Aseptic Practice Flashcards
(148 cards)
1
Q
What is the difference between sterile and aseptic?
A
Sterile describes the state of the product. Aseptic describes the practice of producing products.
2
Q
Describe the BP sterility test.
A
12 hours to perform the BP sterility test and then incubate for 14 days.
3
Q
What came about due to the Manchester incident in 1994?
A
The Farwell Report (1995), Regular Audits, Identification of the need to ensure there are standards in place.
4
Q
Who can be issued a Full Product License?
A
Large pharmaceuticals companies (i.e. GSK), to make specific (named) forms/strengths of a drug.
5
Q
Who can be issued a Specials License?
A
Hospital specials departments and specials manufacturers overseen by a pharmacist.
6
Q
What can be produced under a Specials License?
A
Specified medicinal forms, strengths etc. They can have a longer shelf life, be manufactured in batches, and do not need a prescription for production.
7
Q
Can you produce, under a specials license, a formulation produced by another specials manufacturer?
A
No, you must buy from them.
8
Q
Why are specials produced in bulk?
A
Because the physician may prescribe this medication multiple times.
9
Q
Can specials be advertised?
A
Other users can be told what the drugs strenght and form is but the producer cant say the drug has x effect.
10
Q
What does section 10 say?
A
That a registered pharmacist in registered premises can produce extemperaneous products for a named patient (on a prescription).
11
Q
What doccumentation is needed in an aseptic suite?
A
SOPs, product specifications, dispensing and preparation records, site records, site master file.
12
Q
Can an SOP include multiple activities?
A
No, they must be specific for one activity.
13
Q
What is a clean room?
A
A clean room is a space in which the number and concentration of viable (living organisms) and non-viable (dust etc.) airborne particles is controlled.
14
Q
What are clean room designed to prevent?
A
Clean rooms, by design, are clean in order to prevent contamination and in turn prevent infection (microorganisms – viable particles), phlebitis (particulate effect – non-viable particles), and ADRs.
15
Q
Define phlebitis.
A
“damage to the vein wall from injection of irritant substances, and injection using infected needles can cause thrombophlebitis as can prolonged insertion of cannulas for intravenous infusion.”
16
Q
Describe a Grade A area in a clean room.
A
This is the area inside the laminar flow hood and the isolator, where pharmaceutical manipulation occurs.
17
Q
Describe a Grade B area in a clean room.
A
The environment outside of the laminar flow hood.
Should be a small space to reduce particles forming when staff move about but not too small so staff don’t bump.
18
Q
Describe a Grade C area in a clean room.
A
This area is used for the preparation of solutions to be filtered and is also the grade of clean room found in changing rooms.
19
Q
How many air changes are there every hour in grade C and D areas in a clean room?
A
20.
20
Q
How many air changes are there every hour in grade B clean rooms?
A
30.
21
Q
Is the pressure in a clean room higher or lower than the rooms outside?
A
Higher.
22
Q
What is the air in clean rooms higher than the outside?
A
So when doors are opened, the air flows out and carries particulates out instead of bringing them into the clean room and increasing contamination.
23
Q
What is the minimum clothing requirements for the grade D environment in a clean room?
A
Hair, and where relevant, facial hair, beards, and moustaches including stubble should be completely covered, for example with a beard snood. A non-shedding protective coat and suit. Dedicated shoes or overshoes.
24
Q
What is the minimum clothing requirements for the grade C environment in a clean room?
A
Hair, and where relevant, facial hair, beards, and moustaches including stubble should be completely covered, for example with a beard snood. A single- or two-piece trouser suit (which sheds virtually no fibres or particulate matter), gathered at the wrists and with a high neck. Dedicated shoes or overshoes.
25
What is the minimum clothing requirements for the grade B environment in a clean room?
Headgear should totally enclose hair, and where relevant, facial hair, beards and moustaches including stubble; it should be tucked into the neck of the suit. A sterile face mask. Non-powdered sterile gloves. A single piece clean room overall, gathered at the wrists and with a high neck. Trouser legs should be tucked inside the footwear and garment sleeves into the gloves. Dedicated footwear (e.g. clean room slippers). All clothing should shed virtually no fibres or particulate matter.
26
What is a skin squame?
A scale or flake of skin.
27
How many skin squames does a person produce when they sit?
100,000.
28
How many skin squames are produced when a person moves?
1,000,000.
29
How many skin squames does a person produce when they walk?
5,000,000.
30
What should the number of skin squames a person produces be monitored and reduced where possible?
These squames may carry microorganisms that can infect the products and also act as non-viable particles.
31
Why is washing hands essential before working in a clean room?
Washing hands is essential before working in a clean room to prevent the transmission of any viable and non-viable particles on the hands of the person working in the clean room.
32
What should happen to tattoos and open wounds on a person working in a clean room?
Open wounds, such as tattoos should be covered in a plaster and then gloved/covered in PPE.
33
What percentage of contamination in a clean room comes from filtration equipment?
15%.
34
What percentage of contamination in a clean room comes from equipment?
25%.
35
What percentage of contamination in a clean room comes from human sources?
60%.
36
How is the cleanliness of the air in a clean room assessed?
To assess the cleanliness of the air in the clean room, one can simply open a culture plate and let viable particles fall onto it. It is then cultured and gives information on the extent and type of viable particles in the air of the clean room.
37
What colour plate are Pseudomonas (bacteria) cultured on?
White/cream.
38
How do the colonies of Pseudomonas (bacteria) present?
Earthy-green cultures of rod-shaped bacteria.
39
What colour plate are Staphylococcus (bacteria) cultured on?
Blood red plate.
40
How do the colonies of Staphylococcus (bacteria) present?
Creamy gold cultures of spherical bacteria.
41
What colour plate are Sporotrichosis (fungus) cultured on?
Green/clear plate.
42
How do the colonies of Sporotrichosis (fungus) present?
Typical round fungal growths (the type can’t be determined so the plate must be sent to histology).
43
How is the presence of the herpes simplex virus assessed?
Assessed on a microscope slide in which a dye is used to make the cell membranes fluoresce.
44
Endotoxins are a viable contaminant; what are they?
They are protein complexes released from the cell membranes of gram-negative bacteria (e.g. E. coli) at cell lysis. They cause non-specific toxicity including pyrexia. They are heat stable so can’t be killed by high temperatures.
45
Exotoxins are viable contaminants; what are they?
Exotoxins are proteins secreted from cells (e.g. Vibro cholerae) and have a specific toxic action. These are heat labile, they can be killed by heat.
46
How many particles does the typical TPN bag contain?
2.5 million.
47
What particles, viable or non-viable, would one prefer to have in a product?
Non-viable.
48
Where should isolators be situated?
Isolators must be situated in a minimum of a grade D room, however, in practice they are often put into grade C rooms. This room must be a dedicated room with access control and no sinks.
49
What types of isolators are there?
Negative and positive pressure isolators.
50
Describe the air flow within an isolator.
The air flow within the isolators is turbulent, to aid in particle removal.
51
In most cases, which type of isolator is prefered? Why?
Positive pressure isolators are often preferred in most cases. The reason the air within the isolator is at a greater pressure than the surrounding air is to prevent any particulates from the outside of the isolator entering the isolator should the seal be broken. Any particles would be forced out by the pressure.
52
When are negative pressure isolators most often used?
Negative pressure isolators are used when the item being worked on in the isolator may give of particularly harmful particles. An example of this is radiopharmaceuticals; if the seal was broken and the isolator pressure was greater than that of the surrounding air, the harmful particles of radiation may be forced out of the isolator and irradiate the area. It increases the safety of the operator.
53
What processes are used in cleaning a clean room?
Cleaning, decontamination, disinfection, sterilisation.
54
What equipment is used to clean a clean room?
Vacuum, mop, buckets, wipes.
55
Describe the 'cleaning' step of cleaning a clean room.
Removal of visible items.
56
Describe the 'decontamination' step of cleaning a clean room.
Removal of contamination that can't be seen (particulates).
57
Describe the 'disinfection' step of cleaning a clean room.
Destruction of microorganisms (viable).
58
Describe the 'sterilisation' step of cleaning a clean room.
Desctuction of all microorganisms - must conform to BP sterility test requirements.
59
Describe the process of mopping the floor in a clean room.
A triple bucket mopping system is used - one bucket for clean disinfectant, one to rinse disinfectant, and one for waste. A new mophead must be used every time the mop touches the floor. Mop in an S-shaped motion.
60
How often should a Grade A area in a clean room be cleaned?
Every time it is worked in.
61
How often should a GRade B area in a clean room be cleaned?
Every time one works the area.
62
How often should a Grade C area in a clean room be cleaned?
Start and end of the day.
63
How often should floors, walls, and ceilings be disinfected and decontaminated in a clean room?
The floors, walls, and ceilings need decontaminating and disinfecting weekly (or monthly depending on the workload).
64
What can happen if cleaning isn't carried out when it is needed?
If cleaning isn’t carried out when it is needed then the contamination can rapidly increase, increasing the risk to patients.
65
What steps should be carried out before and during entry to the aseptic suite?
1. SOP training (everything from entry to dressing and aseptic technique).
2. Prescription verification.
3. Print out labels and ‘dispensing and preparation record’.
4. Obtain stock.
5. General hand wash.
6. Gown up.
7. Retrieve stock (from spraying in hatch).
8. Move to grade A.
66
Explain the process of spraying in when working in a clean room.
This is the process of cleaning the containers of materials used in the production of aseptic products before they are brought into the aseptic suite.
The technique spray, wipe, spray is used. This means one should spray the product with 80% alcohol spray, then wipe with an alcohol wipe, and then re-spray with the alcohol solution.
Whilst carrying this procedure out, one must invert and inspect the containers for any damage that may compromise their cleanliness.
67
What products are used in the process of spraying in, in a clean room?
Spraying and alcohol wipes are used in conjunction with one another as not all contaminating bacteria are killed by alcohol wipes alone. The spray is able to get into all the nooks and crannies of the container as well.
68
What are critical surfaces on a product/piece of equipment?
Critical surfaces are surfaces on products that should never be touched as they come into contact with the aseptic solutions and products themselves.
69
Give some examples of critical surfaces on a product/piece of equipment.
* Needles.
* The joint between needle and syringe.
* The seal on the top of a vial/ampoule.
* The plunger of a syringe.
70
How should packaging be opened in a clean room? Why is this important?
Packaging should always be peeled open by the dedicated opening. This helps reduce the generation of particulates that would occur if the packaging was ripped open.
71
Explain proper needle technique in a clean room setting.
When working with needles, one should always attach the needle to the syringe as soon as possible. The needle should also remain sheathed when not in use.
Needles should be inserted into the rubber bung of vials at an angle and then should be straightened. It is inserted at an angle to ensure the bung isn’t cored and the product isn’t contaminated. Never twist or turn the needle.
When filling a syringe, the vial should be turned upside down.
72
Explain laminar flow of air.
The air in the laminar flow hood is described as such as it features air which flows in only one direction. This can be either horizontal or vertical and each flow direction has different characteristics and uses.
73
Describe horizontal laminar flow and its uses.
Horizontal flow flows from the back of the cabinet out of the front. It is used when the product needs specific protection from particulates and contaminants in the air, forcing them out of the cabinet.
74
Describe vertical laminar flow and its uses.
Vertical flow flows from the top of the cabinet to the bottom. It is used when the operator needs protection from any particulates that may come from the cabinet (e.g. cytotoxics) but the need for protection isn’t important enough to warrant the use of the isolator.
75
In terms of clean rooms and aseptic practice, what is first air?
This is the most contaminant-free air in the whole room, being air straight from the air filtration system. Ideally, the product should only be exposed to this air. It is very expensive to produce.
As soon as the first air touches anything, it is no longer first air.
76
Where may turbulent air be seen in a laminar flow hood?
Turbulence is created in a transitional cone-shaped zone behind any item or particle in the laminar flow hood.
77
What may be the consequences of turbulent air in a laminar flow hood?
This turbulence causes the deposition of particulates behind the item causing the turbulence, in the transition zone.
78
How can the effects of turbulent air in a laminar flow hood be reduced?
The spacing of items in the work area is very important. No item should be behind another, to prevent deposition of particles in the transitional zone of the front item.
79
What is TPN/PN?
TPN/PN is a way of supplying a patient’s total or partial nutritional requirements intravenously.
80
How long do TPN bags last for?
24-48 hours.
81
When should TPN bags be administered?
They should be administered as soon as they are made up (unless they are commercially available bags containing preservatives).
82
Who may need TPN/PN?
Healthcare professionals should consider parenteral nutrition in people who are malnourished or at risk of malnutrition and meet either of the following criteria:
• Inadequate or unsafe oral and/or enteral nutrition intake.
• A non-functional, inaccessible, or perforated (leaking) gastrointestinal tract.
83
What conditions may TPN be considered in?
* Bowel surgery.
* Crohns Disease.
* Burns.
* Fistulas.
84
What does TPN contain?
Nitrogen, calories, vitamins, trace elements.
85
From what source does the nitrogen in TPN bags come?
Amino acids.
86
From what sources do the calories in TPN bags come?
o Glucose/Dextrose.
| o Fat emulsion.
87
Why should amino acids be given instead or proteins and dextrose be given instead of carbohydrates?
The digestive process is bypassed so digested substrates are needed.
88
Which trace elements are found in a TPN bag?
```
o Sodium.
o Potassium.
o Calcium.
o Phosphate.
o Magnesium.
o Zinc.
```
89
In what form is sodium given in TPN bags?
Sodium chloride.
90
In what form is potassium given in TPN bags?
Potassium chloride.
91
How is the level of chloride balanced out in TPN bags?
The level of chloride is balanced out with the level of acetate in the TPN mixture. Chloride induces hydrogen ion retention which induces metabolic acidosis.
Acetate is converted to bicarbonate which can induce metabolic alkalosis.
92
If metabolic acidosis or alkalosis is diagnosed, what about the TPN solution can be changed?
The chloride:acetate ratio.
93
Glucose should be used to supply what percentage of the patient's energy need?
50-70%.
94
What is the maximum and minimum dose of glucose given in a TPN solution?
Giving a minimum of 3.0g/kg/day and a maximum of 7.0g/kg/day.
95
Lipids should be used to supply what percentage of the patient's energy need?
30-50%.
96
What is the maximum and minimum dose of lipids given in a TPN solution?
Giving a minimum of 0.3g/kg/day and a maximum of 3.0g/kg/day.
97
How much amino acids should an adult with normal metabolism and organ function receive in a TPN solution?
Adults with normal metabolism and organ function should receive 0.8g/kg/day.
98
How should the dosage of amino acids be increased, in a TPN bag, for metabolic needs?
This should be increased to 1.2-1.5g/kg/day for metabolic needs.
99
What should the max daily allowance of amino acids per day in a TPN bag not exceed?
The max daily allowance of amino acids should not exceed 2-2.5g/kg/day.
100
What characteristic of TPN bags helps to prevent interactions and issues of stability between the components?
In a TPN bag, the different components are separated until they are administered into the patient, this lowers the chance of the components interacting and causing issues of stability.
101
Patients with renal impairment, who are given TPN, need special consideration. Explain this special consideration.
When ordering TPN for these patients, one should use a lower fluid amount in order to not fluid overload the patient. Also, the levels of electrolytes should be altered, normally lowered, to account for their impairment.
102
In most situations, which line is preferred for the administration of TPN solutions to a patient? Why?
In most situations the peripheral line is preferred for TPN as is in the patient’s hand and doesn’t require any complex surgery, making administration easier, quicker and safer.
103
Which line may be used when administering large volumes of fluid or hypertonic solutions to a patient?
However, when large volumes of fluid or hypertonic solutions need to be administered, the central line may need to be used.
104
When may the central line be used?
However, when large volumes of fluid or hypertonic solutions need to be administered, the central line may need to be used.
105
Why can the central line be used to administer larger volumes of fluid to a patient?
Larger volumes can be administered through the central line as the veins here are larger in diameter so the chance for damage to the vessels by large volumes of fluids is reduced. Also, the blood flows through central veins at a greater rate so the increased fluid volume can be dispersed quicker.
106
Why can the centra line be used to administer hypertonic solutions to a patient?
The central line is used for hypertonic solutions for the same reasons as the central line is used for high volumes of fluids. The high-volume flow of blood in the central lines dilutes the hypertonic solutions, bringing them closer to the osmolarity of the blood and mitigating the damage that would be done if hypertonic solutions are given via the peripheral route.
107
What would happen if a hypertonic solution was given via the peripheral route?
If hypertonic solutions are given by the peripheral route, due to the slow flow and low volume of blood, the red blood cells in contact with it would lose water from within them to try and balance the osmotic gradient and would shrink and die.
108
What is the main drawback of using the central line?
The drawback of using the central line is that it needs surgery to be set up, which can put the patient’s body undue stress if the TPN solution can be given by the peripheral route.
109
After the Manchester 1994 incident, what did the Farwell Report identify?
In the aftermath of this tragedy, The Farwell Report was carried out and this identified the need to ensure standards of practice in pharmacy aseptic units. This included the need for regular audits.
110
What is required on an SOP for aseptic practice?
1. Designed and prepared (author) and date.
2. Approved by and date.
3. Orderly and easy to check.
4. Reproduction of the master must be error free.
5. Typed.
6. Traceable (number).
7. Prevents use of a superseded document.
8. Regular reviews.
9. Persons capable of or training for operation.
111
Do aseptic suite product specifications allow for the substitution of materials?
Replacement of specific materials is not allowed, only the ones listed in the specification are allowed. The product specifications do at least allow a supplier to vary the item in a limited way.
112
What must the dispensing and preparation record (work order) include?
* Name and formula.
* Batch number (in case of recalls).
* Expiry date.
* Date of preparation.
* Copy of the label (to double check).
* Batch and supplier name for medicinal products.
* A written protocol.
* Reconciliation procedure for labels.
* Signature or initials of technical staff.
* Supervising pharmacist signatures.
* Signature for final check.
* Patients name.
* Comments section.
113
Site records consist of a batch record book, what must this contain?
* Batch number.
* Product code.
* Product name, strength, and quantity.
* Container.
* Label reference.
* Expiry date.
* Number manufactured.
* Batch size.
* Date prepared.
* Ward, patients name, consultant.
* Prepared and checked by.
114
What is CIVAS (central intravenous additive service)?
The central intravenous additive service supplied many medications that require complex aseptic preparation before administration. CIVAS agents are added to normal infusions e.g. saline.
115
When verifying an aseptic prescription, what must be on the document?
* Signature and date (authorised prescriber).
* Patient details (name, hospital number, weight).
* Calculation of BSA.
* Dose calculation.
* Compliance with dosage regimen.
* Administration (route, diluent, volume, rate, duration).
* Compatibility of the constituents.
* Stability of the formulation.
* Correct presentation for the route of administration.
* Contraindications of drug interactions.
116
Give examples of drugs often given as part of CIVAS.
```
• Antibiotics.
o Amoxycillin, teicoplanin.
• Analgesics.
o Morphine, fentanyl, bupivacaine.
• Cytotoxic drugs.
• Radiodiagnostics.
```
117
What pharmaceutical parameters should be considered when carrying compounding of medication?
```
• Method and route of administration.
o Final volume.
• Dosage and concentration.
• Reconstituting solution.
o Ringers lactate.
o Ringers.
o Normal saline.
o Water for injection.
• Precipitation of active or complexation.
• Osmolarity, pH, ionic strength.
• ADR’s.
```
118
What infusion fluid should diabetics avoid?
Glucose.
119
What infusion fluid should hypertensive patients avoid?
Saline.
120
Ringer's lactate has many species in it, what can this cause?
Ringer’s lactate contains many species so has osmolarity problems and many drug interactions.
121
What is drug instability?
This term regards irreversible chemical reactions (oxidation, photolysis, hydrolysis, trace element catalysis) by which the product is modified due to storage conditions (e.g. time, light, temperature, sorption).
122
What can drug instability lead to?
These reactions result in different chemical entities being formed, either generating inactive or toxic species leading to therapeutic inefficacy or toxicity respectively.
123
Can drug instability reactions be stopped?
Drug instability/degradation reactions can be slowed down but can’t be fully stopped.
124
What factors can affect the instability of infusions?
* Temperature effects.
* Concentration effects.
* Sorption phenomena.
* Leaching of plasticisers.
* Photodegradation.
* pH.
125
For each 10-degree temperature rise, how does the rate of an endothermic reaction change?
2-5x.
126
How can temperature effect drug instability?
Higher temperatures can increase the rate of drug degradation reactions. Higher temperatures can evaporate solvents or concentrate the drug solution. Lower temperatures can affect some molecules such as ampicillin.
127
How can concentration effect drug instability?
Increases in drug concentration may increase the rate of degradation. This may be more significant in syringe drivers where higher drug concentrations are usually present (central line administration).
128
Explain sorption phenomena.
This where the drug may be adsorbed onto the material making up the container it is contained in or passes through.
129
What is the extent of binding in sorption phenomena affected by?
The extent of binding is affected by drug concentration, vehicle, flow rate, temperature, pH, time, surface area, and material.
130
Give examples of drugs affected by sorption phenomena.
Examples of drugs affected by this include; insulin, diazepam, nimodipine, nitrates, chlormethiazole.
131
Explain the case study of a patient on TPN experiencing night blindness with regards to sorption phenomena.
There was a case study of a patient on TPN experiencing night blindness even though they had no previous vision problems. When she was removed from TPN her vision recovered. Then when she was re-administered with TPN the condition returned.
This was because the vitamin A in the TPN was being adsorbed onto the plastic of the system, leading to a deficiency and night blindness.
132
How can the leaching of plasticizers affect drug instability?
Formulations containing oils and surfactants can leach out plasticisers in PVC containers e.g. cyclosporin. Leaching from rubber plungers of plastic syringes can affect stability.
133
Give examples of drugs which can be affected by photodegradation.
This is significant for a small number of drugs, including vitamin A and sodium nitroprusside.
This is usually due to UV light although sodium nitroprusside is also degraded by fluorescent light.
134
How can pH affect drug instability? How can this be combated in the solution?
Extremes of pH may affect the degradation rate of some drugs (instabilities), buffers may be included in the formulation to improve stability.
135
What are drug incompatibilities?
Drug incompatibilities are physiochemical reactions (acid-base reactions) which are preventable and/or reversible. They are often concentration-dependent precipitations or insolubility.
136
If drug incompatibility changes are visible, what are they termed?
If the changes are visible, then they are termed physical incompatibilities.
137
With regards to drug incompatabilities, why may a product be unsuitable for administration?
* The active drug has been modified e.g. leading to an increase in toxicity.
* A physical change has occurred e.g. a change in solubility.
138
What factors can affect the incompatibility of drugs/compounds in an infusion?
* Saturation or solubility limits.
* pH.
* Drug-drug co-precipitation.
* Choice of diluent or infusion fluid.
* Salting out.
139
Explain saturation or solubility limits when it comes to drug incompatibilities.
The drug will remain in solution as long as its concentration is below saturation solubility. For syringe drivers this may be affected by time and temperature. A specific example is calcium and phosphate ions; one should take care when preparing these bags.
140
How can pH affect drug incompatibilities?
Some drugs (weak acids) are formulated at high pH to achieve solubility. If pH is reduced by addition of a less alkaline solution, precipitation may occur. One should check the likely impact of changes in pH on stability if mixing drugs.
141
WHen may drug-drug co-precipitation be seen?
This is usually achieved by mixing organic anions with cations (e.g. heparin and aminoglycosides (gentamicin)). This may depend on the concentration of the solution.
142
If two drugs are likely to give co-precipitation, what should be done?
If drugs are likely to have this reaction, one shouldn’t ever mix them. If they need to be given in close succession, one should flush the infusion line with saline between administrations.
143
Explain the phenomenon of salting out?
This is a phenomenon seen when the solubility of non-electrolytes and weakly hydrated organic ions is reduced when in the presence of strong electrolytes (inorganic electrolytes). The strong electrolytes tend to take up all the water molecules when they dissolve, forcing the less strong electrolytes and non-electrolytes out of solution.
144
Give an example of the phenomenon of salting out.
An example of this is mixtures of diamorphine hydrochloride and cyclizine lactate forming cyclizine hydrochloride which has low solubility.
145
Define shelf-life.
Shelf life is defined as the time it takes for 10% of the concentration limits outlined in the BP take to degrade, leaving 90%.
146
How are shelf-life boundries tested?
These parameters are tested through accelerated stability testing.
147
Give some consequences of precipitation of drugs.
• Inactive drug (drug not in solution so can’t be absorbed).
• Blocked catheters.
o Less drug gets through per unit time hence reduced therapeutic effect.
• Damage to capillaries.
• May lead to coronary and pulmonary emboli.
o Calcium phosphate related emboli deaths have been reported.
• Thrombophlebitis.
• Site reactions in subcutaneous tissue (immune response).
148
How are milliequivalents calculated?
One milliequivalent (mEq) is equal to 1 mM divided by its valence.
