Key messages

- If damaged teeth are filled with a "bulk-fill" (material placed in one large layer) or a standard resin-based composite (RBC) material (placed in multiple layers), there is probably little or no difference in failure between the filling materials.

- Older evidence found that dental amalgam (silver-coloured fillings) may have fewer material failures than RBC. But this finding was based on older studies. Modern RBCs are better, dentists have more experience using them, and there are likely fewer failures.

Why do we need fillings and what are they?

Sometimes the tooth tissue becomes damaged, and holes (cavities) may form in the teeth. Cavities are caused by tooth decay, which is mainly a preventable disease if people adopt good oral hygiene and limit sugary foods and drinks.

When tooth decay leads to permanent damage, dentists may use a filling in the cavity to restore the tooth's shape and function.

What are the different materials used for fillings?

Traditionally, cavities were filled with amalgam. This silver-coloured filling material (made mainly from tin, silver and copper, and mixed with liquid mercury) is low cost and easy to use. But, it is now known that mercury can be harmful to people's health and the environment. At an international meeting, agreement was reached to reduce (or stop) the use of mercury, including in dental fillings. Alternative mercury-free filling materials that can be placed in a single dental appointment include:

- RBC: standard white or tooth-coloured material, applied in layers or in bulk.

- glass ionomer cement (GIC): sometimes used as a temporary filling, not as strong in some situations, so not suitable for chewing surfaces of teeth.

- resin-modified GIC (RMGIC): a hybrid GIC, stronger than GICs but not as strong as RBC.

- compomers: alternative to RMGIC but closer to composite than GICs.

RBC, RMGIC and compomers use an adhesive system to fix the material to the teeth, and need light-curing to harden the material. These are not needed with GIC.

What did we want to find out?

We wanted to find out:

- the benefits of one filling material compared to another for reducing tooth loss (because the filling has failed), failure (when the filling does not work as intended), length of time to failure, and tooth sensitivity after the procedure.

- whether one filling material is more cost-effective than another.

What did we do?

We searched for systematic reviews that looked at materials used for dental fillings in people's permanent back teeth. These reviews collect all the available evidence from published studies and analyse their results. We summarised the results of reviews alongside ratings of confidence (based on factors such as review or study methods and sizes) in the evidence that they reported.

We also looked for economic studies about the cost-effectiveness of these materials.

What did we find?

We found 14 reviews with 57 studies. The studies were undertaken between 1980 and 2023; one study had follow-up for 10 years but generally follow-up was much shorter. Some reviews did not report results for our critical outcomes, and sometimes the same studies were included in more than one review. We prioritised evidence from six reviews, with 25 unique studies.

We found seven studies about cost-effectiveness.

Main results

We found no reviews with evidence for tooth loss or length of time to failure.

- Although amalgam fillings may lead to fewer failures than RBC fillings (8 studies, 3486 fillings), the studies started in the late 1990s. RBCs, and dentists' experience using them, have improved since then. Failure with RBC is more likely to be 5% today (compared to 15% in the older studies). This means that older evidence comparing amalgam with RBC is less useful in modern settings.

- There is probably no difference between bulk-fill and standard RBC at reducing failures (7 studies, 511 fillings). It is likely that most people will experience no tooth sensitivity after either type of RBC material (5 studies, 510 fillings).

- There may be no difference between standard RBC and GIC at reducing failures (1 study, 60 fillings) or tooth sensitivity (4 studies, 311 fillings). RMGIC may be more likely to reduce failures than GIC (1 study, 50 or 38 fillings). We found reviews comparing GIC with amalgam and compomer, but these did not report failures or postoperative sensitivity.

- Most economic studies gave no overall conclusions about the cost-effectiveness of any of the materials. One economic study found that amalgam fillings were likely to last longer and be more cost-effective than RBC fillings, though this was based on an older study (from the late 1990s).

What are the limitations of the evidence?

Most reviews did not meet the highest standards. We judged only two reviews to be well-conducted. However, reviews mostly reported very similar results, even when they included different studies.

We were less confident in the evidence including GIC and RMGIC because studies were often small with few participants.

How current is this evidence?

The evidence is current to April 2025.

Key messages

• Live births are probably slightly decreased with recombinant follicle-stimulating hormone (rFSH) compared to purified (HMG) or highly purified (HP-HMG) human menopausal gonadotropin, but probably increased with rFSH compared to biosimilars (manufactured gonadotropins). There is probably little to no difference in live births between rFSH and purified follicle-stimulating hormone (FSH-HP) or follitropin delta. Clinical pregnancy is probably decreased with rFSH compared to HMG/HP-HMG but probably increased with rFSH compared to biosimilars. There is probably little to no difference in clinical pregnancy with rFSH compared with FSH-HP and follitropin delta.

• OHSS is probably higher with rFSH compared to HMG/HP-HMG and follitropin delta, but there is probably little to no difference with rFSH compared to FSH-HP, and there may be little or no difference with rFSH compared to biosimilars.

• Future research should focus on frozen embryos and cumulative outcomes across multiple frozen embryo transfer cycles to give a more complete picture of treatment effectiveness. Strategies for the prevention and management of OHSS should be prioritised.

What is in vitro fertilisation?

In vitro fertilisation (IVF) is a type of fertility treatment. Ovarian stimulation helps women’s ovaries produce more eggs, which are collected, fertilised and transferred back to the woman. Various hormones, including gonadotropins, are used to stimulate the ovaries:

• purified human menopausal gonadotropin (HMG) and highly purified (HP-HMG);

• purified follicle-stimulating hormone (FSH-P) or highly purified follicle-stimulating hormone (FSH-HP);

• recombinant follicle-stimulating hormone (rFSH) was developed in a laboratory to obtain higher purity of the hormone;

• follitropin delta was developed to work in a more personalised way; and

• 'biosimilars' are manufactured to offer similar results to rFSH at a potentially lower cost.

Ovarian hyperstimulation syndrome (OHSS) is an unwanted and sometimes serious effect of IVF, in which the ovaries swell and fluid can leak into the abdomen.

What did we want to find out?

We wanted to know which gonadotropin produced more live births, caused less OHSS, and led to more 'clinical' pregnancies, confirmed by ultrasound.

What did we do?

We searched for studies that compared one type of gonadotropin with another for women undergoing IVF. Studies could use fresh or frozen embryos.

What did we find?

We included 59 studies with a total of 18,119 women undergoing fertility treatment in a clinic.

rFSH versus HMG/HP-HMG (17 studies, 5639 women)

• Live births probably decrease with rFSH compared to HMG/HP-HMG. If the chance of live birth with HMG/HP-HMG is 28%, then the chance of live birth with rFSH is between 22% and 27%.

• OHSS is probably higher with rFSH compared to HMG/HP-HMG. If the risk of OHSS with HMG/HP-HMG is 2.6%, then the risk of OHSS with rFSH is between 2.9% and 4.7%.

• Clinical pregnancies probably decrease with rFSH compared to HMG/HP-HMG.

rFSH versus FSH-HP (23 studies, 4612 women)

• There is probably little to no difference in live births between rFSH and FSH-HP. If the chance of a live birth with FSH-HP is 27%, then the chance of a live birth with rFSH is between 24% and 31%.

• There is probably little to no difference in OHSS with rFSH compared to FSH-HP. If the risk of OHSS with FSH-HP is 2.5%, then the risk of OHSS with rFSH is between 1.7% and 3.8%.

• There is probably little to no difference in clinical pregnancy between rFSH and FSH-HP.

rFSH versus follitropin delta (7 studies, 3614 women)

• There is probably little or no difference in live births between rFSH and follitropin delta. If the chance of achieving a live birth with follitropin delta is 29%, the chance of a live birth with rFSH is between 24% and 30%.

• OHSS is probably higher with rFSH. If the risk of OHSS with follitropin delta is 4.4%, then the risk with rFSH is between 5.1% and 9.2%.

• There is probably little or no difference in clinical pregnancy between rFSH and follitropin delta.

rFSH versus biosimilars (8 studies, 2870 women)

• Live birth is probably higher with rFSH compared to biosimilars. If the chance of achieving a live birth with biosimilars is 23%, the chance of a live birth with rFSH is between 25% and 32%.

• There may be little or no difference in OHSS between rFSH and biosimilars. If the chance of OHSS with biosimilars is 9.6%, the chance of OHSS with rFSH is between 5.7% and 10%.

• Clinical pregnancy is probably higher with rFSH compared to biosimilars.

What are the limitations of the evidence?

The results mainly reflect IVF cycles with the transfer of a fresh embryo, so the results may be different for frozen embryos. Many studies were sponsored by pharmaceutical companies that manufacture the hormones in question, which could have affected the results. Furthermore, although we excluded some studies by using an integrity checklist, we have some concerns about the trustworthiness of the data from several of the studies.

How up to date is the evidence?

This updates a review previously published in 2011. The evidence is current to March 2025.

Key messages

• In adults who had treatment to reopen a blocked brain artery, lowering blood pressure very intensively (usually below 160 mmHg) does not improve the chances of living independently three months after the stroke compared with standard blood pressure targets (usually below about 180 mmHg). “Living independently” means being able to walk and manage most everyday activities without help.

• Intensive blood pressure lowering probably increases the risk of death and poor recovery after stroke. Differences in brain bleeding between intensive and standard blood pressure strategies were small.

• Most of the people in the studies were treated in hospitals in upper-middle and high-income countries with specialized stroke services. We do not know whether the results would be the same in countries with fewer resources or in all groups of people who have an ischemic (blood blockage) stroke.

What is an ischemic stroke?

A stroke occurs when the blood supply to part of the brain is suddenly interrupted. In an ischemic stroke, this interruption is caused by a blood clot blocking an artery in the brain. It can lead to various neurological problems, such as weakness, decreased sensitivity, lack of coordination, and difficulty speaking.

How is a stroke treated?

Doctors can sometimes reopen the blocked artery using clot-busting medicines given into a vein, or by performing a procedure to remove the clot with a thin tube passing through the blood vessels (often called mechanical thrombectomy). These are called reperfusion treatments because they restore blood flow to the brain.

After reperfusion, many people have very high blood pressure, which can increase the risk of bleeding in the brain. However, lowering blood pressure too much or too quickly can reduce blood flow to brain tissue that is still at risk and be harmful to the brain.

What did we want to find out?

We wanted to find out whether intensive blood pressure lowering after reperfusion treatment, compared with standard blood pressure control:

• improves recovery and ability to live independently;

• improves health-related quality of life;

• improves survival;

• increases or reduces bleeding in the brain;

• decreases the duration of days in hospital;

• affects the frequency of other unwanted effects.

What did we do?

We searched for clinical studies (in which people are assigned to groups by chance) that included adults with ischemic stroke who had received reperfusion treatment with a clot-busting medicine, mechanical thrombectomy, or both, and compared more intensive blood pressure targets (less than 160 mmHg) with standard targets (less than 180 mmHg) shortly after reperfusion.

We combined and summarized the results of the studies. We also considered how the studies were conducted, the number of participants included, and the similarities and differences between the studies to judge how much confidence we can have in the results.

What did we find?

We found nine studies, involving 4381 adults with ischemic stroke who had reperfusion treatment. Most participants were treated in hospitals in high-income countries, with a smaller number in hospitals in middle-income countries. None of the studies took place in low-income countries. In most studies, the intensive strategy aimed to keep systolic blood pressure (the top number in a blood pressure reading) below 140 mmHg, while the standard strategy aimed to keep it below about 180 mmHg.

Main results

• Intensive blood pressure lowering makes little or no difference to the chance of living independently about three months after the stroke, compared with standard blood pressure control.

• Intensive blood pressure lowering probably makes little or no difference to health-related quality of life.

• Differences in brain bleeding (including severe bleeding that worsens symptoms) between intensive and standard blood pressure strategies were small and uncertain.

• Intensive blood pressure lowering probably increases the risk of death and probably increases the chance of a poor recovery after stroke.

Overall, the results suggest that lowering blood pressure to very low levels after reperfusion is unlikely to provide additional benefit and might cause harm in some people, compared with keeping blood pressure within more standard targets.

What are the limitations of the evidence?

The evidence has several important limitations, such as the relatively small numbers of people in some studies, which reduce the reliability of the results. Additionally, most participants were treated in specialized centers in middle and high-income countries; there is no evidence from low-income countries. Some groups of people may be under-represented (for example, older adults with many other health problems), and many studies did not provide detailed results separately for women and men.

Because of these limitations, the results should be interpreted with caution. More research is needed to determine whether specific groups of people might benefit from different blood pressure targets.

How up to date is this evidence?

The evidence in this review is up to date as of March 2025.

Key messages

• Compared to placebo (a 'dummy' treatment with no active ingredient), weight-loss medicines may reduce body mass index (which measures whether someone's weight is in a healthy range) and weight slightly. Weight-loss medicines probably make little to no difference to the number of people experiencing unwanted or harmful events.

• We do not know if weight-loss medicines plus lifestyle changes are more effective than lifestyle changes alone, or whether they lead to any unwanted events.

• To better understand the benefits and risks, we need more studies that follow young people for at least one year and measure their physical and mental well-being.

What is obesity?

Obesity means having too much body fat. Obesity in children (0 to 9 years) and adolescents (10 to 19 years) increases the risk of several diseases in the short term and adulthood. Obesity also affects how young people feel about themselves and interact with others, often resulting in low self-esteem, anxiety, depression, and social difficulties.

How is obesity treated?

Obesity is a complex problem with many factors. Children and adolescents with obesity may benefit from lifestyle changes, such as improvements in diet and exercise, counseling, and behavioral support. Weight-loss medicines are typically only considered when lifestyle changes have not worked.

Several medicines are used for obesity in children and adolescents, including newer medicines called GLP-1 agonists, better known by brand names such as Wegovy and Ozempic. We considered the effects of all weight-loss medicines together.

What did we want to find out?

We wanted to learn if weight-loss medicines are better than a placebo (a 'dummy' treatment with no active ingredient) or lifestyle changes at:

• reducing body mass index (BMI) — a number calculated from a person's weight and height that indicates whether their weight is in a healthy range, expressed as kilograms per meter squared (kg/m2);

• reducing weight (kg);

• improving well-being.

We also wanted to find out if these medicines lead to:

• unwanted events;

• people leaving the studies early due to unwanted events;

• obesity-related health problems, including high blood sugar, high blood pressure, and unhealthy blood fat levels.

What did we do?

We searched for studies that compared weight-loss medicines with placebo, no treatment, another weight-loss medicine, or lifestyle changes in children and adolescents, and lasted at least three months. We compared and summarized the results of the studies and rated our confidence in the evidence based on factors such as study methods and the number of young people involved.

What did we find?

We included 37 studies with 4218 young people. Twenty-eight studies involved adolescents only. Eight included children and adolescents. One study planned to include children as well as adolescents, but did not mention their ages. Thirty-one studies compared weight-loss medicines to placebo. Six compared weight-loss medicines plus lifestyle changes (changes to diet, physical activity, or both) to lifestyle changes alone.

Main results

Compared to placebo, weight-loss medicines:

• may reduce BMI by an average of 1.8 kg/m2, based on evidence from 25 studies with 3091 young people. This is a small reduction, and may not meaningfully improve young people's health;

• may reduce weight by an average of 5.47 kg (20 studies, 2380 people);

• probably make little to no difference to young people's well-being (4 studies, 741 people);

• probably make little to no difference to the number of people experiencing unwanted events, which was high in both groups: 872 of 1000 people given weight-loss medicines and 846 of 1000 given placebo experience unwanted events (8 studies, 1877 people);

• may make little to no difference to the number of people leaving studies early due to unwanted events: 36 people per 1000 given medicine leave early, compared to 24 people per 1000 given placebo (13 studies, 2213 people);

• may make little to no difference to obesity-related health problems (1 study, 51 people).

There are important differences in the reductions in BMI and weight for different weight-loss medicines.

We are very uncertain about the effects of weight-loss medicines plus lifestyle changes compared to lifestyle changes alone on:

• BMI change;

• weight change;

• the number of people leaving studies early due to unwanted events.

No studies in this comparison measured young people's well-being, the number who experienced unwanted events, and obesity-related health problems.

What are the limitations of the evidence?

For both comparisons, our confidence in the evidence for most outcomes was reduced because the studies used methods likely to introduce errors in their results.

For weight-loss medicines versus placebo, our confidence in the evidence for BMI and weight was also reduced because the studies' results varied. We had little confidence in the evidence about the number of people who left studies early due to unwanted events because it was based on only a few cases. We had only moderate confidence in the evidence for well-being because there were too few studies to be certain about the results.

How up to date is this evidence?

The evidence is current to July 2023. In June 2025, we checked the status of ongoing studies, and updated the results accordingly.

Key messages

• Several medications can help rheumatoid arthritis symptoms after failure of a biologic or targeted synthetic (b/ts) disease‐modifying antirheumatic medicine (DMARD) (a type of medication that stops or slows the disease process).

• We are unsure how the medications compare with placebo (dummy treatment) or with each other in terms of unwanted effects.

• We need more studies that directly compare drugs to get a better idea of which is best. Treatment decisions should consider individual health factors and preferences.

What is rheumatoid arthritis?

Rheumatoid arthritis is a disease where the body’s immune system, which normally fights infections, mistakenly attacks the joints. This causes joint pain, swelling, stiffness, and disability. Rheumatoid arthritis is a long-term condition, but treatments can help manage symptoms and slow the damage.

How is rheumatoid arthritis treated?

Rheumatoid arthritis is typically treated with disease-modifying antirheumatic drugs (DMARDs), which work to control the inflammation responsible for symptoms and also prevent joint damage. There are various kinds of DMARDS. Targeted synthetic (ts) DMARDs work by targeting specific cells or proteins. Biologic (b) DMARDs also target specific cells or proteins, but are made from material that comes from living organisms. Lastly, conventional synthetic DMARDs affect the whole immune system rather than targeting specific parts of it.

What did we want to find out?

We wanted to explore the effectiveness of DMARDs in adults with rheumatoid arthritis for whom treatment with a b/ts DMARD didn't work. This is a 'living' systematic review, meaning that it will be updated regularly. As this field of medicine is always growing and changing, we want to have the most up-to-date evidence reflected in this review.

What did we do?

We searched for studies that tested the effectiveness of DMARDs in adults with rheumatoid arthritis for whom treatment with one b/ts DMARD didn't work.

We looked at how well the available DMARDs reduced the symptoms of rheumatoid arthritis, including pain, joint swelling, and issues with joint movement. We measured this using the American College of Rheumatology 50% response criteria, or ACR50 response. An ACR50 response means the rheumatoid arthritis medication is effective and symptoms have improved by at least half. We also looked at any unwanted effect that might cause a person to stop using the medication.

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 19 studies that involved 4779 people with rheumatoid arthritis who had tried a tumour necrosis factor inhibitor (a type of bDMARD) in the past, but it did not improve their symptoms. Most people in these studies were women, with an average age of 49 to 58 years, who had been living with rheumatoid arthritis for an average of 6 to 14 years. The studies were conducted worldwide, including in North America, Europe, and Asia. Nine studies were funded by pharmaceutical companies, while the other 10 were funded by national research grants.

Several medications reduced the symptoms of rheumatoid arthritis in patients who have failed a b/ts DMARD:

• a different tumour necrosis factor inhibitor (2 studies; 343 people);

• sarilumab (1 study, 365 people);

• tocilizumab 4 mg/kg (1 study, 319 people);

• tocilizumab 8 mg/kg (1 study, 328 people);

• intravenous (into a vein) abatacept (2 studies, 665 people);

• rituximab (1 study, 499 people);

• upadacitinib (1 study, 333 people);

• tofacitinib (1 study, 263 people);

• a higher dose of baricitinib (1 study, 353 people).

We are unsure how the medications compare with placebo (dummy treatment) or with each other in terms of unwanted effects, as the evidence for this outcome was generally of low quality.

What are the limitations of the evidence?

Our confidence in the evidence varied from high to very low. In cases where our confidence was limited, this was because there were not enough studies to be certain about the results. When we searched for studies to include in the review, we found some gaps in the available evidence. Specifically, we found that there were fewer studies that directly compared medications with each other and more studies that compared medications to a placebo. More studies that compare drugs directly would better help us understand which drug is best.

How up to date is this evidence?

The evidence is current to 28 November 2025. As this is a living review, we will be updating this research yearly to ensure our results reflect new evidence.

Key messages

• Compared to no physical activity, any type of physical activity may help children with obesity to reduce their BMI slightly (the 'body mass index' is used to check if someone is a healthy weight) and may lead to considerably more minor unwanted events, but we are very uncertain about these results.

• We do not know if physical activity has any effect on the weight, body fat percentage, well-being, and blood sugar levels of children with obesity compared to no physical activity or another type or amount of physical activity. We also do not know if physical activity has any effect on the number of serious unwanted effects.

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

What is obesity?

Obesity is when a person has too much body fat. Worldwide, obesity amongst children (aged 0 to 9 years) has increased substantially since 1975. More than 300 million children and adolescents (aged 10 to 19 years) may be living with obesity by 2050.

Children with obesity are more likely to develop health problems such as heart disease, stroke, type 2 diabetes, some cancers, liver disease, asthma, joint and muscle problems, and infections later in life. Childhood obesity is also linked to higher rates of anxiety and depression.

Weight loss is the best way to reduce the health risks caused by obesity. In children, this is usually done through lifestyle changes such as doing more physical activity (e.g. running games or interactive video games that encourage movement (sometimes called 'exergaming')) and eating healthier foods.

What did we want to find out?

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

• reduce their BMI (the 'body mass index' indicates if someone is a healthy weight; their weight is divided by their height multiplied by itself, expressed as kg/m2) or BMI z-score (how someone's BMI compares to BMIs of others of the same age and sex);

• lose weight;

• improve their well-being;

• reduce body fat percentage or improve how body fat is distributed in the body; and

• lower their blood sugar levels.

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

What did we do?

We searched for studies that compared participating in physical activity to:

• no physical activity;

• another type or amount of physical activity.

The children 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 four studies including 517 children. The studies were small: the smallest included only 59 children and the largest, 222. Just under half of the children involved were girls (46%). Their average age was 9 years.

In three studies, the children did the physical activities for 12 or 13 weeks; the fourth study's physical activity programme lasted 32 weeks. The studies took place in three countries: one study each in Brazil and Iran, and two studies in the USA. In the American studies, 73% of the children were Black. The other studies did not describe the children's ethnicities.

• All four studies compared physical activity to no physical activity.

• One study also compared one type of physical activity (exergaming) to another type (swimming pool exercises).

• One study also compared doing 20 minutes versus 40 minutes of the same physical activities.

Main resultsPhysical activity versus no physical activity

Compared to no physical activity, children with obesity who participated in any physical activity programme may have:

• slightly reduced their BMI: the BMI of children in the active groups was on average 1.52 kg/m2 lower (2 studies, 118 children);

• experienced more minor unwanted effects: children in the active groups may have been about 3.5 times more likely to experience minor unwanted effects (1 study, 222 children).

However, we are very uncertain about these results.

We do not know if physical activity makes any difference to children's:

• BMI z-score;

• weight;

• well-being;

• body fat percentage or how fat is distributed in the body;

• blood sugar levels;

• risk of experiencing serious unwanted events.

One type or amount of physical activity versus another type or amount

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

What are the limitations of the evidence?

We have limited confidence in the evidence because:

• there were few studies and they were small;

• the types of physical activities varied;

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

• three out of four studies did not report all their results.

How up to date is this evidence?

This evidence is current to December 2025.

Key messages

• Medicines that help the body's immune system recognise and attack cancer cells can shrink the cancer and likely slow its return in people aged 65 years and older having surgery for the most common type of lung cancer. However, it probably does not increase how long people live overall.

• We do not have enough evidence yet to know if its benefits outweigh the harms, and no study assessed well-being.

What is resectable non-small cell lung cancer?

About 85% of people with lung cancer have what is called non-small cell lung cancer (NSCLC). It is most often found in older adults, with an average age at diagnosis of 71. When the cancer has not spread out of the lung, and if the person is fit enough to have surgery, the tumour can be removed. However, the cancer can come back after treatment, and between 30% and 55% of people eventually die from the disease. To reduce the risk of cancer coming back, different treatments can be used together.

How is resectable non-small cell lung cancer treated?

In recent years, lung cancer treatment has been transformed with the discovery of medicines that help the body's immune system recognise and attack cancer cells (immunotherapy). Immunotherapy works together with drugs that kill cancer cells (chemotherapy). When given before surgery, after surgery, or both, immunotherapy improves the chances of curing the cancer and helps delay its return.

What did we want to find out?

The ageing process affects the immune system, reducing its capacity to fight cancer: this is called immunosenescence. The elderly population is a very diverse group, and each person needs to be carefully assessed because age alone is not enough to base the best treatment decisions on. We wanted to find out if, despite immunosenescence, immunotherapy is effective in people aged 65 years and older, to cure lung cancer and prolong life without unwanted treatment effects.

What did we do?

We searched for high-quality studies that tested immunotherapy, either alone or in combination with chemotherapy, given before surgery, after surgery, or both, in people aged 65 and older. We summarised their results and assessed how confident we can be in the evidence, based on criteria such as how the studies were done and how many people were included.

What did we find?

For people aged 65 and older, we found results from 11 studies involving 3152 people with NSCLC. The studies compared immunotherapy alone or in combination with chemotherapy to a placebo (a sham or ‘dummy’ treatment) or no treatment, with or without chemotherapy. Treatments were given either only before surgery, only after surgery, or both before and after surgery.

Immunotherapy reduces the amount of cancer found at surgery and probably delays the cancer from coming back. Immunotherapy probably makes little or no difference to overall survival. There was not enough evidence to determine its effect on potential harms, and no study assessed well-being.

What are the limitations of the evidence?

Our confidence in most of the evidence is moderate because of some concerns about how the studies were conducted. More complete and longer-term data are needed to better estimate how much a person's lifespan might be extended. We have very limited confidence in the assessment of unwanted effects, because only one study provided data about these.

How up to date is this evidence?

The evidence is up to date to 3 July 2025.

Key messages

• Overall, we did not find sufficient evidence to show that medicines that block interleukin-1 (a protein involved in immune responses) are effective treatments for people with COVID-19, or whether they cause unwanted effects.

• We found 16 studies with unpublished results. We will update this review when new data are available.

• In future, we need high-quality studies to evaluate medicines that block interleukin-1 to treat COVID-19.

What is interleukin-1 and what is its role in COVID-19?

Interleukin-1 (IL-1) is a type of protein called a cytokine, which helps to regulate the body’s immune system. In particular, IL-1 triggers inflammation to help fight infection. In COVID-19, as the immune system fights the virus, the lungs and airways become inflamed, causing breathing difficulties. However, in some people, the immune system can over-react (called a ‘cytokine storm’) and produce dangerously high levels of inflammation and tissue damage. This can lead to severe breathing difficulties, organ failure and death.

What are interleukin-1 ‘blockers’?

IL-1 blockers are medicines that stop IL-1 from working by blocking signals from IL-1 to other parts of the immune system. This reduces inflammation and may help the immune system to fight COVID-19. In turn, this may reduce the need for breathing support with a ventilator (a machine that breathes for a patient) and reduce the number of deaths from COVID-19. Three IL-1 blockers are available: anakinra, canakinumab and rilonacept.

What did we want to find out?

We wanted to know if IL-1 blockers are effective treatments for people with COVID-19, compared with standard care alone or with placebo (a dummy treatment that appears identical to the medicine being tested but without any active medicine). We were particularly interested in the effects of IL-1 blockers on:

• whether people’s symptoms got better or worse;

• how many people died; and

• any unwanted effects and serious unwanted effects.

What did we do?

We searched for studies that assessed the effects of IL-1 blockers to treat people with COVID-19 compared with standard care alone or with placebo. People in the studies could have suspected or confirmed COVID-19 of any severity (mild, moderate or severe), and be any age or sex.

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 six studies with 2132 people. Four studies assessed anakinra (1633 people) and two assessed canakinumab (499 people). People in the studies were aged between 58 and 68 years old on average, and the majority were men. All the people in the studies were in hospital, mainly with moderate to critical COVID-19. The studies varied in size, from 45 to 2253 people. At the start of the studies, 67% to 100% of people were receiving oxygen, and 0% to 33% were on a ventilator.

We also found 16 studies that have not yet published their results.

Anakinra compared to usual care and placebo to treat people with COVID-19

• Anakinra probably results in little or no improvement in COVID-19 symptoms (defined as improvement on a clinical scale or discharge from hospital) at 28 days after treatment (three studies, 837 people) but we do not know if it makes a difference at 60 days (one study, 115 people).

• We do not know if anakinra makes a difference to the number of deaths at 28 days after treatment (two studies, 722 people) or at 60 days (four studies, 1633 people).

• Anakinra probably results in little or no increase in any unwanted effects at 28 days after treatment, but we are not sure about its effect on serious unwanted effects (two studies, 722 people).

Canakinumab compared to usual care and placebo to treat people with COVID-19

• Canakinumab probably results in little or no improvement in COVID-19 symptoms (defined as improvement on a clinical scale or discharge from hospital) at 28 days after treatment (two studies, 499 people).

• We do not know if canakinumab makes a difference to the number of deaths at 28 days after treatment (two studies, 499 people) or at 60 days (one study, 45 people).

• Canakinumab probably results in little or no increase in any unwanted effects (one study, 454 people), but we are not sure about its effect on serious unwanted effects (two studies, 499 people) at 28 days.

What are the limitations of the evidence?

Our confidence in the evidence is limited for several reasons. All the people in the studies were hospitalised, but some were more seriously ill than others - some studies only included people on a ventilator. Usual care also differed between studies, and studies measured and reported their results using different methods.

How up to date is this evidence?

The evidence is up to date to 5 November 2021.

Key messages

In people who have had previous rheumatic fever (the body attacking itself in response to bacterial infection) or have rheumatic heart disease (long-term damage to the heart due to rheumatic fever):

- long-term antibiotics (either injected into the muscle every month or taken as a tablet every day) probably reduce the risk of getting more episodes of rheumatic fever compared to no antibiotics;

- intramuscular antibiotics probably reduce the progression (getting worse) of early heart disease compared to no antibiotic; however, there is no evidence to compare intramuscular with oral antibiotics for progression of late-stage heart disease;

- antibiotics may not increase the risk of complications, such as a severe allergic reaction (anaphylaxis).

What is rheumatic heart disease?

Rheumatic heart disease is the top cause of heart disease in young people worldwide and kills about one-third of a million people every year. Rheumatic fever happens when the body's own defences go wrong, often because of a throat infection, fighting the heart instead of the bacteria. This can then lead to damage to the heart valves (gateways between rooms in the heart) called rheumatic heart disease. Antibiotics kill bacteria that can cause infections, reducing the risk of people developing rheumatic fever.

What did we want to find out?

We wanted to find out whether and, if so, how effective antibiotics are at reducing the chances of getting rheumatic fever again, and this leading to rheumatic heart disease.

What did we do?

We included studies that randomly gave people with past rheumatic fever or rheumatic heart disease antibiotics or not (e.g. based on flipping a coin). We were interested in comparing, firstly, long-term antibiotics with no antibiotics and, secondly, long-term intramuscular penicillin with long-term oral antibiotics. Participants in the studies we included had previous rheumatic fever or rheumatic heart disease, but could be any age. We looked for lots of different events that could have happened, including the rheumatic fever coming back (rheumatic fever recurrence), rheumatic heart disease getting worse (progression of rheumatic heart disease), problems with the heart (carditis), problems around pregnancy and birth (obstetric complications and foetal/neonatal events), death (mortality), whether people stuck to their treatment (treatment adherence), other problems such as dangerous breathing problems (anaphylaxis), complications such as nerve injury and whether the people included were happy with having antibiotics.

What did we find?

We found 11 studies (3951 participants) to help us answer our questions. People in these studies were an average of 12.3 years of age and were 50.6% male. Most had had previous episodes of rheumatic fever.

We found that using long-term antibiotics (either injected into the muscle every month or taken as a tablet every day) compared with no antibiotic probably reduces the risk of getting more episodes of rheumatic fever. The injection into a muscle route probably works better than the tablets. If you have the early stages of rheumatic heart disease picked up on an echocardiogram of the heart (a scan that uses sound waves to see the internal structure of the heart), then penicillin antibiotics injected into the muscle every month compared with no antibiotic likely reduces the risk of these heart problems getting worse. We found some evidence that antibiotics injected into the muscle compared with no antibiotics may not cause a very high risk of allergic reaction that affects breathing (anaphylaxis), but probably comes with a higher chance of redness at the injection side and allergic reactions to antibiotics. There was not much information on death rates or nerve injury, and no evidence on whether an antibiotic injection is better than tablets for preventing latent (early) rheumatic heart disease getting worse.

What are the limitations of the evidence?

The majority of the included studies (nine) were not carried out in low-income countries, which currently have the most cases of rheumatic heart disease. This makes these results potentially less relevant to people in these countries. There is also little information on important questions other than recurrence of rheumatic fever or progression of rheumatic heart disease. There were some other potential limitations in the evidence: we flagged six studies as having issues with blinding (study participants or staff knowing whether they received antibiotics and so potentially answering based on this information). It is possible that people in many of the included studies were aware of which treatment they were getting. Four studies may have had a problem with the process for placing people randomly into groups. For some of the results in the review, we only had one study.

More high-quality work is needed that is relevant to the parts of the world where rheumatic fever is currently most common. More research looking at early (latent) rheumatic heart disease, where the biggest differences may be made, is also needed.

How up-to-date is this evidence?

The evidence is current to 10 March 2024. Whilst this is the most up-to-date review available currently, most of the evidence in this review is from the 1950s to 1960s, so some of the treatments may be outdated.

Key messages

• All the studies only included people with two copies of the most common cystic fibrosis-causing gene variant (F508del).

• Most studies were entirely or partly funded by medicine companies. No studies reported any deaths. None of the single medicines we looked at were clearly better than placebo (dummy treatment) for improving quality of life or lung function, and there was no evidence of the medicines causing more harm than placebo. However, we are unsure about these results.

• The evidence for using a single CFTR modulator is weak, and future research is likely to focus on combination therapies.

What is cystic fibrosis and how can it be treated?

Cystic fibrosis is a serious inherited illness that shortens life. It damages many organs in the body, particularly the lungs, pancreas, and liver. In the lungs, it causes a build-up of thick, sticky mucus that leads to repeated infections and progressive damage. Most people with cystic fibrosis experience breathing difficulties, poor nutrition, and a reduced quality of life.

Cystic fibrosis is caused by a fault in a gene that makes a protein called CFTR. CFTR regulates the movement of salt and water across cell surfaces, keeping the mucus thin and slippery. The most common CFTR gene variant (found in over 80% of people with cystic fibrosis) is F508del, which is a class II variant. People with two copies of F508del usually have more severe disease than people with one copy. In people with class II variants, the CFTR protein is degraded and cannot move properly through the cell. Laboratory experiments suggest that if the protein reaches the cell wall, it may be able to function, restore salt movement, and correct the chronic problems people with cystic fibrosis experience. CFTR modulators are medicines that help the faulty CFTR protein reach the cell wall.

What did we want to find out?

We wanted to know if CFTR modulator monotherapy (single-medicine treatment) can help people of any age with cystic fibrosis who have a class II variant. Specifically, we wanted to know if these medicines can improve survival, quality of life, lung function, and time to the first worsening of lung symptoms. We also wanted to know if this treatment is associated with any unwanted effects.

What did we do?

We searched for studies that investigated the effects of any single CFTR modulator compared with placebo (dummy treatment) or any other single CFTR modulator in people with cystic fibrosis who had at least one copy of a class II variant. 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 10 studies (with 424 participants, all of whom had two copies of F508del) assessing eight different medicines given as monotherapy. Nine studies included only adults, and one study included people from age 14 years. All the studies were small (including between 18 and 89 participants) and lasted between one day and 29 days. They took place in North America (mainly the USA), Europe, and Australia. Our main findings are for two of the eight medicines, lumacaftor and cavosonstat, which have gone on to be evaluated in larger populations.

Main findings

No studies reported any deaths or meaningful improvements in quality of life. We did not find enough evidence to show any effect of CFTR modulators on lung function. The studies reported a wide range of unwanted effects, but each occurred in only a few participants per study. We did not find enough evidence to support using CFTR modulator monotherapy in people with cystic fibrosis who have two copies of F508del.

What are the limitations of the evidence?

We are not confident in the evidence, for the following reasons.

• The studies were small.

• Most results are based on evidence from a single study.

• The evidence is not applicable to children.

• Not all studies provided enough data for us to analyse the results.

• The evidence related to unwanted effects of treatment was based on very few events.

How up-to-date is this evidence?

This review updates our earlier review of single- and multiple-medicine therapy. The evidence is current to 27 June 2025.

Key messages

• Introducing preterm infants to the smell of maternal breast milk may slightly reduce the time it takes for them to feed fully by mouth. Introducing them to food smells such as vanilla and cinnamon may slightly reduce how often they stop breathing. Finally, introducing preterm babies to the smell of rose or a parent's scent may reduce slightly the time they have to stay in hospital. All other results are very uncertain.

• Future studies should include more infants, use more rigorous designs, and measure outcomes such as breathing problems, low blood oxygen levels, exclusive breastfeeding, and long-term neurodevelopmental outcomes.

What is preterm birth?

A normal pregnancy usually lasts from 37 weeks to 42 weeks. Preterm birth is when a baby is born before 37 weeks of pregnancy. Babies born preterm have not had enough time to fully develop before birth. Their organs may not yet be ready to work on their own, which means they often need intensive medical care and are at greater risk of breathing and feeding difficulties, infection, and problems that can affect their long-term development.

What is olfactory stimulation, and how does it work?

Preterm infants often take time to build up the skills or physical capacity to feed by mouth, and in the meantime are fed through a tube passed into the stomach. Olfactory stimulation involves introducing smells to preterm infants while they are in hospital to see if it helps them start breastfeeding more quickly. These smells include breast milk, food smells such as vanilla or cinnamon, and other smells such as a floral scent or a parent's scent.

What did we want to find out?

We wanted to find out whether introducing a smell to preterm infants in hospital could be helpful and safe for their short-term and long-term well-being. More specifically, we wanted to find out whether introducing a smell to preterm infants is better than placebo (dummy treatment), no treatment, or usual care for:

• reducing the number of infants who have apnea (brief pauses in breathing);

• reducing the number of infants with low oxygen levels in the blood;

• reducing the time spent in hospital;

• reducing the time needed for the infants to learn to feed fully by mouth;

• increasing the number of infants that are fed only with breast milk;

• reducing the number of infants with blindness or deafness between 18 and 24 months of age.

What did we do?

We searched for studies that compared olfactory stimulation with placebo, no treatment, or usual care in preterm infants.

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

What did we find?

We included 14 studies with 1087 infants. Nine studies used the smell of maternal breast milk, five used food-associated smells (vanilla, cinnamon, or anise), and three studies used other smells (rose or parents' scent). All studies compared these smells with no treatment, placebo, or usual care.

Main results

Introducing the smell of maternal breast milk may reduce slightly the time it takes infants to feed fully by mouth. It is unclear whether stimulation with this smell has any effect on how often infants have apnea episodes and how long they stay in hospital.

Introducing the smell of cinnamon, vanilla, or anise may slightly reduce how often infants have apnea episodes. It is unclear whether stimulation with these smells has any effect on how long infants stay in hospital or how long it takes them to feed fully by mouth.

Introducing the scent of rose or a parent's scent may slightly reduce how long infants spend in hospital. It is unclear whether stimulation with these smells has any effect on how often infants have apnea episodes or how long it takes them to feed fully by mouth.

What are the limitations of the evidence?

We have little confidence in these results, as the studies included could have been better designed and included more babies. Several studies did not report outcomes we were interested in.

How up to date is this evidence?

The evidence is current to 2 April 2025.

Key messages

• Tailored education (staff, patient/family and multicomponent) probably reduces the rate of falls and risk of falling.

• Service model changes (where there is a change in the way a hospital delivers care to patients with the goal of reducing falls) in acute hospitals probably reduce the rate of falls.

• Multifactorial interventions (where two or more categories of intervention are given based on an assessment of a person's risk factors for falling) probably reduce the rate of falls and risk of falling, although it is also possible these interventions have no effect or slightly increase falls.

• Exercise may have little or no effect on the risk of falling in hospital settings overall.

• Across all intervention types, fall prevention approaches that include integration with the local setting, tailoring approaches to the needs and abilities of patients, and engaging patients and/or family or carers may reduce the rate of falls in older people in hospitals.

• Further research on the effectiveness of all intervention types aiming to prevent falls in hospitals is needed, particularly for people with cognitive impairment (memory or thinking problems) and in low- and middle-income countries.

Why is reducing falls in older people in hospitals important?

Falls by older people in hospitals are common events that may cause loss of independence, injuries, and sometimes death. Effective interventions to prevent falls are therefore important.

How do we report the interventions used to assess falls?

Trials testing interventions designed to reduce falls in older people are grouped by type, guided by the fall prevention classification system (taxonomy) developed by the Prevention of Falls Network Europe (ProFaNE).

Interventions are classified as single, multifactorial, or multiple, as follows.

• Single interventions: one category of intervention is delivered to all participants in the group. Categories include exercise, interventions aiming to improve medication prescribing (medication optimisation), environment/assistive technology, education, and service model change (where there is a change in the way a hospital delivers care to patients with the goal of reducing falls). Interventions designed to provide education about falls and falls prevention to staff and/or patients or family members are grouped together.

• Multifactorial interventions: two or more categories of intervention are given based on an assessment of a person's risk factors for falling. 

• Multiple interventions: the same combination of interventions is delivered to all participants.

What did we want to find out?

We wanted to know which interventions reduce falls in older people in hospitals in terms of the rate of falls (the actual number of falls over a period of time) and risk of falling (the likelihood that an individual will experience a fall). We also examined the impact on risk of fractures, unwanted effects, and economic outcomes.

What did we do?

We searched for studies that compared falls outcomes in people who received fall prevention interventions with falls outcomes in people who did not receive fall prevention interventions. 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 55 studies involving a total of 104,474 participants. On average, participants were 79 years old, and 45% were women.

• Education (staff, patient/family and multicomponent) probably reduces the rate of falls and risk of falling.

• Service model changes in acute hospitals probably reduce the rate of falls. We are uncertain about the effect of service model changes on the risk of falling. There were no trials of service model changes in subacute settings.

• We are uncertain about the effect of exercise on the rate of falls. Exercise may have little or no effect on the risk of falling in hospital settings overall.

• We are uncertain about the effect of medication optimisation on falls.

• Multifactorial interventions probably reduce the rate of falls and risk of falling, although it is also possible these interventions have no effect or slightly increase falls.

What are the limitations of the evidence?

We have moderate to very low confidence in the evidence. Our confidence was limited because people in most of the trials were aware of which treatment they were getting, and not all studies provided information about everything that we were interested in. Also, there were problems with the way data were collected in some studies.

How up-to-date is the evidence?

This review updates previous versions of the review published in 2010, 2012, and 2018. The evidence is current to 28 October 2025.

Key messages

• The imaging tests sono-hysterosalpingography (sono-HSG), hysterosalpingography (HSG), and transvaginal hydrolaparoscopy (THL) can reliably show whether the fallopian tubes are blocked.

• HSG seems to suggest blockage of the tubes when there is none more often than sono-HSG and THL.

• We need more research comparing one test against another, and on fluid-filled tubes and magnetic resonance hysterosalpingography (MR-HSG).

Why is it important to diagnose blocked fallopian tubes?

The fallopian tubes connect the ovaries to the womb (uterus). Blocked tubes can prevent pregnancy, as the egg and sperm cannot meet. Diagnosing blocked tubes (tubal occlusion) and fluid-filled tubes (hydrosalpinx) is essential for choosing the right treatment. Traditionally, keyhole surgery (laparoscopy with dye) is used, but this method is invasive and expensive. Alternative tests have been developed using imaging methods, which are less expensive and less invasive, and can be performed during an outpatient clinic visit.

What are the imaging tests?

• Sono-hysterosalpingography (sono-HSG): salt water or foam is placed in the womb, and an internal ultrasound is used to see if the fluid passes through the fallopian tubes.

• Hysterosalpingography (HSG): a contrast fluid is placed in the womb, and X-ray pictures show whether it flows through the tubes.

• Transvaginal hydrolaparoscopy (THL): a tiny camera is placed through the vaginal wall. At the same time, salt water is placed in the womb to see if it comes through the tubes.

• Magnetic resonance hysterosalpingography (MR-HSG): similar to HSG, but a magnetic resonance imaging (MRI) scan is used to make detailed pictures of the tubes.

What did we want to find out?

We wanted to find out how well these tests can show blocked fallopian tubes and fluid-filled tubes, compared with the traditional keyhole surgery test.

What did we do?

We looked for studies that investigated these imaging tests compared to traditional keyhole surgery. We brought together the results from all the studies and checked how well each test could correctly show when the tubes are blocked and when they are fluid-filled.

What did we find?

The review included 21 studies with a total of 1939 women:

• 8 studies on sono-HSG;

• 8 studies on HSG;

• 3 studies for TLH;

• no studies for MR-HSG;

• 2 studies for sono-HSG and HSG

Only two studies on sono-HSG and two studies on HSG reported on fluid-filled tubes.

Three studies were not in English; we translated them online. Nine studies did not clearly explain whether the participants were women with a low or high risk of having blocked tubes. Seven studies did not mention whether the tests were done by a trained person.

Blocked tubes

Sono-HSG, HSG and THL are reliable tests for blocked fallopian tubes. HSG may be more likely than sono-HSG and THL to suggest that tubes are blocked when they are not.

If 1000 women were tested for blocked fallopian tubes by the different imaging tests, and 182 of them actually had blockages in both tubes (this number was based on how often the condition was actually found in the studies we included), then:

• for sono-HSG: 186 women would be told they have blocked tubes based on sono-HSG results. Of these, 8 women would actually have open tubes; 814 women would be told their tubes are open, and of these, 4 women would actually have blocked tubes.

• for HSG: 189 women would be told they have blocked tubes based on HSG results. Of these, 49 women would actually have open tubes; 811 women would be told their tubes are open, and of these, 57 women would actually have blocked tubes.

• for THL: 181 women would be told they have blocked tubes based on THL results. Of these, 8 women would actually have open tubes; 819 women would be told their tubes are open, and of these, 9 women would actually have blocked tubes.

Fluid-filled tubes

• One sono-HSG study reported results by tube and the other reported results by woman, so we could not combine their results.

• Two HSG studies reported results by tube. They showed that all women diagnosed with fluid-filled tubes had this condition, and four out of 100 women diagnosed with fluid-filled tubes did not have this condition.

What are the limitations of the evidence?

The included studies looked at blockages in a single tube, on one side, or on both sides. Only a few studies reported each of these things for each test, so it was difficult to draw conclusions. Also, only a few studies compared one imaging test against another, so we could not say for sure which test is better.

How up to date is this evidence?

The evidence is up to date to November 2023.

Key messages

• Offering counselling plus nicotine replacement therapy (a treatment that provides nicotine in a safer form than tobacco smoking to help people reduce cravings and withdrawal symptoms), during a stay in a psychiatric ward, and continuing this support after leaving hospital, may help more people to stop (quit) smoking tobacco (when measured six months later) than usual care.

• We did not find enough information to draw conclusions about the effects of any other smoking cessation interventions initiated in the psychiatry inpatient setting. We need more, better designed studies that test different ways to help people quit smoking, particularly medicines.

Why is smoking a problem for people with mental illness?

People experiencing mental illness die up to 15 to 20 years earlier than people in the general population from preventable physical illnesses, such as heart and blood vessel disease, airway and lung disease, diabetes, and cancer. Smoking tobacco is one of the main causes of these illnesses. People being treated in hospital for mental illness smoke more than people in the general population and are less successful at quitting, despite wanting to stop. Many hospitals are smoke-free environments and should be a good place to deliver quit-smoking programmes to people with mental illness.

What did we want to find out?

We wanted to know whether quit-smoking programmes started while people are being treated in a hospital psychiatry ward help these people to stop smoking, and which programmes are most effective. We were particularly interested in how many people were still not smoking after six months and whether anyone suffered any serious unwanted effects, such as death or a life-threatening event.

What did we do?

We searched for studies that investigated any quit-smoking programme started in a psychiatric ward compared to usual care, being put on a waiting list, or receiving a placebo (a ‘fake’ medicine with no active ingredients). People taking part could have any psychiatric diagnosis but had to be adults (aged 18 years and older) who were tobacco smokers.

We 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 10 studies that included a total of 2262 people in emergency or long-stay psychiatry wards. Most studies included people with a variety of mental health diagnoses (for example, mood disorders, anxiety disorders, schizophrenia), and three studies involved only people with schizophrenia or schizophrenia-type disorders. The studies took place in five countries (Australia, USA, Taiwan, Israel, and Iran).

The programmes included:

• counselling plus nicotine replacement therapy and continued support with quitting smoking after leaving hospital (versus usual care);

• a group behavioural (psychological support without medicine) smoking reduction programme (versus being put on a waiting list);

• medicines including bupropion (versus placebo) or cytisine (versus nicotine replacement therapy);

• comparisons between different types and doses of nicotine replacement therapy.

Main results

Counselling plus nicotine replacement therapy together with continued support after leaving hospital compared with usual care (5 studies, 1611 people):

• may increase the number of people who are still not smoking six months after leaving hospital by about 6 more people per 100; and

• may result in fewer deaths (1 less death per 100 people), but this result is very uncertain.

What are the limitations of the evidence?

Our results are based on a limited number of studies, and our confidence in the evidence is low. We had very low confidence in the result for deaths because there were very few deaths in the studies.

Anti-smoking medicines, such as varenicline, have previously been shown to work for people with mental illness in the community, but we found no studies that tested their use in a hospital psychiatry ward.

How up to date is this evidence?

This review is up to date to 10 February 2026.

Key messages

• School-based programmes may prevent adolescents from starting to use electronic cigarettes (e-cigarettes) and a community-based programme delivered by text message probably helps adolescents quit using e-cigarettes.

• The evidence is very limited because only three studies contributed to the results.

• Another 30 studies are underway, and we have five more published studies to check. They may provide more answers in the future.

What are electronic cigarettes?

E-cigarettes, also known as vapes, are battery-operated devices that heat a liquid and produce an aerosol (a mix of small particles released in the air) which is inhaled through the mouth into the lungs. They can include electronic cigars, 'snus' (a Swedish tobacco device) or water pipes, and may or may not contain nicotine.

It was generally thought that these devices might lead to people stopping smoking ('current-users') and it is clear that they help adults to quit. However, young people who are not smoking ('never-users') are more likely to try these devices, and they can cause harm to the lungs, such as asthma and effects on development and learning.

What type of programmes are used to stop children and adolescents from using e-cigarettes?

The types of programmes included: education, training and communication (either community- or school-based) or public announcements; other programmes could include family strategies, medicines or counselling, all designed to influence children or adolescents to prevent or stop e-cigarette use.

What did we want to find out?

We wanted to find out:

• whether programmes designed to prevent children and adolescents from starting to use e-cigarettes, or to quit using them, are effective;

• if the programmes had any unwanted effects on children's and adolescents' health, or on the organisations that delivered them.

What did we do?

We searched for studies that investigated programmes to prevent children and adolescents from starting to use e-cigarettes (never-users) or to help them quit using e-cigarettes (current-users).

• Studies could compare programmes with no programme, being on a waiting-list for a programme or another general health programme. The programmes had to be delivered in the community, school, health services, hospitals, or the home.

• People had to be children or adolescents aged 19 years or younger, but also included their parents or caregivers and health professionals.

• The use of tobacco was measured either in the laboratory or by parent- or self-reports, questionnaires or surveys.

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 three studies with 10,510 adolescents.

• All participants in the studies were adolescents, with an age range from 12 to 17 years.

• Two of the studies (undertaken in Sweden and Australia) targeted never-users and were delivered in schools. The Swedish study (1176 adolescents) lasted three years and required an agreement signed between caregivers or parents and the adolescent pledging to not take up smoking; they also received an annual education session. This programme was compared with four annual educational sessions. The Australian study (7654 adolescents) had four weeks of programmes (40-minute lessons) and was compared with the usual health curriculum.

• One US prevention study (with 1681 current-users), delivered in the community, used a text-based message system which lasted four or 14 weeks (depending on whether a quit date was given or no quit date was given, respectively). It was compared with either monthly text messages that reported e-cigarette use or a waiting-list control (that is, people on a waiting list to receive treatment).

Main results

• The two combined studies of never-users found that school-based programmes may help prevent adolescents from ever trying e-cigarettes, but we are very uncertain about the results: 33% of ever-users on school programmes started trying using e-cigarettes compared to 31% of those having an alternative programme (two studies, 8830 people).

• The remaining study found that a community-based programme (for current-users) probably helps adolescents quit e-cigarette use: 45% of adolescents on the programme reported continuing the use of e-cigarettes compared to 62% with an alternative programme or a waiting-list (1 study, 1681 people).

• No studies provided information on the unwanted effects of the programmes.

What are the limitations of this evidence?

Given that the review only included three studies, very limited evidence is available for us to determine what programmes may work to help prevent or stop adolescent e-cigarette use. Our confidence in the evidence was very low-to-moderate because there were very few studies found, the programmes were different, and the studies lasted for different time periods.

How up-to-date is this evidence?

This evidence is current to September 1, 2025. This updates our previous review published in 2024.

Key messages

• Due to limited evidence, the effect of liver support systems used alongside standard care compared with standard care alone in people with acute liver failure (rapid loss of liver function) is unclear, and definite conclusions cannot be reached.

• We do not know if the use of liver support systems (therapeutic devices) may decrease or increase death from any cause within 28 days or by the end of the study, the number of serious unwanted effects, the need for liver transplantation, hepatic encephalopathy (brain dysfunction due to liver failure), or the number of multi-organ failures at maximal follow-up, because the evidence is very uncertain.

• No studies reported well-being.

What is acute liver failure?

Acute liver failure is a life-threatening condition. People with acute liver failure have severe liver injury, reduced ability of the liver to produce proteins (e.g. for blood clotting, fluid balance, and production of glucose), and hepatic encephalopathy (altered mental status). Acute liver failure is often caused by viral infections, overdoses of drugs or alcohol.

How can acute liver failure be treated?

Treatment of acute liver failure depends on its causes. In addition to standard medical care, doctors use liver support systems to clean patients' blood of drugs and other harmful substances until the liver works as usual or until a new liver is available for transplantation. There are two types of liver support system: artificial (referred to as non-biological devices or cell-free techniques) and bioartificial liver support systems (referred to as biological liver support devices).

What did we want to find out?

As liver support systems are being used despite the conflicting results of studies and guideline recommendations, we wanted to find out if any of the liver support systems may decrease death due to any cause within 28 days or by the end of the study, the number of serious unwanted effects, the need for liver transplantation, hepatic encephalopathy, the number of multi-organ failures, and non-serious unwanted effects for adults with acute liver failure.

What did we do?

We searched for clinical studies that randomly assigned adults with acute liver failure to have any type of liver support system alongside standard care or receive standard care alone. We 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 identified 11 studies. The studies were conducted before the year 2019 and varied in size, quality, and outcomes. All participants had acute liver failure due to various causes, mainly drug poisoning, viral hepatitis, alcohol, or indeterminate causes. The diagnosis of acute liver failure varied across countries and over time. The studies mostly included adults, although a few children were also included; ages ranged from 10 to 69 years old. People were admitted to intensive care units as they were seriously ill, and almost all participants needed liver transplantation. We measured results at the end of the studies.

It is very uncertain whether liver support systems may have any effect on the risk of dying within 28 days (9 studies with 539 participants), within one year (11 studies with 681 participants), on the number of serious unwanted effects (11 studies with 681 participants), and on the need for liver transplantation (5 studies with 519 participants). No study included health-related well-being as an outcome. The evidence is very uncertain about the effect of liver support systems on hepatic encephalopathy (2 studies with 34 participants). Liver support systems may result in little to no difference in the number of multi-organ failures (6 studies with 501 participants), but the evidence is very uncertain. Only one study reported non-serious unwanted effects. Four studies were fully or partially funded by industry, five had no industry funding, and two did not mention their funding sources.

We found no ongoing studies.

What are the limitations of the evidence?

Two of the 11 included studies were only published in short formats rather than full academic papers. We identified studies published between 1973 and 2019 that used various types of liver support systems. Most were small single-centre studies.

We are not confident in the evidence because all studies had problems with study design and there were not enough people in the studies to be sure of their results. Most liver support systems used in the studies were produced by small manufacturers and were on the market for only a short time. Currently, none of the bioartificial liver support systems are available on the market.

How up to date is this evidence?

Date of last search: 10 July 2025

Key messages

• The time of day when on-pump heart surgery (which uses a heart-lung machine) is performed may affect patient outcomes.

• We found one small study suggesting that late surgery (afternoon start) could reduce heart muscle injury compared to early surgery (morning start), but it did not provide clear evidence on survival during hospitalisation, heart attacks, complications such as irregular heartbeats, or how long someone needed to stay in hospital. We did not find any studies looking at short-term or long-term survival after hospital discharge, heart function, how long someone needed intensive care, and quality of life after surgery.

• More research is needed to determine whether scheduling heart surgery later in the day improves patient outcomes.

What is heart surgery, and why does timing matter?

Heart surgery is commonly used to treat problems involving the valves that control blood flow through a person's heart and the vessels that control blood supply to the heart. Many operations require a heart-lung machine (on-pump surgery) to temporarily take over the function of the heart and lungs during surgery.

The body follows a natural 24-hour cycle, known as the circadian rhythm, which we know affects heart function. Some studies suggest the heart may tolerate the stress of surgery better in the afternoon, reducing the risk of complications. However, the evidence is unclear, and it is important to determine if changing surgery schedules could improve patient outcomes.

What did we want to find out?

We wanted to find out whether having heart surgery in the afternoon improves survival, reduces heart damage, and prevents complications compared to having surgery in the morning.

What did we do?

We searched for high-quality studies (randomised controlled trials) that compared outcomes between people who had heart surgery in the morning versus those who had it in the afternoon. We 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 one study with 88 participants that compared early and late surgery.

• Survival: no study reported whether the time of surgery affected survival in the short term or long term. In the included study, no patients died in either group while in the hospital.

• Heart attacks: the included study found no clear difference in the number of heart attacks that occurred during or after surgery between morning and afternoon groups.

• Heart muscle injury: the included study suggested that heart muscle injury (measured by a blood test called troponin) was lower in patients who had surgery in the afternoon.

• Complications: there was no difference in complications such as irregular heartbeats (atrial fibrillation), heart function (left ventricular ejection fraction), or hospital length of stay.

What are the limitations of the evidence?

The evidence is limited because we found only one small study. We cannot be certain whether surgical timing truly affects outcomes or whether the results were due to chance. More high-quality studies that include more patients are needed.

How up to date is this evidence?

The evidence in this review is up to date as of 26 January 2025.

Key messages

• Vitamin D supplements compared with placebo (a sham treatment) may slightly reduce the number of young children who need a doctor or hospital visit for sudden infections in the lungs and airways (acute respiratory infections (ARIs)). They probably do not change how often each child visits a doctor or hospital. Higher doses of vitamin D compared with lower doses probably do not reduce how many children need a doctor or hospital visit for an ARI and do not reduce how often each child visits.

• Vitamin D supplements appear safe, showing little to no impact on the risk of developing high blood calcium levels.

• High-quality studies comparing vitamin D supplements with placebo are needed to find out whether vitamin D prevents ARIs in young children.

What are acute respiratory infections?

Acute respiratory infections are sudden infections that can affect the nose, ears, throat, airways, or lungs and are a major cause of illness and death in children younger than five years of age. Typically caused by viruses or bacteria, ARIs are a common reason for doctor or hospital visits in this age group. Symptoms often include a cough, runny nose, sore throat, fever, or difficulty breathing. In children under five years, symptoms may also include fast breathing, wheezing, poor feeding, vomiting, or being unusually sleepy or irritable.

What is vitamin D, and why is it important?

Vitamin D is a nutrient best known for supporting bone health. It also plays a role in developing a healthy immune system (the body's defence against infections). People get vitamin D from sunlight, a small number of foods, foods with vitamin D added, or from supplements. Many pregnant women and young children around the world do not get enough vitamin D because of limited sun exposure, diet, or other factors, which may increase the risk of ARIs in children.

What did we want to find out?

This review aimed to find out whether vitamin D supplementation during pregnancy or early childhood:

• reduces the number of young children who require a doctor or hospital visit for an ARI;

• reduces how often each child needs to visit a doctor or hospital for ARIs;

• causes harm by increasing calcium levels in the blood (hypercalcaemia) of pregnant women or children.

What did we do?

We searched for studies that compared either:

• giving vitamin D versus a placebo (a sham treatment); or

• using a higher dose of vitamin D compared to a lower dose.

We compared and summarised the findings and assessed how confident we could be in the evidence, based on the quality of the study methods.

What did we find?

We found 107 studies involving 31,521 pregnant women and children. Vitamin D was given during pregnancy, early childhood, or both. The amount and timing of vitamin D varied. It was most often given daily, but sometimes less frequently, including as large single doses. The studies were conducted in many countries. For each participant, the study duration ranged from one day to 18 months. The studies were conducted in hospitals, day-care centres, communities, or homes.

When vitamin D is compared with a placebo, supplementation may slightly reduce the number of children who need a doctor or hospital visit for an ARI. However, vitamin D does not reduce how often each child visits a doctor or hospital for an ARI.

When higher doses of vitamin D are compared with lower doses, higher doses probably do not reduce the number of children who need a doctor or hospital visit for an ARI and do not reduce how often each child visits.

Vitamin D supplementation appears to be safe. High blood calcium levels were rare, and vitamin D supplementation may have little to no effect on the risk of developing high blood calcium levels in pregnant women and young children.

What are the limitations of the evidence?

We have low confidence in the evidence about whether vitamin D reduces doctor or hospital visits for ARIs. Results varied between studies, with some suggesting a small benefit and others showing no clear effect.

Many studies were small, which limits how reliable they are. Additionally, differences in vitamin D dosing and how ARIs were measured made it difficult to combine and interpret the results across studies.

How up to date is this evidence?

This evidence is current to 18 March 2025.

Key messages

• For making symptoms go away (remission), ustekinumab works slightly better than placebo (sham treatment). Adalimumab plus immune system drugs, guselkumab and upadacitinib probably work slightly better than placebo, while vedolizumab and natalizumab probably work only a little better than placebo.

• For stopping symptoms coming back (preventing active disease) within one to two years of remission, adalimumab probably works slightly better than placebo.

• In the short term (about one year), compared to placebo, upadacitinib, ustekinumab and vedolizumab probably lead to fewer people stopping treatment due to unwanted effects. We can’t be sure about unwanted effects of biologics in the long term based on the existing evidence.

What is Crohn's disease?

Crohn's disease is a life-long (chronic) inflammatory disease that can affect any part of the gut. Common symptoms include bloody poo (stool or faeces), diarrhoea, stomach ache, fever, weight loss, fatigue and others. When someone is experiencing symptoms of Crohn's, they are said to have 'active' disease, and when their symptoms are under control, then they are said to be 'in remission'. We don't know what exactly causes Crohn's, but it could be related to a combination of genes, immune system malfunction, 'bad' gut bacteria and environmental reasons. There is no known cure, but the symptoms are usually managed with medications, such as steroids, immune system medications and, if necessary, surgery.

What are biologics?

At the turn of the century, a new category of medications called biologics, or advanced treatments, became available and started being widely used for the treatment of Crohn's. These are new and different treatments that target parts of the immune system more specifically than the older treatments, and they are thought to be better and have fewer unwanted effects. They can be delivered through a vein (intravenous), under the skin or sometimes orally.

What did we want to find out?

We wanted to find out whether all the biologics (medications that target specific parts of the immune system) or advanced treatments that are being used (or have been tested) can treat Crohn's, whether they have unwanted effects and how they compare to each other. The things we looked for were whether a medication can make symptoms go away, improve symptoms or make the gut look healed during a colonoscopy (examination inside the colon), as well as whether these medications have unwanted effects in the short term (up to one to two years) and long term (longer than two years).

What did we do?

We searched for studies that compared biologics with any other medical treatment or a placebo (a sham treatment) for adults with Crohn’s disease. People in the studies could be men or women. They could have had Crohn’s disease for any length of time and have used any medication for their Crohn’s disease. We summarised the findings and assessed how confident we could be in the results, based on how the studies were designed and carried out.

What did we find?

We included 94 studies with 27,476 people, with about equal numbers of men and women. Most people were around 30 to 40 years old, but they ranged from older adolescents to people in their sixties. Severity in the induction studies was moderate to severe. In the maintenance studies, some people were in remission and some had responded to previous therapy and still had some symptoms. Most induction studies followed people for three to six months and maintenance studies for about one year.

Main results

• There were 66 induction studies, involving 20,653 people, and 22 maintenance studies, involving 6823 people.

• For making symptoms go away (remission), ustekinumab works slightly better than placebo (sham treatment). Adalimumab plus immune system drugs, guselkumab and upadacitinib probably work slightly better than placebo, while vedolizumab and natalizumab probably work only a little better than placebo. Risankizumab, BI695501 (a medication that resembles adalimumab), a combination of infliximab with immune system medications, and filgotinib may also work, but we are less certain about them.

• We are uncertain whether other medications work or not, compared to placebo.

• For stopping symptoms coming back (preventing active disease) within one to two years of remission, adalimumab probably works slightly better than placebo.

• In the short term (about one year), compared to placebo, upadacitinib, ustekinumab and vedolizumab probably lead to fewer people stopping treatment due to unwanted effects. Other medications like risankizumab, certolizumab and filgotinib could be similar to placebo too, but we're less certain about them.

• We can’t be sure about unwanted effects of biologics in the long term based on the existing evidence.

What are the limitations of the evidence?

The included studies had people with very different characteristics between them, such as mixes of people who have or have not used biologics or advanced treatments before, people with more or less serious disease, and people using or not using other treatments at the same time. When these characteristics of people are not similar across the studies, it can make it difficult to be sure of the results.

The information we have is mainly around clinical symptoms, and information from colonoscopies or microscope examination was limited. There were also some issues with the way the included studies were carried out and the quality of the methods they used.

How up to date is this review?

This review is up to date to June 2025.

Key messages

- Audit and feedback in healthcare is when a health professional's performance is evaluated and compared to professional standards (audit). Then the health professionals are given the results of the comparison (feedback), with the hope that it might help them improve their performance.

- Audit and feedback helps to improve health professional performance a little to a moderate amount. It works best when it shows health professionals how they compare to top performers, focuses on important areas for improvement, and includes tips for making changes. Audit and feedback can be even more helpful when combined with other supports like reminders or extra training.

- Future research should focus on finding the best ways to improve audit and feedback interventions.

What is meant by audit and feedback in healthcare?

Audit and feedback is often used in healthcare organisations to improve healthcare professionals’ performance. In an audit and feedback process, an individual’s professional practice or performance is measured and then compared to professional standards or targets. In other words, their professional performance is “audited”. During the "feedback", the results of this comparison are then provided to health professionals. The aim of this process is to encourage healthcare professionals to take action or make changes to follow standards.

What did we do?

We searched for all the studies in which healthcare professionals were randomised to receive audit and feedback and in which the results on professional practice were measured.

What did we find?

We found 292 studies that met the requirements. We found that audit and feedback is often used together with other strategies to improve quality of care, such as educational meetings or reminders. Most studies measured the effect of audit and feedback on doctors, although some studies measured the effect on nurses or pharmacists. Audit and feedback was used to influence their performance in different areas, including the proper use of prescription treatments or test-ordering.

The exact way that audit and feedback was delivered varied widely across the studies. Sometimes health professionals were given feedback verbally, other times in writing, on an electronic dashboard or through multiple modes. In some studies, this feedback was given to them by the researchers responsible for the study, while in other studies, feedback was given by supervisors or colleagues. In some studies, health professionals were given feedback only once, while others were given feedback monthly. Sometimes, they were also given or supported to create an action plan with suggestions or advice about how to improve their performance.

Main results: What happens when health professionals are audited and provided with feedback?

The effect of using audit and feedback varied widely across the included studies, but most often it achieves small-to-moderate improvements in quality of care.

Audit and feedback may be most effective when recipients can see how their own performance compares to their high-performing peers, when it helps the health professional to identify and take action on high-priority clinical issues, and when it focuses on areas where health professionals have substantial room for improvement. Other features of audit and feedback that are associated with greater effects are when it involves measurement of the individual recipient's practice (rather than their team or organisation); comes from a respected peer with an existing relationship to the recipient; includes multiple modalities (e.g., verbal and written); and features an action plan with advice for improvement.

In addition, the effect of audit and feedback may change when combined with other strategies that support improved quality of care, such as education or reminders.

What are the limitations of the evidence?

The quality of the evidence is moderate and further research is needed to confirm the features of audit and feedback that are most likely to achieve the greatest effects in different situations.

How up to date is this evidence?

This review updates our previous review. The evidence analysed is up-to-date to June 2020.