidence based on factors such as the size of the study (number of babies) and the methods of the study.

What did we find?

We found 4 studies with 196 premature infants. Three studies took place in the USA and 1 in Canada. Healthcare professionals carried out vestibular stimulation in all studies. The studies investigated different types of vestibular stimulation.

• One study evaluated vestibular stimulation with an air mattress swinging back and forth in a regular rhythm.

• One study evaluated vestibular stimulation with a waterbed swinging back and forth in a regular rhythm.

• One study evaluated rocking.

• One study evaluated stimulation with a rocking chair (VestibuGlide).

No studies provided evidence about disabilities such as cerebral palsy, delayed physical or mental development, blindness or deafness. We did not find any studies that directly compared different types of vestibular stimulation.

Main resultsVestibular stimulation compared to no intervention

It is very uncertain whether vestibular stimulation, compared to no stimulation, has any effect on death (1 study, 122 babies).

Three studies (169 babies) investigated weight gain, but they all defined it differently and measured it over different periods, so we could not combine their results. We don't know whether vestibular stimulation makes any difference to weight gain compared to no stimulation.

What are the limitations of the evidence?

We have little confidence in these results, as the few studies we found were not well-designed and included few babies. Several studies did not report on outcomes or lacked data that we were interested in.

How up-to-date is this evidence?

The evidence is current up to 26 October 2025.