Diabetes Flashcards
(101 cards)
1
Q
Ix T1DM (5 things)
A
urine dip: glucose and ketones
fasting glucose and random glucose
HbA1c: may not accurately reflect a recent rapid rise in serum glucose
C-peptide: low
diabetes-specific autoantibodies: useful to distinguish between type 1 and type 2 diabetes
2
Q
T1DM autoantibodies
A
- glutamic acid decarboxylase (anti-GAD)
- insulin (IAA)
- islet cells (ICA)
- insulinoma-associated-2 (IA-2A)
3
Q
T1DM diagnostic criteria
A
symptomatic:
- fasting glucose >7.0 mmol/l
- random glucose > 11.1 mmol/l
(or after 75g oral glucose tolerance test)
asymptomatic:
- above criteria demonstrated on two separate occasions.
4
Q
T1DM
- age
- speed of onset
- features
A
- < 20 years
- more acute, hours-days
- features of DKA, weight loss, ketonuria
5
Q
T2DM
- age
- speed of onset
- features
A
- > 40 years
- slower, weeks-months
- milder symptoms, polyuria, polydipsia, obesity, ketonuria is rare
6
Q
T2DM diagnostic criteria
A
symptomatic:
- fasting glucose >7.0 mmol/l
- random glucose >11.1 mmol/l
(or after 75g oral glucose tolerance test)
asymptomatic
- above criteria apply but must be demonstrated on two separate occasions.
7
Q
HbA1c diagnosis of diabetes
A
HbA1c >48 mmol/mol (6.5%) = diabetes mellitus
8
Q
cause of misleading HbA1c results
A
increased red cell turnover
9
Q
conditions where HbA1c may not be used for diagnosis:
A
haemoglobinopathies
haemolytic anaemia, untreated iron deficiency anaemia
suspected gestational diabetes
children
HIV
chronic kidney disease
people taking medication that may cause hyperglycaemia (for example corticosteroids)
10
Q
fasting glucose
>6.1 but <7.0 mmol/l implies
A
impaired fasting glucose (IFG)
11
Q
Impaired glucose tolerance (IGT) is defined as
A
fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l implies
OGTT 2-hour value greater than or equal to 7.8 mmol/l but less than 11.1 mmol/l
12
Q
The main focus of diabetes management now is
A
reducing incidence of complications:
- macrovascular: ischaemic heart disease, stroke
- microvascular: eye, nerves and kidney damage
13
Q
T1DM
A
an autoimmune disorder where insulin-producing beta cells of the islets of Langerhans in the pancreas are destroyed by the immune system
this results in an absolute deficiency of insulin resulting in raised glucose levels
patients tend to develop T1DM in childhood/early adult life and typically present unwell, possibly in diabetic ketoacidosis
14
Q
T2DM
A
most common cause of diabetes in the developed world.
relative deficiency of insulin due to an excess of adipose tissue.
in simple terms there isn’t enough insulin to ‘go around’ all the excess fatty tissue, leading to blood glucose creeping up.
15
Q
prediabetes
A
patients who don’t yet meet the criteria for a formal diagnosis of T2DM to be made but are likely to develop the condition over the next few years.
they require closer monitoring and lifestyle interventions such as weight loss
16
Q
gestational diabetes
A
raised glucose levels during pregnancy.
important to detect as untreated it may lead to adverse outcomes for the mother and baby
17
Q
maturity onset diabetes of the young (MODY)
A
group of inherited genetic disorders affecting the production of insulin.
results in younger patients developing symptoms similar to those with T2DM
asymptomatic hyperglycaemia with progression to more severe complications such as diabetic ketoacidosis
18
Q
latent autoimmune diabetes of adults (LADA)
A
majority of patients with autoimmune-related diabetes present younger in life.
there are however a small group of patients who develop such problems later in life.
these patients are often misdiagnosed as having T2DM
19
Q
pathological processes which damage insulin-producing cells of pancreas and cause diabetes to develop.
A
chronic pancreatitis
haemochromatosis
20
Q
drugs which cause raised glucose levels
A
glucocorticoid
21
Q
polyuria and polydipsia are due to
A
water being ‘dragged’ out of the body
due to the osmotic effects of excess blood glucose being excreted in the urine (glycosuria).
22
Q
four main ways to check blood glucose:
A
finger-prick bedside glucose monitor
one-off blood glucose
- fasting
- non-fasting
HbA1c
- measures amount of glycosylated haemoglobin
- represents average blood glucose over past 2-3 months
glucose tolerance test
- fasting blood glucose is taken - 75g glucose load is taken
- after 2 hours a second blood glucose reading is then taken
23
Q
principle of managing T1DM
A
patients always require insulin to control the blood sugar levels.
this is because there is an absolute deficiency of insulin with no pancreatic tissue left to stimulate with drugs
different types of insulin are available according to their duration of action
24
Q
principle of managing T2DM
A
first-line: metformin
second-line: sulfonylureas, gliptins and pioglitazone.
if oral medication is not controlling the blood glucose to a sufficient degree then insulin is used
25
Insulin
Mechanism:
Route:
Main side effects:
Direct replacement for endogenous insulin
Subcutaneous
Hypoglycaemia, Weight gain, Lipodystrophy
Used in all patients with T1DM and some patients with poorly controlled T2DM
26
What is first line in T2DM?
Metformin
27
Metformin
Mechanism:
Route:
Main side effects & considerations?
Increases insulin sensitivity & Decreases hepatic gluconeogenesis
Oral
Gastrointestinal upset, Lactic acidosis
Cannot be used in patients with an eGFR of < 30 ml/min
28
```
Sulfonylureas
Mechanism:
Route:
Main side effects:
Examples:
```
Stimulate pancreatic beta cells to secrete insulin Oral
Hypoglycaemia, Weight gain, Hyponatraemia
Examples include gliclazide and glimepiride
29
```
Thiazolidinediones
Mechanism:
Route:
Main side effects:
Examples:
```
Activate PPAR-gamma receptor in adipocytes to promote adipogenesis and fatty acid uptake
Oral
Weight gain, Fluid retention
Only currently available thiazolidinedione is pioglitazone
30
```
DPP-4 inhibitors
Mechanism:
Route:
Main side effects:
Examples:
```
Increases incretin levels which inhibit glucagon secretion Oral Generally well tolerated but increased risk of pancreatitis
(-gliptins)
31
```
SGLT-2 inhibitors
Mechanism:
Route:
Main side effects:
Examples:
```
Inhibits reabsorption of glucose in the kidney Oral Urinary tract infection
(-gliflozins)
32
```
GLP-1 agonists (-tides)
Mechanism:
Route:
Main side effects:
Examples:
```
Incretin mimetic which inhibits glucagon secretion
Subcutaneous
Nausea and vomiting, Pancreatitis
(-tides)
33
Which diabetes meds result in weight loss
SGLT-2 inhibitors (-gliflozins)
| GLP-1 agonists (-tides)
34
What is glucagon-like peptide-1 (GLP-1),
hormone released by the small intestine in response to an oral glucose load
Increasing GLP-1 levels, either by the administration of an analogue (glucagon-like peptide-1, GLP-1 mimetics, e.g. exenatide) or inhibiting its breakdown (dipeptidyl peptidase-4 ,DPP-4 inhibitors - the gliptins), is therefore the target of two recent classes of drug.
35
What is the incretin effect
In normal physiology an oral glucose load results in a greater release of insulin than if the same load is given intravenously - this known as the incretin effect. This effect is largely mediated by GLP-1 and is known to be decreased in T2DM.
in t2dm insulin resistance and insufficient B-cell compensation occur
36
example of a glucagon-like peptide-1 (GLP-1) mimetic.
exenatide
| Liraglutide
37
Examples of Dipeptidyl peptidase-4 (DPP-4) inhibitors
Vildagliptin, sitagliptin
38
Key points of GLP-1 mimetics?
ne of the major advances of GLP-1 mimetics is that they typically result in weight loss, in contrast to many medications such as insulin, sulfonylureas and thiazolidinediones. They are sometimes used in combination with insulin in T2DM to minimise weight gain.
Exenatide must be given by subcutaneous injection within 60 minutes before the morning and evening meals. It should not be given after a meal.
Liraglutide is the other GLP-1 mimetic currently available. One the main advantages of liraglutide over exenatide is that it only needs to be given once a day.
Both exenatide and liraglutide may be combined with metformin and a sulfonylurea. Standard release exenatide is also licensed to be used with basal insulin alone or with metformin. Please see the BNF for a more complete list of licensed indications.
39
Consider adding exenatide to metformin and a sulfonylurea if:
BMI >= 35 kg/m² in people of European descent and there are problems associated with high weight, or
BMI < 35 kg/m² and insulin is unacceptable because of occupational implications or weight loss would benefit other comorbidities.
40
NICE like patients to have achieved a > 11 mmol/mol (1%) reduction in HbA1c and ?% weight loss after 6 months to justify the ongoing prescription of GLP-1 mimetics.
3%
41
The major adverse effect of GLP-1 mimetics is
nausea and vomiting. The Medicines and Healthcare products Regulatory Agency has issued specific warnings on the use of exenatide, reporting that is has been linked to severe pancreatitis in some patients.
42
Key points DPP-4 inhibitors?
dipeptidyl peptidase-4, DPP-4 inhibitors increase levels of incretins (GLP-1 and GIP) by decreasing their peripheral breakdown
oral preparation
trials to date show that the drugs are relatively well tolerated with no increased incidence of hypoglycaemia
do not cause weight gain
43
NICE guidelines on DPP-4 inhibitors
NICE suggest that a DPP-4 inhibitor might be preferable to a thiazolidinedione if further weight gain would cause significant problems, a thiazolidinedione is contraindicated or the person has had a poor response to a thiazolidinedione
44
NICE updated its guidance on the management of type 2 diabetes mellitus (T2DM) in 2015. there is more flexibility in the second stage of treating patients (i.e. after metformin has been started) - you now have a choice of 4 oral antidiabetic agents, what are these
sulfonylurea
gliptin
pioglitazone
SGLT-2 inhibitor
45
Dietary advice T2DM
encourage high fibre, low glycaemic index sources of carbohydrates
include low-fat dairy products and oily fish
control the intake of foods containing saturated fats and trans fatty acids
limited substitution of sucrose-containing foods for other carbohydrates is allowable, but care should be taken to avoid excess energy intake
discourage the use of foods marketed specifically at people with diabetes
initial target weight loss in an overweight person is 5-10%
46
HBA1C targets in T2DM
Lifestyle 48 mmol/mol (6.5%)
Lifestyle + metformin 48 mmol/mol (6.5%)
Includes any drug which may cause hypoglycaemia (e.g. lifestyle + sulfonylurea) 53 mmol/mol (7.0%)
Already on one drug, but HbA1c has risen to 58 mmol/mol (7.5%) 53 mmol/mol (7.0%)
47
a patient is newly diagnosed with T2DM and wants to try lifestyle treatment first. You agree a target of ?
you review a patient 6 months after starting metformin. His HbA1c is 51 mmol/mol (6.8%)
What next?
48 mmol/mol (6.5%)
| You increase his metformin from 500mg bd to 500mg tds and reinforce lifestyle factors
48
Outline mx T2DM for someone who tolerates metformin?
metformin is still first-line and should be offered if the HbA1c rises to 48 mmol/mol (6.5%)* on lifestyle interventions
if the HbA1c has risen to 58 mmol/mol (7.5%) then a second drug should be added from if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then triple therapy OR insulin therapy should be considered
49
Criteria for glucagon-like peptide1 (GLP1) mimetic (e.g. exenatide) in T2DM
if triple therapy is not effective, not tolerated or contraindicated then NICE advise that we consider combination therapy with metformin, a sulfonylurea and a glucagonlike peptide1 (GLP1) mimetic if:
BMI >= 35 kg/m² and specific psychological or other medical problems associated with obesity or
BMI < 35 kg/m² and for whom insulin therapy would have significant occupational implications or
weight loss would benefit other significant obesity-related comorbidities
only continue if there is a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss of at least 3% of initial body weight in 6 months
50
Outline mx T2DM for someone who
Cannot tolerate metformin or contraindicated
AND
HbA1c rises to 48 mmol/mol (6.5%)
if the HbA1c rises to 48 mmol/mol (6.5%) on lifestyle interventions, consider one of the following:
sulfonylurea
gliptin
pioglitazone
51
Outline mx T2DM for someone who
Cannot tolerate metformin or contraindicated
AND
if the HbA1c has risen to 58 mmol/mol (7.5%)
one of the following combinations should be used:
gliptin + pioglitazone
gliptin + sulfonylurea
pioglitazone + sulfonylurea
if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then consider insulin therapy
52
starting insulin in t2dm
metformin should be continued. In terms of other drugs NICE advice: 'Review the continued need for other blood glucose-lowering therapies'
NICE recommend starting with human NPH insulin (isophane, intermediate-acting) taken at bed-time or twice daily according to need
53
bp targets are the same in T2DM patients as everyone else
true
54
mx hypertension t2dm?
ACE inhibitors or angiotensin II receptor blockers (ARB) are first-line
an ARB is preferred if the patient has a black African or African–Caribbean family origin
55
mx lipids t2dm?
following the 2014 NICE lipid modification guidelines only patients with a 10-year cardiovascular risk > 10% (using QRISK2) should be offered a statin. The first-line statin of choice is atorvastatin 20mg on
56
T2DM pts should be offered antiplatelets
Antiplatelets
| should not be offered unless a patient has existing cardiovascular disease
57
The long-term management of type 1 diabetics is an important and complex process requiring the input of many different clinical specialties and members of the healthcare team.
true
58
A diagnosis of type 1 diabetes can still reduce the life expectancy of patients by 13 years and the micro and macrovascular complications are well documented.
true
59
T1DM HbA1c
| should be monitored HOW OFTEN
every 3-6 months
60
T1DM adults should have a target of HbA1c level of
48 mmol/mol (6.5%) or lower. NICE do however recommend taking into account factors such as the person's daily activities, aspirations, likelihood of complications, comorbidities, occupation and history of hypoglycaemia
61
How often should patients self-monitor blood glucose? T1DM
recommend testing at least 4 times a day, including before each meal and before bed
more frequent monitoring is recommended if frequency of hypoglycaemic episodes increases; during periods of illness; before, during and after sport; when planning pregnancy, during pregnancy and while breastfeeding
62
Blood glucose targets in T1DM?
5-7 mmol/l on waking and
| 4-7 mmol/l before meals at other times of the day
63
Insulin regime of T1DM?
offer multiple daily injection basal–bolus insulin regimens, rather than twice‑daily mixed insulin regimens, as the insulin injection regimen of choice for all adults
twice‑daily insulin detemir is the regime of choice. Once-daily insulin glargine or insulin detemir is an alternative
offer rapid‑acting insulin analogues injected before meals, rather than rapid‑acting soluble human or animal insulins, for mealtime insulin replacement for adults with type 1 diabetes
64
When should you add metformin in T1DM
considering adding metformin if the BMI >= 25 kg/m²
65
Type 2 diabetes mellitus is more common in people of which ethnicity?
Asian ethnicity
66
ound 79% of Muslim patients with type 2 diabetes mellitus fast Ramadan
true
67
If a patient with type 2 diabetes mellitus does decide to fast what advice do u give
they should try and and eat a meal containing long-acting carbohydrates prior to sunrise (Suhoor)
patients should be given a blood glucose monitor to allow them to check their glucose levels, particularly if they feel unwell
for patients taking metformin the expert consensus is that the dose should be split one-third before sunrise (Suhoor) and two-thirds after sunset (Iftar)
expert consensus also recommends switching once-daily sulfonylureas to after sunset. For patients taking twice-daily preparations such as gliclazide it is recommended that a larger proportion of the dose is taken after after sunset
no adjustment is needed for patients taking pioglitazone
68
people with diabetes who used insulin can not hold a HGV licence.
false
Until recently people with diabetes who used insulin could not hold a HGV licence. The DVLA changed the rules in October 2011.
69
DVLA rules for diabetes?
| (and also apply to patients using other hypoglycaemic inducing drugs such as sulfonylureas)?
there has not been any severe hypoglycaemic event in the previous 12 months
the driver has full hypoglycaemic awareness
the driver must show adequate control of the condition by regular blood glucose monitoring*, at least twice daily and at times relevant to driving
the driver must demonstrate an understanding of the risks of hypoglycaemia
here are no other debarring complications of diabetes
70
From a practical point of view patients on insulin who want to apply for a Group 2 (HGV) licence need to complete a
VDIAB1I form.
71
if on insulin then patient can drive a car as long as
hey have hypoglycaemic awareness, not more than one episode of hypoglycaemia requiring the assistance of another person within the preceding 12 months and no relevant visual impairment. Drivers are normally contacted by DVLA
72
if on tablets or exenatide no need to notify DVLA.
true
If tablets may induce hypoglycaemia (e.g. sulfonylureas) then there must not have been more than one episode of hypoglycaemia requiring the assistance of another person within the preceding 12 months
73
if diet controlled alone then no requirement to inform DVLA
true
74
The following are key messages that should be given to all patients with diabetes if they become unwell:
Increase frequency of blood glucose monitoring to four hourly or more frequently
Encourage fluid intake aiming for at least 3 litres in 24hrs
If unable to take struggling to eat may need sugary drinks to maintain carbohydrate intake
It is useful to educate patients so that they have a box of 'sick day supplies' that they can access if they become unwell
Access to a mobile phone has been shown to reduce progression of ketosis to diabetic ketoacidosis
75
Possible indications that a patient might require admission to hospital would include: (7 things)
Suspicion of underlying illness requiring hospital treatment eg myocardial infarction
Inability to keep fluids down - admit if persisting more than a few hours
Persistent diarrhoea
Significant ketosis in an insulin dependent diabetic despite additional insulin
Blood glucose persistently >20mmol/l despite additional insulin
Patient unable to manage adjustments to usual diabetes management
Lack of support at home e.g. a patient who lives alone and is at risk of becoming unconscious
76
Sick day rules If a patient is taking oral hypoglycaemic medication then what are the key points
they should be advised to continue taking their medication even if they are not eating much. Remember that the stress response to illness increases cortisol levels pushing blood sugars high even without much oral intake. The possible exception is with metformin, which should be stopped if a patient is becoming dehydrated because of the potential impact upon renal function.
77
Sick day rules If a patient is on insulin what are the key points?
If a patient is on insulinas per, they must not stop it due to the risk of diabetic ketoacidosis.
ensure that they are checking their blood sugars frequently.
check their ketone levels and if these are raised and blood sugars are also raised they may need to give corrective doses of insulin.
The corrective dose to be given varies by patient, but a rule of thumb would be total daily insulin dose divided by 6 (maximum 15 units).
78
Diabetic foot disease is an important complication of diabetes mellitus which should be screen for on a regular basis. How is this done?
All patients with diabetes should be screened for diabetic foot disease on at least an annual basis
screening for ischaemia: done by palpating for both the dorsalis pedis pulse and posterial tibial artery pulse
screening for neuropathy: a 10 g monofilament is used on various parts of the sole of the foot
79
Diabetic foot disease occurs due to?
neuropathy: resulting in loss of protective sensation (e.g. not noticing a stone in the shoe), Charcot's arthropathy, dry skin
peripheral arterial disease: diabetes is a risk factor for both macro and microvascular ischaemia
80
Presentations of diabetic foot disease?
neuropathy: loss of sensation
ischaemia: absent foot pulses, reduced ankle-brachial pressure index (ABPI), intermittent claudication
complications: calluses, ulceration, Charcot's arthropathy, cellulitis, osteomyelitis, gangrene
81
How do you risk stratify for diabetic foot disease?
Low risk
• no risk factors except callus alone
Moderate risk
deformity or
• neuropathy or
• non-critical limb ischaemia.
High risk
previous ulceration or
• previous amputation or
• on renal replacement therapy or
• neuropathy and non-critical limb ischaemia together or
• neuropathy in combination with callus and/or deformity or
• non-critical limb ischaemia in combination with callus and/or deformity.
82
Diabetic neuropathy is now managed in the same way as other forms of neuropathic pain:
first-line treatment: amitriptyline, duloxetine, gabapentin or pregabalin
if the first-line drug treatment does not work try one of the other 3 drugs
tramadol may be used as 'rescue therapy' for exacerbations of neuropathic pain
topical capsaicin may be used for localised neuropathic pain (e.g. post-herpetic neuralgia)
pain management clinics may be useful in patients with resistant problems
83
Diabetes typically leads to what type of neuropathy?
sensory loss and not motor loss in peripheral neuropathy. Painful diabetic neuropathy is a common problem in clinical practice.
84
How can diabetes affect the GI system?
Gastrointestinal autonomic neuropathy
Gastroparesis
symptoms include erratic blood glucose control, bloating and vomiting
management options include metoclopramide, domperidone or erythromycin (prokinetic agents)
Chronic diarrhoea
often occurs at night
Gastro-oesophageal reflux disease
caused by decreased lower esophageal sphincter (LES) pressure
85
Diabetic ketoacidosis (DKA) may be a complication of existing type ? diabetes mellitus or be the first presentation, accounting for around 6% of cases. Rarely, under conditions of extreme stress, patients with type ? diabetes mellitus may also develop DKA.
Diabetic ketoacidosis (DKA) may be a complication of existing type 1 diabetes mellitus or be the first presentation, accounting for around 6% of cases. Rarely, under conditions of extreme stress, patients with type 2 diabetes mellitus may also develop DKA.
86
Pathophysiology
| DKA
caused by uncontrolled lipolysis (not proteolysis) which results in an excess of free fatty acids that are ultimately converted to ketone bodies
The most common precipitating factors of DKA are infection, missed insulin doses and myocardial infarction.
87
DKA
abdominal pain
polyuria, polydipsia, dehydration
Kussmaul respiration (deep hyperventilation)
Acetone-smelling breath ('pear drops' smell)
88
Diagnostic criteria of DKA?
glucose > 11 mmol/l or known diabetes mellitus
pH < 7.3
bicarbonate < 15 mmol/l
ketones > 3 mmol/l or urine ketones ++ on dipstick
89
mx DKA
fluid replacement
insulin - long-acting insulin should be continued, short-acting insulin should be stopped
correction of electrolyte disturbance
90
Describe fluid replacement in DKA
most patients with DKA are deplete around 5-8 litres
| isotonic saline is used initially, even if the patient is severely acidotic
91
Describe insulin mx in DKA
an intravenous infusion should be started at 0.1 unit/kg/hour
once blood glucose is < 15 mmol/l an infusion of 5% dextrose should be started
92
Describe correction of electrolyte disturbance in dka
serum potassium is often high on admission despite total body potassium being low
this often falls quickly following treatment with insulin resulting in hypokalaemia
potassium may therefore need to be added to the replacement fluids
if the rate of potassium infusion is greater than 20 mmol/hour then cardiac monitoring may be required
93
JBDS potassium guidelines
Potassium level in first 24 hours (mmol/L)
Over 5.5 Nil Potassium replacement in mmol/L of infusion solution
3.5-5.5 40 Potassium replacement in mmol/L of infusion solution
Below 3.5 Senior review as additional potassium needs to be given
94
DKA resolution is defined as:
| Key points of discharge?
pH >7.3 and
blood ketones < 0.3 mmol/L
both the ketonaemia and acidosis should have been resolved within 24 hours. If this hasn't happened the patient requires senior review from an endocrinologist
if the above criteria are met and the patient is eating and drinking switch to subcutaneous insulin
the patient should be reviewed by the diabetes specialist nurse prior to discharge
95
Complications may occur from DKA itself or the treatment:
gastric stasis
thromboembolism
arrhythmias secondary to hyperkalaemia/iatrogenic hypokalaemia
iatrogenic due to incorrect fluid therapy: cerebral oedema*, hypokalaemia, hypoglycaemia
acute respiratory distress syndrome
acute kidney injury
96
Who is at high risk of CE and how to mx this
children/young adults following fluid resuscitation in DKA
monitor for headache, irritability, visual disturbance, focal neurology etc.
It usually occurs 4-12 hours following commencement of treatment
If there is any suspicion a CT head and senior review should be sought
97
level of HbA1c is dependant on
red blood cell lifespan
| average blood glucose concentration
98
HbA1c
produced by the glycosylation of haemoglobin at a rate proportional to the glucose concentration
99
lower-than-expected levels of HbA1c
(reduced red blood cell lifespan)
Sickle-cell anaemia
GP6D deficiency
Hereditary spherocytosis
100
higher-than-expected levels of HbA1c
| due to increased red blood cell lifespan
Vitamin B12/folic acid deficiency
Iron-deficiency anaemia
Splenectomy
101
HbA1c should be checked every
3-6 months until stable, then 6 monthly'.
