Critical appraisal

Question 1

What 4 factors are involved when making an evidence based decision?

Answer 1

1) Evidence from research
2) Clinical expertise
3) Available resources
4) Patient preferences

Question 2

State 3 reasons why we need evidence based medicine.

Answer 2

1) Increases medical knowledge
2) There is limited time to read
3) Traditional resources such as books can prove to be inadequate (are often out of date)
4) There is a disparity between diagnostic skills/ clinical judgement and up to date knowledge.

Question 3

What is evidence based medicine?

Answer 3

A process for identifying and using the most up to date and relevant evidence to inform decisions for individual patient problems.

Question 4

Give 3 reasons why evidence based medicine is possible.

Answer 4

1) The development of strategies for effectively identifying and appraising evidence.
2) The creation of systematic reviews and summaries
3) The creation of evidence-based journals and clinical guidelines
4) The creation of information systems
5) The identification and application of strategies for lifelong learning.

Question 5

What are background questions?

Answer 5

Background questions are informational questions that improve the understanding of a topic.

The questions usually have one or two concepts and do not require the process used in formulating a research or evidence based decision-making questions.

They basically ask general knowledge about a disorder.

E.G. What causes breast cancer?

Question 6

What are foreground questions?

Answer 6

Foreground questions ask for specific knowledge to inform clinical decisions.

These questions typically concern a specific patient or particular population.
Foreground questions tend to be more specific and complex compared to background questions.

E.G. In younger women with breast cancer, is mastectomy with chemotherapy more effective than mastectomy done alone, in reducing the risk of cancer recurrence?

Question 7

What are typically the 4 essential components to a foreground question?

Answer 7

1) Patient, problem, population
2) Intervention
3) Comparison intervention/ control
4) Clinical outcomes

Question 8

When asking foreground questions, accuracy can be classed as what?

Answer 8

Having a low false positive rate and a low false negative rate.

Question 9

What are the aspects of a PICO question?

Answer 9

• Patient/ population/ problem
• Intervention
• Comparator/ control
• Outcome

Question 10

What are the aspects of a PEO question?

Answer 10

• Population/ patient/ problem
• Exposure
• Outcome

Question 11

When are PEO questions used over PICO questions?

Answer 11

When there is no obvious control group.

Question 12

Which studies are used for the following question types?

1) Diagnosis
2) Aetiology/ harm
3) Prognosis
4) Treatment
5) Evaluation

Answer 12

1) Cross sectional analytical study/ SR
2) Cohort study/ population based case-control study/ SR
3) Cohort study/SR
4) RCT/ SR of RCTs
5) Qualitative research/ SR/ meta-analysis

Question 13

What is the difference between case-control and cohort studies?

Answer 13

Case control studies are retrospective. Cohort studies follow people prospectively.

Question 14

Describe 3 benefits of systematic reviews over individual primary studies.

Answer 14

1) Include all available research evidence to answer a question.
2) Include research that is unpublished or has been published in non-English language journals.
3) Increase the total sample size (increases levels of certainty and precision).
4) Indicate heterogeneity (variation) among studies
5) Permit sub-group analyses
6) Permit sensitivity analysis.

Question 15

What is bias?

Answer 15

The systematic introduction of error into a study that can distort the results in a non-random way.

Question 16

What are the 3 discrete steps in appraising some evidence?

Answer 16

1) Are the results of the study valid?
2) What are the results?
3) Can I apply the results to this patient’s care?

Question 17

What 5 things must you assess a research study for?

Answer 17

1) Bias
2) Applicability
3) Limits
4) Value
5) Whether the evidence provided is useful for patient care.

Question 18

In terms of results, what must you report for studies looking at each of the following factors?

1) Therapy (RCT)
2) Diagnosis
3) Prognosis
4) Aetiology/ harm

Answer 18

1) Relative risk reduction, absolute risk reduction, odds ration, NNT, confidence intervals.
2) Sensitivity, specific, PPV, NPV, likelihood ratios.
3) Likelihood of outcomes overtime, how precise prognosis estimates are (relative risk/ odds ratio).
4) Relative risk, odds ration, NNtH.

Question 19

What must you consider when deciding if you can use the results of a study?

Answer 19

GENERALISABILITY:

1) How similar are the patients in the study to your patient?
2) Can the local health service provide the intervention/ diagnostic test?
3) What are the benefits and costs (potential harms/ financial costs)?

Question 20

For systematic reviews, state what must be considered for each of the following questions:

1) Did the review ask a clearly focused question?
2) Did the review include the right type of study?

Answer 20

1) Consider if the question is focused in terms of: the population studied, the intervention given/ the exposure and the outcomes considered.
2) Consider if the included studies: address the review’s question and have an appropriate study design.

Question 21

For systematic reviews, state what must be considered for each of the following questions:

1) Did the reviewers try to identify all relevant studies?

Answer 21

Consider:

• which bibliographic databases were used.
• if there was a follow-up from the reference list.
• if there was personal contact with experts.
• if the reviewers searched for unpublished studies.
• if the reviewers searched for non-English language studies.

**Increases the number of studies and ensures all relevant studies (incl. those with null or negative results) are included in the review.

Question 22

For systematic reviews, state what must be considered for each of the following questions:

1) Did the reviewers assess the quality of the included studies?

Answer 22

Consider:

• if a clear, pre-determined strategy was used to determine which studies were included.
• a scoring system
• more than one assessor.

**Look for individual studies assessed for quality by more than one reviewer, using standard criteria. This means that it is more likely that only studies of good quality are included.

Question 23

For systematic reviews, state what must be considered for each of the following questions:

1) If the results of the studies have been combined, was it reasonable to do so?

Answer 23

Consider whether:

• the results of each study are clearly displayed.
• the results were similar from study to study.
• the reasons for any variations in results are discussed.

**If studies are very dissimilar, then results should not be combined. Combined results provide stronger evidence, but only when it is appropriate to do so.

Question 24

For systematic reviews, state what must be considered for each of the following questions:

1) How are the results presented and what is the main result?

Answer 24

Consider:

• how the results are expressed (odds ratio/ relative risk, etc)
• how large this size of result is and how meaningful it is.
• how you would sum up the bottom-line result in one sentence.

Question 25

For systematic reviews, state what must be considered for each of the following questions: 1) How precise are these results?

Answer 25

Consider: - if a confidence interval were reported. - would your decision about whether or not to use this intervention be the same at the upper confidence limit as at the lower confidence limit? - if a p-value is reported where confidence intervals are unavailable.

Question 26

For systematic reviews, state what must be considered for each of the following questions: 1) Can the results be applied to the local population?

Answer 26

Consider whether: - the population sample covered by the review could be different from your population in ways that would produce a different result. - your local setting differs much from that of the review. - you can provide the same intervention in your setting. **Because SRs can use heterogenous study populations, there may be details on sub-groups.

Question 27

For systematic reviews, state what must be considered for each of the following questions: 1) Were all important outcomes considered? 2) Should policy or practice change as a result of the evidence contained in this review?

Answer 27

1) Consider outcomes from the POV of the individual, policy makers and professionals, family/ carers and the wider community. 2) Consider whether any benefit reported outweighs any harm and/or cost. If this information is not reported, can it be filled in from elsewhere?

Question 28

For randomised control trials, state what must be considered for each of the following questions: 1) Did the study ask a clearly focused question? 2) Was this a randomised control trial and was it appropriately so?

Answer 28

1) Consider if the question is focused in terms of: population studied, intervention given and outcomes considered. 2) Consider why this study was carried out as an RCT and if this was the right research approach for the question being asked.

Question 29

For randomised control trials, state what must be considered for each of the following questions: 1) Were participants appropriately allocated to intervention and control groups?

Answer 29

Consider: - how participants were allocated to intervention and control groups. Was the process truly random? - whether the method of allocation was described. Was a method used to balance the randomisation, e.g. stratification? - how the randomisation schedule was generated and how a participant was allocated to a study group - if the groups were well balanced. Are any differences between the groups at entry to the trial reported? - if there were differences reported that might have explained any outcome(s) (confounding)

Question 30

For randomised control trials, state what must be considered for each of the following questions: 1) Were participants, staff and study personnel 'blind' to participants' study group?

Answer 30

Consider: - the fact that blinding is not always possible - if every effort was made to achieve blinding - if you think it matters in this study - the fact that we are looking for ‘observer bias’

Question 31

For randomised control trials, state what must be considered for each of the following questions: 1) Were all of the participants who entered the trial accounted for at its conclusion?

Answer 31

Consider: - if any intervention-group participants got a control group option or vice versa. - if all participants were followed up in each study group (was there loss-to-follow-up?) - if all the participants' outcomes were analysed by the groups to which they are originally allocated (intention to treat analysis). - what additional information would you liked to have seen to make you feel better about this.

Question 32

For randomised control trials, state what must be considered for each of the following questions: 1) Were the participants in all groups followed up and data collected in the same way? 2) Did the study have enough participants to minimise the play of chance?

Answer 32

1) if, for example, they were reviewed at the same time intervals and if they received the same amount of attention from researchers and health workers. Any differences may introduce performance bias. 2) if there is a power calculation. This will estimate how many participants are needed to be reasonably sure of finding something important (if it really exists and for a given level of uncertainty about the final result).

Question 33

For randomised control trials, state what must be considered for each of the following questions: 1) How are the results presented and what is the main result?

Answer 33

Consider: 1) if, for example, the results are presented as a proportion of people experiencing an outcome, such as risks, or as a measurement, such as mean or median differences, or as survival curves and hazards 2) how large this size of result is and how meaningful it is 3) how you would sum up the bottom-line result of the trial in one sentence

Question 34

For randomised control trials, state what must be considered for each of the following questions: 1) How precise are the results?

Answer 34

Consider: 1) if the result is precise enough to make a decision 2) if a confidence interval were reported. Would your decision about whether or not to use this intervention be the same at the upper confidence limit as at the lower confidence limit? 3) if a p-value is reported where confidence intervals are unavailable

Question 35

For randomised control trials, state what must be considered for each of the following questions: 1) Were all important outcomes considered so the results can be applied?

Answer 35

Consider whether: 1) the people included in the trial could be different from your population in ways that would produce different results 2) your local setting differs much from that of the trial 3) you can provide the same treatment in your setting Consider outcomes from the point of view of the: 1) Individual 2) policy makers and professionals 3) family/ carers 4) wider community Consider whether: 1) any benefit reported outweighs any harm and/or cost. If this information is not reported can it be filled in from elsewhere? 2) policy or practice should change as a result of the evidence contained in this trial

Question 36

What is meant by the term 'statistical power'?

Answer 36

Statistical power, or the power of a hypothesis test is the probability that the test correctly rejects the null hypothesis. That is, the probability of a true positive result. It is only useful when the null hypothesis is rejected.

Question 37

What does a statistical power of 80% mean?

Answer 37

0% power in a clinical trial means that the study has a 80% chance of ending up with a p value of less than 5% in a statistical test (i.e. a statistically significant treatment effect) if there really was an important difference (e.g. 10% versus 5% mortality) between treatments.

Question 38

For a cohort study, state what must be considered for each of the following questions: 1) Did the study address a clearly focussed question?

Answer 38

Consider: - the population studied - the risk factors studied - the outcomes considered - is it clear whether the study tried to detect a beneficial or harmful effect?

Question 39

For a cohort/ case-control study, state what must be considered for each of the following questions: 1) Did the study address a clearly focussed question?

Answer 39

Consider: - the population studied - the risk factors studied - the outcomes considered - is it clear whether the study tried to detect a beneficial or harmful effect?

Question 40

For a cohort/ case-control study, state what must be considered for each of the following questions: 1) Did the authors use an appropriate method to answer their question?

Answer 40

Consider: - Is a cohort/ case-control study a good way of answering the question under the circumstances? - Did it address the study question?

Question 41

For a cohort study, state what must be considered for each of the following questions: 1) Was the exposure accurately measured to minimise bias?

Answer 41

We are looking for measurement or classification bias: - Did they use subjective or objective measurements? - Do the measures truly reflect what you want them to (have they been validated)? - Were all the subjects classified into exposure groups using the same procedure?

Question 42

For a cohort study, state what must be considered for each of the following questions: 1) Was the outcome accurately measured to minimise bias?

Answer 42

HINT: We are looking for measurement or classification bias: - Did they use subjective or objective measurements? - Do the measures truly reflect what you want them to (have they been validated)? - Has a reliable system been established for detecting all the cases (for measuring disease occurrence)? - Were the measurement methods similar in the different groups? -Were the subjects and/or the outcome assessor blinded to exposure (does this matter)?

Question 43

For a cohort study, state what must be considered for each of the following questions: 1) Have the authors identified all important confounding factors? List the ones you think might be important but the author has missed. 1a) Have they taken account of the confounding factors in the design and/ or analysis?

Answer 43

HINT: Look for restriction in design, and techniques eg modelling, stratified-, regression-, or sensitivity analysis to correct, control or adjust for confounding factors

Question 44

For a cohort study, state what must be considered for each of the following questions: 1) Was the follow up of subjects complete enough? 1a) Was the follow up of subjects long enough?

Answer 44

- The good or bad effects should have had long enough to reveal themselves. - The persons that are lost to follow-up may have different outcomes than those available for assessment - In an open or dynamic cohort, was there anything special about the outcome of the people leaving, or the exposure of the people entering the cohort?

Question 45

For a cohort study, state what must be considered for each of the following questions: 1) What are the results of this study?

Answer 45

- What are the bottom line results? - Have they reported the rate or the proportion between the exposed/unexposed, the ratio/the rate difference? - How strong is the association between exposure and outcome (RR,)? - What is the absolute risk reduction (ARR)?

Question 46

For a cohort study, state what must be considered for each of the following questions: 1) How precise are the results? How precise is the estimate of the risk?

Answer 46

Consider the size of the confidence intervals.

Question 47

For a cohort study, state what must be considered for each of the following questions: 1) Do you believe the results?

Answer 47

- Big effect is hard to ignore! - Can it be due to bias, chance or confounding? - Are the design and methods of this study sufficiently flawed to make the results unreliable? - Consider Bradford Hills criteria (eg time sequence, dose-response gradient, biological plausibility, consistency).

Question 48

For a cohort study, state what must be considered for each of the following questions: 1) Can the results be applied to the local population?

Answer 48

Consider whether: - The subjects covered in the study could be sufficiently different from your population to cause concern. - Your local setting is likely to differ much from that of the study - Can you quantify the local benefits and harms? **Always consider if the results of the study fit with other available evidence as recommendations from observational studies are always stronger when supported by other evidence.

Question 49

For a case control study, state what must be considered for the following question: were the cases recruited in an acceptable way?

Answer 49

HINT: We are looking for selection bias which might compromise the validity of the findings: - Are the cases defined precisely? - Were the cases representative of a defined population (geographically and/or temporally)? - Was there an established reliable system for selecting all the cases? - Are they incident or prevalent? - Is there something special about the cases? - Is the time frame of the study relevant to the disease/exposure? - Was there a sufficient number of cases selected? - Was there a power calculation?

Question 50

For a case control study, state what must be considered for the following question: were the cases recruited in an acceptable way?

Answer 50

HINT: We are looking for selection bias which might compromise the validity of the findings: - Are the cases defined precisely? - Were the cases representative of a defined population (geographically and/or temporally)? - Was there an established reliable system for selecting all the cases? - Are they incident or prevalent? - Is there something special about the cases? - Is the time frame of the study relevant to the disease/exposure? - Was there a sufficient number of cases selected? - Was there a power calculation?

Question 51

For a case control study, state what must be considered for the following question: were the controls recruited in an acceptable way?

Answer 51

HINT: We are looking for selection bias which might compromise the generalisability of the findings: - Were the controls representative of a defined population (geographically and/or temporally)? - Was there something special about the controls? - Was the non-response high? Could non- respondents be different in any way? - Are they matched, population based or randomly selected? - Was there a sufficient number of controls selected?

Question 52

For a case control study, state what must be considered for the following question: Was the exposure accurately measured to minimise bias?

Answer 52

HINT: We are looking for measurement, recall or classification bias: - Was the exposure clearly defined and accurately measured? - Did the authors use subjective or objective measurements? - Do the measures truly reflect what they are supposed to measure? (have they been validated)? - Were the measurement methods similar in cases and controls? - Did the study incorporate blinding where feasible? - Is the temporal relation correct (does the exposure of interest precede the outcome?)

Question 53

For a case control study, state what must be considered for the following question: 1) What confounding factors have the authors accounted for? List the other ones that you think might be important but the authors missed. 1b) Have the authors taken account of the potential confounding factors in the design and/ or in their analysis?

Answer 53

HINT: Look for restriction in design, and techniques e.g. modelling, stratified-, regression-, or sensitivity analysis to correct, control or adjust for confounding factors.

Question 54

For a case control study, state what must be considered for the following question: What are the results of this study?

Answer 54

Consider: - What are the bottom line results? - Is the analysis appropriate to the design? - How strong is the association between exposure and outcome (look at the odds ratio)? - Are the results adjusted for confounding and might confounding still explain the association? - Has adjustment made a big difference to the OR ??

Question 55

For a case control study, state what must be considered for the following question: How precise are the results?

Answer 55

Consider: - Size of the P-value - Size of the confidence intervals - Have the authors considered all the important variables? - How was the effect of subjects refusing to participate evaluated?

Question 56

For a case control study, state what must be considered for the following question: Do you believe the results?

Answer 56

- Big effect is hard to ignore! - Can it be due to chance, bias or confounding? - Are the design and methods of this study sufficiently flawed to make the results unreliable? - Consider Bradford Hills criteria (e.g. time sequence, dose-response gradient, strength, biological plausibility)

Question 57

For a case control study, state what must be considered for the following question: Can the results be applied to the local population?

Answer 57

Consider whether: - The subjects covered in the study could be sufficiently different from your population to cause concern. - Your local setting is likely to differ much from that of the study. - Can you estimate the local benefits and harms?

Question 58

For a case control study, state what must be considered for the following question: Do the results of this study fit with other available evidence?

Answer 58

HINT: Consider all the available evidence from RCTs, systematic reviews, cohort studies and case-control studies as well for consistency. **Recommendations from observational studies are always stronger when supported by other evidence.

Question 59

What is selection bias?

Answer 59

Error in the process of selecting participants for the study and assigning them to particular arms of the study. **Bias introduced by the selection of individuals, groups or data for analysis in such a way that proper randomization is not achieved, thereby ensuring that the sample obtained is not representative of the population intended to be analyzed

Question 60

What is attrition bias?

Answer 60

Occurs when those patients who are lost to follow-up differ in a systematic way to those who did return for assessment or clinic. **Bias that arises from systematic differences in the way participants are lost from a study.

Question 61

What is measurement bias?

Answer 61

Measurement bias refers to any systematic or non-random error that occurs in the collection of data in a study. **when information is recorded in a distorted manner (e.g. an inaccurate measurement tool).

Question 62

What is observer bias?

Answer 62

Occurs when variables are reported differently between assessors.

Question 63

What is procedure bias?

Answer 63

Occurs when subjects in different arms of the study are treated differently (other than the exposure or intervention).

Question 64

What is misclassification bias?

Answer 64

Occurs when a study participant is categorised into an incorrect category altering the observed association or research outcome of interest. **Basically occurs when a variable is classified incorrectly.

Question 65

What is information bias?

Answer 65

Information bias is any systematic difference from the truth that arises in the collection, recall, recording and handling of information in a study, including how missing data is dealt with. **Happens when key information is either measured, collected, or interpreted inaccurately.

Question 66

What are the 4 major types of information bias?

Answer 66

Misclassification bias Observer bias Recall bias Reporting bias

Question 67

What are Bradford Hill criteria used for?

Answer 67

The Bradford Hill criteria are a group of nine principles which can be useful in establishing epidemiological evidence of a causal relationship between a presumed cause and an observed effect. **They describe reasons that indicate causality.

Question 68

What are the 9 Bradford Hill criteria?

Answer 68

1) strength of association 2) consistency 3) specificity 4) temporality 5) biological gradient 6) plausibility 7) coherence 8) experiment 9) analogy

Question 69

What is confounding?

Answer 69

Happens when a relationship between an exposure and an outcome is distorted by their shared relationship with another variable.

Question 70

Name 4 ways in which confounding can be addressed in study design and/or analysis.

Answer 70

1) Restriction 2) Matching 3) Stratification 4) Mutliple variable regression

Question 71

How is restriction carried out in terms of addressing confounding variables?

Answer 71

- exclusion of participants with the identified confounding factor - means that you will have less data - difficult to implement when there are multiple confounding factors.

Question 72

How is matching carried out in terms of addressing confounding variables?

Answer 72

- equal distribution among exposed and unexposed groups of the variables believed to be confounding variable. - used commonly in case-control studies - used for strong confounders like age and sex - not the most effective answer to most confounding variables

Question 73

How is stratification carried out in terms of addressing confounding variables?

Answer 73

- an analytical approach where exposure: outcome associations are categorised into different subgroups of the confounder. - different subgroups are known as different strata.

Question 74

How is multiple variable regression carried out in terms of addressing confounding variables?

Answer 74

Allows us to estimate the association between a given independent variable and the outcome holding all other variables constant. It provides a way of adjusting for (or accounting for) potentially confounding variables that have been included in the model.

Question 75

What is the additional step required if using stratification to manage confounding factors?

Answer 75

Adjustment. The final step in stratified analysis is to recombined the results of the strata to get an adjustment measure of effect.

Question 76

What is a limitation of stratification and how can this be overcome?

Answer 76

If all potential confounders were stratified, then each strata would have very few people in it and so there would be very little data available to use. Regression is used in some cases and this is a mathematical model used to 'fill in the gaps'.

Question 77

Give 3 examples of confounding factors.

Answer 77

1) Age 2) Sex 3) Smoking status 4) Socioeconomic status

Question 78

What is evidence based decision making?

Answer 78

The process for identifying and using the most up to date and relevant evidence to inform decisions for individual patient problems.

Question 79

What does critical appraisal assess a research study for?

Answer 79

Bias, applicability and value. CA identifies whether the evidence a study provides is useful for patient care.

Question 80

What does phase III of a clinical trial often involve?

Answer 80

RCTs with one or more experimental treatments being compared against control/ standard treatments. Attempts are made to draw a definite conclusion regarding benefit or otherwise.

Question 81

What is the best method of allocation in an RCT?

Answer 81

An independent organisation who centrally organise randomised allocation via a computer programme. This is designed to be unpredictable and is the least subject to potential subversion of the allocation process.

Question 82

What are the advantages of a systematic review?

Answer 82

- All available evidence - Published/Unpublished research - Increased total sample size = certainty and precision - Indicated heterogeneity - Subgroup and sensitivity analyses

Question 83

What are the disadvantages of a systematic review?

Answer 83

- Researcher can only use published or readily available studies - Conclusions may be unreliable - Unpublished studies may be hard to find - Results that are negative or inconclusive may remain unpublished

Question 84

What are the advantages of an RCT?

Answer 84

- Causal inferences - Randomisation minimises bias - Tailored to a specific research question

Question 85

What are the disadvantages of an RCT?

Answer 85

- Not always ethical - High dropout when intervention has undesirable effects - Expensive

Question 86

What are the advantages of cohort studies?

Answer 86

``` -Measurement of exposure to risk factor(s) not biased by the presence or absence of outcome -Can provide data on time course of development of an outcome -More than one outcome can be examined at once -Useful for investigating rare exposures ```

Question 87

What are the disadvantages of cohort studies?

Answer 87

- Potential for bias due to selection of subjects - Danger of losses to follow-up OR historical studies dependent on accuracy of records/ family/ patient recall - Exposure to risk factors/existence of prognostic factors may change over course of study - Can be timely and costly to carry out (e.g. some cohort studies can last for 20 years or more)

Question 88

What are the advantages of case-control studies?

Answer 88

- Rare disease, long latency - Less costly and time consuming - Studying dynamic populations in which follow up is difficult

Question 89

What are the disadvantages of case-control studies?

Answer 89

- Subject to selection bias - Inefficient for rare exposures - Subject to observation bias - Hard to calculate incidence - Bias and confounding. - Recall bias

Question 90

Describe what is meant by the following Bradford Hill criteria: 1) Strength of association 2) Temporal association 3) Consistency

Answer 90

1) Small vs. large association and statistical significance. 2) The effect has to occur after the cause. 3) Are findings consistent with other knowns?

Question 91

Describe what is meant by the following Bradford Hill criteria: 1) Theoretical plausibility 2) Coherence 3) Specificity

Answer 91

1) Not everything that is implausible is false. 2) Coherence between epidemiological and laboratory findings increases the likelihood of an effect. 3) Does this cause only lead to this effect?

Question 92

Describe what is meant by the following Bradford Hill criteria: 1) Dose-response relationship 2) Experimental evidence 3) Analogy

Answer 92

1) Does more of cause = more effect? 2) Strong vs. weak evidence. Some things you cannot test experimentally. 3) The effect of similar factors may be considered.