DSpace Collection:
http://theses.ncl.ac.uk/jspui/handle/10443/207
2024-02-05T07:37:28ZTrends in vitamin D and its influence on outcomes following total hip and knee arthroplasty
http://theses.ncl.ac.uk/jspui/handle/10443/6022
Title: Trends in vitamin D and its influence on outcomes following total hip and knee arthroplasty
Authors: Morrison, Rory John McGillivray
Abstract: There is increasing interest in the extra-skeletal effects of vitamin D. In patients undergoing
total hip (THR) or knee (TKR) replacement surgery, insufficiency has been linked to adverse
outcomes including longer length of stay, lower patient reported outcome measure scores
(PROMs), and increased complication rates. This work aims to explore this further.
Using vitamin D data from an NHS hospital trust, the temporal trends in the local population
were explored. Vitamin D levels in patients undergoing THR and TKR were measured and
linked to Oxford and EQ-5D-3L scores to determine if baseline vitamin D status is associated
with post-operative outcome. The current evidence base for optimising vitamin D levels with
supplementation prior to arthroplasty surgery was sought through a systematic review.
Finally, a randomised trial to establish the feasibility of supplementing patients with
insufficiency prior to surgery to improve outcomes was completed. The influence of this
feasibility study in the design of future interventional trials is discussed.
This work has shown increasing trends in vitamin D testing in the local population. Preoperative deficiency is associated with lower PROM scores following THR/TKR. There is a
paucity of evidence for supplementation prior to arthroplasty surgery, but a randomised trial
investigating the role of optimising vitamin D levels with supplementation is feasible.
Suggestions for how this could be done in the NHS setting are discussed, and future studies
should develop this work through adequately powered multicentre trials.
Description: Ph. D. Thesis.2023-01-01T00:00:00ZUnderstanding the Clinical Impact of Autoimmune Hepatitis
http://theses.ncl.ac.uk/jspui/handle/10443/5771
Title: Understanding the Clinical Impact of Autoimmune Hepatitis
Authors: Wong, Lin Lee
Abstract: Background: Autoimmune hepatitis (AIH) is a heterogenous, chronic inflammatory liver
disease that remains a challenge in diagnosis and management. Failure to achieve biochemical
remission has serious consequences (cirrhosis, liver failure and death). Existing
immunosuppressive treatments (mainly prednisolone and azathioprine) are usually lifelong
and some patients develop intolerable side effects. There is a pervading perception amongst
clinicians that AIH is easy to treat and the treatments are effective. There is a gap between
clinician perception, clinical data and viewpoints of patients.
Aims and Methods: To explore the mechanistic evidence behind three domains of unmet
need in AIH (inadequate response to therapy, effective therapy with undesirable side-effects
and quality of life) using the national UK-AIH multicentre cohort. Clinical indices and quality of
life (QOL) information were analysed. A novel thiopurine metabolite (deoxythioguanosine in
DNA of leukocytes, dtG DNA) as a potential biomarker for treatment optimisation was
explored in a subgroup of 57 patients, divided by treatment response.
Findings: In a cohort of approximately 1000 patients, 29 different treatment regimens were
reported and biochemical remission rate was 59%. Remission rates were significantly higher
in transplant centres compared to non-transplant centres. 55% remain on corticosteroids.
There was no significant correlation in the leukocyte metabolite (dtG DNA) levels with disease
response or azathioprine dose which suggests that this biomarker is not clinically useful. There
was evidence of QOL impairment compared to the general population with corticosteroid use
being strongly associated with decreased QOL, independent of remission status.
Conclusions: This demonstrates suboptimal areas of care for patients with AIH with variable
treatment regimens, suboptimal remission rates, high use of corticosteroids and poor QOL.
This highlights the need for better corticosteroid-free therapy approaches and emphasizes
the need for continued future efforts in improving treatment approaches for AIH (which
encompasses better therapies combined with focus on improving QOL).
Description: Ph. D. Thesis.2022-01-01T00:00:00ZDefining the long term pathophysiological determinants of type 2 diabetes
http://theses.ncl.ac.uk/jspui/handle/10443/5748
Title: Defining the long term pathophysiological determinants of type 2 diabetes
Authors: Zhyzhneuskaya, Sviatlana
Abstract: The prevalence of type 2 diabetes has increased significantly worldwide in recent
decades along with growing rates of obesity. This presents a huge challenge to the
health care systems all over the globe as well as ill health in millions of individuals.
Defining the long-term pathophysiological determinants of type 2 diabetes and the
mechanisms underlying the normalisation of blood glucose levels have great
implications for the effective management of early type 2 diabetes. The Twin Cycle
hypothesis which explains the major pathophysiological changes in type 2 diabetes has
been further validated in this work.
This thesis presents metabolic and clinical data from Tyneside arm of Diabetes
Remission Clinical Trial (DiRECT), unravelling the mechanisms behind the remission of
type 2 diabetes in people with a known duration of the disease of less than 6 years. The
main culprits for non-reversal of type 2 diabetes were the lack of substantial weight loss
and longer diabetes duration. Over 24 months of successful weight maintenance period
the sustained decrease in VLDL-TG production by liver was followed by a reduction in
liver and pancreatic fat content, a rise in first phase insulin secretion, and a near
normalisation of maximum insulin secretory capacity. These factors have permitted to
keep the normal blood glucose control in participants who did not have major weight
regain. A group of non-diabetic individuals were studies specifically to allow comparison
with the Tyneside DiRECT cohort after weight loss to evaluate just how far the
underlying pathophysiological processes returned towards normal.
Weight loss induced decrease in liver enzymes levels reflected the reduction in liver fat
content. The changes were analysed in detail. In routine clinical practice sequential
monitoring of liver enzymes following weight loss can provide a simple assessment of
normalisation of liver fat.
In conclusion, a low-calorie diet intervention induced a durable remission in early type 2
for up to 24 months for most people who achieved substantial weight loss. Overall, the
metabolic findings of this thesis provide clinically important insights into the
pathophysiologic basis of remission of type 2 diabetes
Description: PhD Thesis2022-01-01T00:00:00ZInvestigation and therapeutic targeting of the metabolic relationship between pancreatic stellate cells and pancreatic ductal adenocarcinoma
http://theses.ncl.ac.uk/jspui/handle/10443/5715
Title: Investigation and therapeutic targeting of the metabolic relationship between pancreatic stellate cells and pancreatic ductal adenocarcinoma
Authors: Moir, John Alexander Gibson
Abstract: Introduction
Pancreatic
ductal
adenocarcinoma
(PDAC)
remains
one
of
the
most
aggressive
solid
organ
malignancies
with
persistently
poor
survival
despite
advancements
in
chemotherapy
and
surgical
techniques.
Pancreatic
stellate
cells
(PSCs)
are
key
pro-‐tumourigenic
players
within
the
inflammatory
microenvironment/stroma
of
PDAC,
and
thus
represent
an
attractive
therapeutic
target.
This
project
aimed
to
examine
the
under-‐investigated
relationship
of
PSCs
to
cancer
metabolism,
and
identify
novel
translational
treatment
approaches.
Methodology
Human
PSC
and
PDAC
(Panc1,
Miapaca2
and
Bxpc3)
cell
lines
were
utilised
in
numerous
in
vitro
transwell
co-‐culture
experiments
to
investigate
the
effect
on
activity
and
more
specifically
metabolic
phenotype,
including
the
use
of
qPCR,
western
blot,
metabolic
assays,
and
seahorse
technology.
The
impact
of
drugs
targeting
enzymes
and
transporters
specific
to
lactate
metabolism
were
then
examined.
In
addition
immunohistochemistry
(IHC)
was
performed
on
resected
tumours
to
examine
the
expression
patterns
and
prognostic
relevance
of
certain
metabolic
markers
within
the
tumour
microenvironment.
Results
Initial
co-‐culture
experimentation
revealed
PSCs
and
PDAC
impact
on
lactate
metabolism,
with
a
significant
pro-‐glycolytic
effect
of
PSCs
on
the
PDAC
cell
lines.
In
keeping
with
this,
a
notable
upregulation
in
the
monocarboxylate
transporters
6
MCT1
and
MCT4
was
also
observed,
indicating
an
impact
on
lactate
flux.
PSC
interactions
with
the
PDAC
lines
were
influenced
by
the
underlying
genetic/metabolic
phenotype
of
each
cell
line.
IHC
staining
revealed
distinct
MCT
expression
patterns,
with
a
positive
correlation
between
the
tumoural
and
stromal
compartments,
whilst
expression
of
MCT1
and
MCT4
within
the
stroma
and
tumour
respectively
correlating
with
reduced
overall
survival.
The
MCT1
inhibitor
AZD3965
exerted
a
KRAS-‐dependent
de-‐activating
effect
on
PSCs,
with
a
reduction
in
αSMA
and
IL6
expression.
AZD3965
also
exerted
a
KRAS-‐
dependent
anti-‐proliferative
effect
on
the
PDAC
lines,
a
cell
line-‐specific
PSC-‐
dependent
reduction
in
PDAC
metabolic
processes,
as
well
as
a
reduction
in
PSC
lactate
transporter
expression.
Inhibition
of
all
LDH
isoforms
with
Galloflavin
revealed
a
mixed
effect
on
both
PDAC
proliferation
and
apoptosis,
although
an
over-‐riding
reduction
in
lactate
acidification.
Conclusion
This
project
has
proven
a
metabolic
symbiosis
exists
between
PDAC
and
PSCs,
which
appears
to
be
inextricably
related
to
lactate
metabolism.
Inhibition
of
lactate
transporters
or
enzymes
has
demonstrated
effects
on
both
cancer
cells
and
PSCs
which,
in
combination
with
the
correlation
to
poor
prognosis
in
resected
specimens,
holds
great
promise
in
a
potentially
beneficial
translational
impact
for
patients.
The
heterogeneity
of
results
observed
between
cell
lines,
postulated
to
be
due
to
either
KRAS
status
or
underlying
metabolic
phenotype,
suggests
a
patient/tumour-‐specific
personalized
approach
to
MCT
or
LDH
inhibition
should
be
adopted
in
any
future
clinical
trials.
Description: Ph. D. Thesis2022-01-01T00:00:00Z