1. Diabetes Nurse Consultant @ Brownlow Health
Precision Medicine In Diabetes: What Does it Mean for Student Health & Primary Care Teams?
Peta Navein,
Diabetes Nurse Brownlow Health
Genetic Diabetes Nurse, Merseyside & Greater Manchester

2. Peta’s Role in Student Health @ Brownlow Health
Funding 2013 for focus on students with diabetes.
Student Health; Student Health Advice Centre; Ropewalks; Brownlow Group Practice;

3. For That Piece Of Work BH Was Awarded: ‘GP Clinical Team of the Year’ 2015

5. NHS England: PRECISION MEDICINE
‘A move away from ‘one size fits all’ to the treatment & care of patients with particular a condition, to one which uses new approaches to better manage patients’ health and target therapies to achieve the best outcomes in management of a patient’s disease or predisposition to disease’.
e.g. Genes; Lifestyle; Environment; Technology; Targeted Treatment Approach
NHS England (2016) Improving Outcomes Through Personalised Medicine (September)

6. Diabetetologia (2017) DOI 10.1007/s00125-017-4226-2 17 March
Sulphonylurea therapy in KCNJ11 neonatal diabetes: Precision medicine at its best.
I am sharing Jack’s story. Work of:
Dr Pam Bowman, Clinical Research Fellow in Exeter
Pam is part of the monogenic diabetes team led by Prof Andrew Hattersley
I am a regional Genetic Diabetes Nurse for Merseyside & Greater Manchester and this team is led by Prof Maggie Shepherd.
Prof Hattersley & Dr Kashyap A Patel; Published:
Precision Diabetes: learning from monogenic diabetes.
Diabetetologia (2017) DOI /s March

7. Acknowledgements
Exeter monogenic diabetes and clinical teams Andrew Hattersley, Maggie Shepherd, Sarah Flanagan, Sian Ellard, Kash Patel, Bea Knight, Suzie Hammersley, Nick Thomas, Taz Babiker, Rob Andrews, Richard Oram, Angus Jones, Elisa De Franco, Matthew Johnson , Jane Houghton, Kev Colclough, Franki Mathews, Tamsin Ford, Rhian Clissold, the Exeter Clinical Research Facility
UK Collaborators James Tonks, Emily Broadbridge, Lewis Pettit, Marie-Claire Reville, Adam Zeman, Lorna Torrens, Jon Fulford, Ewan Pearson, Frances Ashcroft, Anna Gloyn, Exeter child health research group
Patients and families affected by KCNJ11 neonatal diabetes
International Collaborators Pal Njolstad, Asta Sulen, Michel Polak, Jacques Beltrand, Fabrizio Barbetti, Dario Iafusco, Maciej Malecki, Magda Spoza, Iwar Klimes, Daniela Gasperikova, Ethel Codner, Ellen Tessmann, neonatal diabetes international collaboration

8. Monogenic Diabetes: Leads The Way
Monogenic Diabetes: Leads The Way. Mutations In The KCNJ11 Gene Cause Permanent Neonatal Diabetes
ATP 
Mutations in KCNJ11 are the commonest cause of neonatal diabetes which affects 1/100,000 live births. They do this by rendering the channel insensitive to ATP – therefore the channel is stuck open and the beta cell is hyperpolarized so insulin is locked inside the cell. In KCNJ11 neonatal diabetes the mutation means the channel is stuck open and the cell is hyperpolarised, meaning the insulin is locked inside the cell. Babies present in first 6 months of life very unwell often with DKA and insulin deficient state. Jack was one of these. Babies present in first 6 months of life very unwell often with DKA and insulin deficient state. Previously treated as T1D with insulin. Mum described huge swings in glucose – really difficult to manage in a baby on insulin.
Gloyn et al NEJM 2004

9. KCNJ11 neonatal diabetes can be treated with sulphonylureas 90% stop insulin, glycaemic control is improved in all patients who stop insulin
Ewan Pearson
P <
8.1%
Michel Polak
6.4%
Pål Njølstad
Pearson et al NEJM 2006

10. Sulphonylurea failure is common in Type 2 Diabetes
100
44% need additional therapy at 6 years 75
Percentage remaining on SU only 50 25
44% needed additional therapy on top of SU after 6 years (40% glibenclamide, 48% chlorpropamide). 1 2 3 4 5 6
Year of follow-up
Adapted from Matthews DR et al Diabetic Medicine 1998, UKPDS 26

11. Results: 93% patients insulin free at 10 years
Percentage On Sulphonylurea Alone
Time From Transfer To Sulphonylurea (Years)
Number At Risk
Bowman et al Lancet D&E 2018

12. Glycaemic control remains excellent long-term without increase in SU dose
HbA1c (%)
Sulphonylurea Dose (mg/kg/day Glibenclamide)
Pre SU transfer
Year Of Follow-Up
Bowman et al Lancet D&E 2018

13. Sulphonylureas are well tolerated with few adverse effects after 10 year of treatment in KCNJ11 PNDM
Side-effects
No serious adverse effects
Mild transient diarrhoea/nausea in 10/81 (12%)
Tooth discolouration in 1 patient
No patients stopped treatment
Hypoglycaemia
No severe hypoglycaemia in 809 patient years
Norway T1D cohort - 45% at least one episode
Diabetes complications
Microvascular complications in 7 of 81 (8.6%) patients
Patients with complications older at age of transfer to sulphonylureas than those without complications (age at transfer 20.5 vs. 4.1 years, P=0.0005).
This contrasts markedly with the hypoglycaemia observed in a cohort of Norwegian patients with Type 1 Diabetes followed up for >9 years, with 45% patients reporting at least one episode of severe hypoglycaemia on insulin treatment.
Bowman et al Lancet D&E 2018

14. Insulin secretion is maintained via the incretin pathway 10 years after transfer to SU
Figure 3A. median incremental increase in glucose and insulin concentration above baseline in an intravenous glucose tolerance test (6 patients) and an intravenous glucose tolerance test (6 patients). The test was performed after a median time of 9.83 years on sulfonylurea treatment. OGTT – glucose maintained. IVGTT – glucose rises due to lack of insulin response.
Pål Njølstad

15. WHO reference population mean
Reduction in BMI during SU treatment even with improved glycaemic control (n=58)
p=0.0009
BMI SD score
WHO reference population mean
Contrast with weight gain seen with better control in DCCT trial (T1D).
Pre-transfer
10 year
Bowman et al Lancet D&E 2018

16. Normal growth in children over 10 years of treatment with SU (n=38)
p=0.31
Height SD score
WHO reference population mean
Contrast with abnormal growth in poorly controlled Type 1 diabetes. Reflects excellent glycaemic control.
Pre-transfer
10 year
Bowman et al Lancet D&E 2018

17. Neurological features in KCNJ11 PNDM fit with the expression of KATP channels in nerve, muscle and brain
ATP 
DEND syndrome Developmental delay
Epilepsy
Neonatal Diabetes
Intermediate DEND syndrome (iDEND)
If no epilepsy in first 12 months of life
Subtle neuropsychological impairments (attention, praxis)
Mention Jack’s main problem being behavioural issues not diabetes. 20% have overt severe neurological phenotype – DEND/iDEND. Talk about V59M mutation being known iDEND mutation. Talk about recent work showing cognitive impairments even in those without DEND/iDEND (French – Busiah / Americans - Carmody). Katp channel expression in many brain areas but mostly cerebellum.
Severity of phenotype related to functional severity of mutation (Flanagan Diabetologia 2006)

18. Beltrand Diabetes Care 2015
Sulphonylurea treatment results in partial improvement of some neurological features
Beltrand Diabetes Care 2015
Fendler Diabetes Care 2013
When Jack first started SU noticed a significant improvement in attention and spoke for the first time, walking out of school and saying ‘hello Mummy’. Lahmann study – systemic administration failed to achieve therapeutic concentrations in CSF and intraventricular administration resulted in detectable glibenclamide in peripheral blood.
Jack, developmental delay, transferred to SU aged 4.
“A few weeks later Jack walked out of school and said ‘Hello Mummy’ for the first time” (Emma, Jack’s mum)

19. IMPACT! Autistic Spectrum Disorder (ASD) Hyperkinetic Disorder (ADHD)
Language
Autistic Spectrum Disorder (ASD)
Social interaction
Restricted / repetitive
behaviours
Hyperactivity
Hyperkinetic
Disorder (ADHD)
Impulsivity
Inattention
IMPACT!
These disorders have high impact on families, relationships, learning and educational attainment, ability to make and keep friends etc.
Clinical diagnoses enable families to access support

20. Neuropsychological impairments occur even in those without severe neurological features
VMI Visual Motor Digit Verbal Vocabulary Symbol Narrative Perception Coordination Span Fluency Search Memory
Sibling controls
population mean
Median Z-score
KCNJ11 patients
Median Z-scores in the children without severe developmental delay (non-V59M) were below school-age population average in all tests (figure 1), and were particularly low (>1SD below population average) in tests of executive function (verbal fluency), verbal comprehension (vocabulary) and visuo-motor performance (VMI). Only 1 child (K170N) scored within the average range in all tests completed. In sibling controls, median scores were within the normal range in all tests (figure 1). Blue circles = sibling controls (n=5-7) Red squares = children with KCNJ11 mutations (n=3-6).
Bowman et al, Diabetic Medicine 2017

21. What is Monogenic diabetes?
Diabetes due to single gene defect
Heterozygous mutation
Homozygous mutation
More common in consanguineous marriage
Diagnosis
Treatment
Prognosis

22. MODY – Clinical Features (Maturity Onset Diabetes of Young)
Autosomal dominant
Significant endogenous insulin
Young age < 30 yrs of onset
Non-obese
Absence of islet autoantibodies
McCarthy and Hattersley, Diabetes 2008

23. Student Health Primary Care Services Can Help Find Missing MODY
Cases per million
Monogenic diabetes accounts for 3% of diabetes diagnosed < 30 years of age
(~40,000 cases in the UK)
But 80% patients misdiagnosed as Type 1 or Type 2
Diabetes teams: lack of knowledge don’t recognise ‘genetic’ diabetes
Average of 12 years from initial diabetes diagnosis to correct genetic diagnosis
Shields et al (2010) Diabetologia
New genes being identified: ongoing training of health care professionals needed

24. Tools to Help: MODY Probability Calculator: Online Or Diabetes Diagnostics App:

25. Initial Screen – calculator for patient clinical details
Scroll down
Scroll down
Scroll down
Scroll down
Info on different diabetes subtypes
Investigations
Conversion calculators
About

26. Results screen – most likely type of diabetes and other possible diagnoses
Links to information on diabetes subtypes
Link to biomarker tests to aid classification of subtypes

27. What about the majority of students with diabetes who don’t have MODY (97%).
Other targeted emerging technologies, evidence and targeted treatments that can help clinicians.

28. Type 1 diabetes is an autoimmune disease
A pancreatic islet (insulin in red) being invaded by T lymphocytes (green).
Taken from Narendran P et al QJMed 2005 28

29. Islet autoantibodies are a marker of the autoimmune destruction
GAD65
IA-2
ZnT8
Zinc Transporter 8 29

30. Non genetic approaches improve diagnosis - but are not 100% - C peptide
In definite Type 1
most patients have C peptide (> T1D cut off) in first 2-3 years
8% have C peptide > 0.2 at > 5 years duration 10 1
0.1
0.01
<LOD
Duration 20 30 40 50
Home post meal UCPCR (nmol/mmol)
5 patients
Prevalence of 1%
C peptide very good discrimination from T1D 5 years after diagnosis ( 3 years children)
Oram McDonald Hattersley UNITED study Diabetes Care 2015

31. Non Genetic Approaches Improve Diagnosis - But Are Not 100% - C Peptide
Urinary C peptide
Assays
Serum/plasma or urine more stable than thought
UCPCR Room Temp 3 days (McDonald Clin Chem 2009)
EDTA Plasma Room Temp 24 hrs
Serum tube Room Temp 6 hrs (McDonald PLoS One) 2012
Samples- fasting or stimulated (non-fasting random)
Review: C peptide utility Jones Hattersley Diab Med 2013
0.2nmol/mmol
T1D
T2D
MODY
5 patients
Prevalence of 1%
C peptide very good discrimination from T1D 5 years after diagnosis ( 3 years children)
Besser et al 2011 Diabetes Care
In definite Type 1
most patients have C peptide (> T1D cut off) in first 2-3 years
8% have C peptide > 0.2nmol/mol (169pmol/l) at > 5 years duration

32. Non Genetic Approaches Improve Diagnosis - But Are Not 100% - Autoantibodies
GAD65 and IA2 antibodies
Assays
Not ICA - good rats poor man
IA2 and GAD (Zn Transp)
Know titre
Know cut off derived by normal data
82%
IA2
Cut off 99th centile
GAD 64 WHO units/ml
IA2 15 WHO units/ml
97.5th centile
GAD 16 WHO units/ml IA2 undetectable < 15
GAD
IA2 & GAD 1%
5 patients
Prevalence of 1%
T1D n=98
MODY n=508
McDonald et al Diab Med 2011

33. Type 1 Genetic Risk Score
~30 Polymorphisms associated with T1D
Calculate the combined effect
Genetic risk score
The genetic risk score is calculated from the genotypes of 10 common genetic variants associated with type 1 diabetes.
Numeric value
Higher score – Higher genetic risk
Genetic predisposition of T1D
Pociot et al, 2010

34. Other targeted emerging technologies, evidence and targeted treatments that can help clinicians...

35. Gran died 'of shock' after being told of teenage granddaughter's sudden death (Liverpool Echo 27 November 2017)
Zara…, 18, who had diabetes, died in her sleep after taking ill in her halls of residence.
At 11-months-old, Zara was diagnosed with type 1 diabetes and began a daily routine of insulin injections and careful management of a strictly controlled diet.
Cousin: “I am sorry for all the boring lectures, sorry if I ever shouted at you as your health was always important to us all.”
In a moving tribute to Zara, a forensic science student, the family wrote: “Your grandma made sure she did not let you go alone and also joined you couple of hours later to hold your hand to heaven.”

36. Risk Of Death Following Admission To A UK Hospital With Diabetic Ketoacidosis
Gibb et al (2016) Diabetologia. 59 (10): )
Retrospective cohort study (FU end 2014)
628 admissions for DKA.
Were able to FU: 298 patients (median age 28yrs [20-40yrs]);
44 (14.8%) deaths the follow- up period (median 4.9yrs [ yrs]):
57.7% admitted with DKA and died in hospital;
52.3% died at home alone;
10 deaths occurred within two months of final DKA admission. All were unanticipated

37. Substantial Short-term Risk of Death (within 5 years) Associated with Recurrent DKA admissions in T1DM
23.4% (15/64) of those with more than five lifetime DKA admissions died over a median of 2.4years (range years)
13.5% {15/111) of those with between two - five admissions died over a median 3.7 years ( years)
5.2% (5/96) of those with a single admission died over a median 4.1years ( years)

38. Looking At The Features Can Help Us Identify Those At Highest Risk.
Features associated with >5 admissions for DKA were:
Diagnosed at a younger age (14 [9-23]);
Higher social deprivation score (SIMD 1825 [ ])
Higher HbA1c (103 [89-108]) vs 79 {66-96])
Longer duration of diabetes (median 12.8yrs [ ]);
Features of those who had died also included:
Older age (median 31years [20-63yrs])
Prior DKA requiring ITU admission;
History of psychological issues;
Neuropathy & previous CVD;
Excess alcohol intake
Longer length of stay during the last hospital admission;
Prescription of antidepressants at anytime was associated with a trend towards increased likelihood of deaths

39. BH HbA1c & Age of Diagnosis 2017/18
Actions: Review New Registrations For DKA Risk: Includes mean Duration of Diabetes & high HbA1c. Duration mean 9.4 yrs ( yrs): 17 students >14yrs; 12 students 9 -14yrs =29 (45%).
High HbA1c: 6 students with HbA1c mmol/mol; Students with both risk factors = 4 students;
Manage message on loading medical record; Prioritise contact, call and appointment; Ensure they have a Ketone testing meter. Consider Freestyle Libre/Dexcom G5/ CGMS; My contact number.

40. Diabetes Nurse Consultant Service @ Brownlow Health 2018/20
Peta Navein is a clinical lead for diabetes care at Brownlow Health (BH). She works at the University of Liverpool with Professor John Wilding and her role actively supports BH staff to improve clinical care and offer patients the opportunity to take part in diabetes and obesity research studies, both of these actives are recognised nationally as benefiting patient care. As the regional genetic diabetes nurse for Merseyside & Greater Manchester she also ensures BH patients have the correct diagnosis and treatment for their diabetes.
Who should I be referring to Peta?
Patients with poor control of their diabetes and those with more complex health needs;
Patients with type 1 diabetes (T1DM) unable to engage with secondary care services.
Students with diabetes whose specialist care is delivered in their home town, so they have term time support in Liverpool.
Patients who have had a recent diabetes related hospital admission or A&E/Out-of-Hours visit.
Patients with a new diagnosis of diabetes or recently registered with the practice. (A records review only: Diagnosis & Treatment)
What is the next step?
Not Urgent: ‘Practice Note’ Peta about these patient’s for her advice/input and a ‘Suggested Diabetes Management Plan’.
Urgent: Call Peta on her mobile. If she cannot answer immediately leave a message and she will call you back that day (ASAP).
Peta is happy to call the patient where needed and for you to give her mobile number to students with T1DM for support with any urgent problems.
Organising care
Peta will review the patient's history and diabetes monitoring tests to verify the type and cause of their diabetes (i.e. type 1 or type 2 diabetes; monogenic diabetes; secondary pancreatic cause for their diabetes).
She can help you by reviewing individual patients care and suggest HbA1c target range in the overall context of their health;
She can recommend treatment changes and/or further investigations for those people with complex health needs, either directly with the patient or so this can be managed by their clinician.
Peta’s clinics
Peta holds a ‘clinician booked’ monthly clinic at each BH site with a blend of face-to-face and telephone consults as appropriate;
Selected patients may also be given Peta’s mobile phone number e.g. those people where timely phone support may help prevent an acute complication/admission such as those at risk of diabetic ketoacidosis or those titrating their insulin dose. (All these patients need to be booked to meet/discuss with Peta their personalised plan.)
Peta Navein Diabetes Nurse Consultant
Brownlow Health
REFERRAL is by ‘Practice Note ‘ or for urgent advice call mobile :
Mobile:
V2 June 2018

41. Case 2: Zoe 18yrs in her first term at university
Saw GP because of headaches
RBG 6.2mmol/l and HbA1c 48mmol/l
She was not symptomatic of diabetes
BMI 20
What other info would be helpful ?
Family history revealed her Mum had been investigated for fasting hyperglycaemia in pregnancy but did not have it now;
Maternal Grandfather has diabetes;
Zoe’s fasting blood glucose 5.9mmol/l
Glucokinase

42. Patients With Glucokinase Mutations Have Stable, Mild Hyperglycaemia
FBG
mmol/l
HbA1c
38-60mmol/mol
Controls
Glucokinase patients have high fasting and low post-prandial plasma glucose 42

43. Glucokinase Patients Do Not Benefit From Treatment - Hba1c Unaltered By Treatment
Cross sectional
Longitudinal
(n=799)
(n=16)
HbA1c %
Random glucose 12, fasting glucose 7
631
168
Stride et al (Diabetologia 2014)

44. GCK patients untreated for 50 yrs have no significant microvascular complications
Nephropathy
31%
Proteinuria 1% 2%
Microalbuminuria
GCK
n=98
Control
n=89
YT2D
n=80
Retinopathy
Advanced eye disease
Proliferative
Pre- proliferative
<5 MAs
Background 4% 8%
≥5 MAs
No retinopathy
Maculopathy 0%
Maculopathy 0%
Maculopathy 8%
Steele, Shields et al JAMA 2014

45. Summary: GCK Glucokinase can be detected at any
age – stable / mild fasting
hyperglycaemia. FBG mmol/l
Easiest to detect in young people: Children (consider when present with incidental hyperglycaemia with FBG>5.5 on 2 occasions) Gestational diabetes (commonest presentation in the UK)
Usually no treatment is required – even in pregnancy if fetus also has a mutation

46. Case 3: Georgia Dx 11 yrs, Presented with blood glucose of 15mmol/l
Type 1 diabetes
Basal Bolus regime 0.6u/kg/day
Now aged 18 yrs
HbA1c 54mmol/mol
BMI 19
UCPCR 1.73 nmol/mmol
GAD and IA2 negative
Family history revealed that her Mum, Emma,
Dx 14 yrs with Type 1
Now 34 yrs, BMI 20
What other information could be helpful ?

47. Case 3 HNF1A MODY confirmed
‘Type 1’
‘Type 1’
Died 35yrs MI
Dx 20yrs
Basal bolus Insulin
Georgia C peptide level was found to be normal and so was her Mum’s 20yrs post diagnosis
Dx 30yrs
OHA
Dx 14 yrs
Insulin
Dx 11 yrs
Insulin
HNF1A MODY confirmed

48. Sulphonylurea sensitivity in HNF1A Change in fpg with treatment
Gliclazide
Metformin 1 2 -1
Change in fpg with treatment -2 -3
Type 2 -4
HNF1A -5 -6
p<0.0001 -7
Pearson et al Lancet 2003

49. Case 3: Impact of diagnosis
Georgia & Mum:
Stopped Insulin and switched to
Gliclazide 20mg od
Improved their diabetes control
Mum’s siblings – had genetic testing also
HNF1A is associated with a higher risk of heart disease & mortality MI/Stoke at a younger age.
Lipid profile looks normal but it does not seem to be cardio protective and so consider statin treatment early.

50. Insulin treated diabetes: could it be MODY ?

51. Case 4
Paul diagnosed 14 years, presented with thirst and polyuria, RBG 14mmol/l, trace ketones
BMI 28, HbA1c 81mmol/mol (9.6%) at diagnosis
Now 3 months post diagnosis on insulin 0.4u/kg/day,
HbA1c 69mmol/mol (8.5%)
What’s the most likely diagnosis ?
What other information would be helpful ?
Neither parent affected, only other FH paternal grandfather Type 2 diagnosed at 65yrs with BMI 29
GAD = 469
Are you thinking he has type 1 diabetes?

52. Case 4 (continued)
Probability calculator score = 1 in 142 chance of being MODY.
IA2 and ZnT8 negative
UCPCR = 0.4nmol/mmol - 3 months post diagnosis
What’s the most likely diagnosis ?
Type 1 diabetes
What treatment / would be best for him ?
1 in 5 AB cases are MODY positive
Increase insulin (control poor and positive c-peptide reduces risk of hypoglycaemia), likely to need further increase as UCPCR decreases), repeat c-peptide over time

53. Case 5
Susan diagnosed at 20 years, presented with thirst and polyuria, RBG 14mmol/l, trace ketones, BMI 28, HbA1c 73mmol/mol.
What’s the most likely diagnosis ?
What other information would be helpful ?
Father diagnosed at 35 years with Type 1 diabetes and paternal grandfather Type 2 diagnosed at 65yrs (now deceased), BMIs not known.
Susan is GAD and ICA negative.
Now 3 months post diagnosis on insulin 0.3u/kg/day
Are you still thinking she has type 1 diabetes?

54. Case 5 (continued)
Probability calculator score = 1 in 8 chance of this being MODY
IA2 and ZnT8 both negative
Susan’s UCPCR 1.4nmol/mmol,
Father’s UCPCR 0.9nmol/mmol, he’s GAD and IA2 negative
What’s the diagnosis ?
HNF1A MODY
What treatment would be best for her?
Transfer from insulin to low dose sulphonylurea, under specialist care. Contact you Genetic Diabetes Nurse so her father can be counselled and consider testing & treatment change.

55. Case 6
David diagnosed 18 years, when screened at army medical, RBG 12 mmol/l, BMI 25, HbA1c 51mmol/mol (6.8%)
What’s the most likely diagnosis ?
What other information would be helpful ?
Mother had GDM in both pregnancies, now on Metformin with HbA1c 54mmol/mol, no other known family history.
David is negative for GAD and ICA.
Now 3 months post diagnosis on insulin, 0.2u/kg/day
What type of diabetes could he have?

56. Case 6 (continued)
Probability calculator score = 1 in 8 chance of this being MODY,
IA2 and ZnT8 (negative)
David’s UCPCR 2.0nmol/mmol
Mother’s OGTT in pregnancy (FBG 5.8, 2 hr 8.1),
What’s the diagnosis ?
Glucokinase (GCK) MODY
What treatment would you recommend ?
Stop treatment. Remove from the Diabetes Register (READ code PJ5)
Refer family to GDN for genetic test for Mother and if GCK positive stop her treatment

57. Thank You for Attending
To contact me it’s:
For more information on monogenic diabetes, genetic testing and UK Genetic Diabetes Nurses see:
A Special thank you to Prof Maggie Shepherd. It is through her leadership & her Genetic Diabetes Nurse courses that I have learnt much of what I have shared with you today.