928 research outputs found
Measuring CRM Performance: An Exploratory Case
Customer relationship management (CRM) is a business philosophy that has emerged and gained prominence in the field of IS in recent years. Organisations have begun to realise that creating a dynamic substantial relationship with each customer may lead to sustained business success. While numerous firms have bought into the CRM concept many organisations are now trying to evaluate whether their CRM initiative is performing. This paper will examine how Irish Life and Permanent, a leading financial services organisation based in Ireland evaluate the performance of their CRM initiative. They developed a set of measures for evaluating the performance of their CRM initiative. We believe that these measures may be useful to other organisations for measuring the performance of their CRM initiatives
Complications of portal hypertension: clinical studies
INTRODUCTION:
With over 1.32 million global liver cirrhosis related deaths annually, the burden of
liver disease is still rising, predominantly due to alcohol and the metabolic syndrome.
The development of portal hypertension occurs in almost 90% of patients with
cirrhosis. It marks the transitin from compensated to decompensated disease, it is
the pathophysiological hallmark of cirrhosis related complica4ons, and is the prequel
to mortality. Oesophageal varices are the most clinically significant of these
complica4ons due to their tendency to rupture and haemorrhage, contribu4ng to 25-
50% of overall deaths. Varices oYen develop before other portal hypertension related
complications such as ascites, hepatorenal syndrome and hepa4c encephalopathy.
Despite significant developments in understanding the pathophysiological
mechanisms of portal hypertension over the last few decades, treatment options for
this condition are dispropor4onately limited. Non-selec4ve beta blockers (NSBBs)
have been the cornerstone of therapy for 40-years; they reduce portal pressure by
reducing cardiac output and increasing splanchnic vascular resistance. NSBBs are
most oYen initiated upon the finding of oesophageal varices on screening endoscopy
to prevent a first bleeding episode, or aYer stabilisa4on of a patient admi;ed to
hospital with oesophageal variceal bleeding (OVB) to prevent rebleeding. Despite
cliniciansâ familiarity with oesophageal varices and OVB, no clear strategy for primary
or secondary prophylaxis of OVB exists, with endoscopic band ligation (EBL) of varices
oYen used in place of, or as an adjunct to NSBBs. Furthermore, reduction in portal
pressure with more invasive procedures such as transjugular intra-hepatic portosystemic
shunt (TIPSS) has been used as rescue therapy in emergency OVB situations
as well as for pharmacotherapy refractory ascites. However, TIPSS placement within
72 hours of successfully treated OVB has also been adopted for use âpre-emptivelyâ
to prevent rebleeding in high-risk patients. Carvedilol, a NSBB that also exhibits
intrinsic anti-α1 adrenergic effects, offers interest to clinicians due to its superior
effect on portal pressure reduction compared to other NSBBs, improvement in
intrahepatic vascular resistance, and potential influence on pleiotropic mechanisms
that contribute towards liver decompensation out with portal hypertension.
Regardless, data supporting novel approaches in the management of portal
hypertension are lacking, with studies oYen limited by low patient numbers,
observational design or absence of long-term outcomes.
AIMS:
The aims of the studies presented in this thesis were: (i) to determine if early / preemptive TIPSS (pTIPSS) offers survival benefit over modern standard of care (SOC)
following OVB; (ii) to determine if the timing of pTIPSS insertion following OVB alters
patient outcome; (iii) to determine the long-term outcomes for patients receiving
either carvedilol or EBL following OVB; and (iv) to determine the long-term
outcomes for patients receiving pTIPSS.
METHODS:
1. In a two-centre open-label parallel-group randomised controlled trial (RCT),
pa4ents with cirrhosis and OVB were recruited following haemostasis with vasoac4ve
drugs and EBL. Participants were randomised to SOC (EBL + carvedilol) or pTIPSS
(formerly known as âearly-TIPSSâ). The primary outcome was 1-year survival,
secondary outcomes included early and late re-bleeding, and other complica4ons of
portal hypertension.
2. A multicentre cohort study of con4nuous, unselected pa4ents referred to four UK
tertiary centres for pTIPSS between 01/01/2010 â 31/12/2018. Time from OVB to
pTIPSS was recorded and pre-defined clinically relevant outcomes were observed
relative to two groups: early pTIPSS (<72hrs of achieving endoscopic haemostasis) and
late pTIPSS (72 hours â 28 days). Primary outcome was 1-year transplant free survival.
Patientsâ clinical progress was observed from pTIPSS inser4on to the close of the
study, 31/12/2020.
3. Long-term follow up of a multi-centre, randomised controlled trial in which
cirrhotic patients with OVB presenting between 2006-2011 were randomised to
receive either carvedilol or EBL as secondary prophylaxis of OVB. Follow-up was
undertaken to April 2020 by review of electronic patient records. The primary
outcome was long-term survival. Other outcomes including variceal rebleeding and
liver decompensation events were compared.
4. Long-term follow-up of a RCT (above) in which cirrhotic patients presenting with
OVB were randomised to receive either SOC or pTIPSS. Follow up was extended to
three years from recruitment, with the study closing on 04/01/2021. Primary
outcome was 3-year transplant free survival on intention to treat and per-protocol
analysis. Secondary outcomes included cause of death, rates of variceal rebleeding,
rates of ascites and rates of encephalopathy.
RESULTS:
1. pTIPSS RCT: 58 patients (58±11.12 years; 32.7% female) were randomised. AYer
one year, seven patients died in the standard of care group and six in the early-TIPSS
group, a 1-year survival of 75.9% versus 79.3% respec4vely (p=0.79). Variceal
rebleeding occurred in eight patients in the standard of care group compared with
three patients in the early-TIPSS group (p=0.09). Not all participants randomised to
early-TIPSS received the intervention within the required 72 hours (13 within 72hrs,
ten between 3-5 days, and no TIPSS placed in six. For those receiving TIPSS perprotocol,
variceal rebleeding rates were reduced (0.0% versus 27.6%, p=0.04) but this
had no effect on survival (76.9% versus 75.9%, p=0.91). Serious adverse events were
similar in both treatment groups, except rates of hepatic encephalopathy which were
higher in patients receiving TIPSS (46.1% vs. 20.7%, p<0.05).
2. UK pTIPSS cohort study: 171 pa4ents were observed, 83 received early pTIPSS and
88 received late pTIPSS. Baseline characteris4cs were similar with no requirement for
propensity score matched analysis. There was no difference between early and late
pTIPSS groups for the predefined outcomes; 1-year transplant free survival rate
(69.9% vs. 71.6%, p=0.73, HR 0.91, 95% CI 0.52-1.58), long-term survival (p=0.52, HR
1.132, 95% CI 0.77 â 1.65), variceal rebleeding (4.8% vs. 11.4%, p=0.09, HR 0.411, 95%
CI 0.14-1.17), hepatic encephalopathy (43.9% vs. 34.6%, p=0.26), and new or
worsening ascites (16.6% vs. 13.5%, p=0.79). Death due to liver failure was
significantly more prevalent in those undergoing early pTIPSS compared to late pTIPSS
(44.0% vs. 16.0%, p=0.046, HR 2.79, 95%CI 1.02-8.32).
3. Carvedilol vs. EBL secondary prophylaxis RCT â long-term follow-up: Of the 64
patients recruited and randomised, 26 out of 33 received carvedilol in the follow-up
period and 28 out of 31 attended for regular EBL sessions. The median number of
follow-up days for all patients recruited was 1459 (SE = 281.74). On intention to treat
analysis, there was a trend towards improved survival in the carvedilol group
(p=0.09). On per-protocol analysis, carvedilol use was associated with improved longterm
survival (p=0.005, HR 3.083, 95%CI 1.397-6.809), fewer liver related deaths (0%
vs. 22.8%, p=0.013, OR â, 95%CI 1.565 - â), and fewer unscheduled hospital
admissions with decompensated liver disease (12.0% vs. 64.3% (p=0.0002, OR 13.2,
95%CI 3.026 â 47.23) compared to the EBL group. There was no statistically significant
difference in variceal rebleeding rates.
4. pTIPSS RCT â long-term follow-up: On intention to treat analysis, 3-year transplant
free survival rate in the SOC group was significantly higher than that of the pTIPSS
group (55.2% vs. 20.1%, p=0.006, HR 2.5, 95%CI 1.3-4.87). On per-protocol analysis,
3-year transplant free survival rate in the SOC group was, again, significantly higher
than that of the pTIPSS group (55.2% vs. 15.4%, p=0.03, HR 2.93, 95%CI 1.27-7.94).
There were significantly higher rates of sepsis related death or sepsis induced liver
decompensation related death in the pTIPSS group compared to the SOC group
(48.2% vs. 3.6%, p<0.001, reciprocal of RR 13.0, 95% CI 2.46 â 75.45). There were no
differences in other outcomes associated with portal hypertension on intention to
treat analysis.
CONCLUSION:
In a randomised trial, early / pTIPSS had no effect on 1-year transplant free survival
in high-risk patients presenting with OVB when compared to SOC using EBL and
carvedilol. An important finding was that pTIPSS within the recommend 72 hours
timeframe may not be feasible in many centres due to its semi-elective nature set
amongst real world clinical practice and emergency care. The 72-hour timeframe is
somewhat arbitrary and based on historical variceal rebleeding data. In a novel,
dedicated cohort study to investigate this, placement of pTIPSS within 72 hours
offered similar short and long-term survival benefit compared to pTIPSS placed
between 72 hours â 28 days. This observation may help improve access to pTIPSS in
centres wishing to pursue this service for their patients. However, early pTIPSS may
be associated with increased risk of liver failure related mortality which raises
concerns over the current patient selection recommendations. Given the reasonable
1-year survival rates reported for cirrhotic patients following OVB, it is sensible to
explore the impact of the interventions used over a long-term period, particularly as
corresponding data are lacking. Carvedilol use was associated with long-term survival
benefit, fewer liver failure related deaths and fewer hospital admissions with
decompensated disease when compared to EBL, in the setng of a RCT. Furthermore,
in a separate long-term follow-up study, pTIPSS was associated with significantly
reduced rates of transplant free survival at 3-years compared to SOC using EBL and
carvedilol together. This may be due to higher rates of sepsis related mortality
observed for those receiving pTIPSS. However, it is unclear whether pTIPSS is an
independent risk factor for sepsis, or whether carvedilol protects against sepsis and
subsequent acute decompensation in an otherwise at-risk population. Further large,
randomised studies are required to validate these findings
The intricate interplay between epigenetic events, alternative splicing and noncoding RNA deregulation in colorectal cancer
Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment. Epithelial-specific epigenetic variations escorting this process include chromatin remodelling, histone modifications and aberrant DNA methylation, which influence gene expression, alternative splicing and function of non-coding RNA. In this review, we first highlight epigenetic modulators, modifiers and mediators in CRC, then we elaborate on causes and consequences of epigenetic alterations in CRC pathogenesis alongside an appraisal of the complex feedback mechanisms realized through alternative splicing and non-coding RNA regulation. An emphasis in our review is put on how this intricate network of epigenetic and post-transcriptional gene regulation evolves during the initiation, progression and metastasis formation in CRC
cudaMap: a GPU accelerated program for gene expression connectivity mapping
BACKGROUND: Modern cancer research often involves large datasets and the use of sophisticated statistical techniques. Together these add a heavy computational load to the analysis, which is often coupled with issues surrounding data accessibility. Connectivity mapping is an advanced bioinformatic and computational technique dedicated to therapeutics discovery and drug re-purposing around differential gene expression analysis. On a normal desktop PC, it is common for the connectivity mapping task with a single gene signature to take > 2h to complete using sscMap, a popular Java application that runs on standard CPUs (Central Processing Units). Here, we describe new software, cudaMap, which has been implemented using CUDA C/C++ to harness the computational power of NVIDIA GPUs (Graphics Processing Units) to greatly reduce processing times for connectivity mapping. RESULTS: cudaMap can identify candidate therapeutics from the same signature in just over thirty seconds when using an NVIDIA Tesla C2050 GPU. Results from the analysis of multiple gene signatures, which would previously have taken several days, can now be obtained in as little as 10 minutes, greatly facilitating candidate therapeutics discovery with high throughput. We are able to demonstrate dramatic speed differentials between GPU assisted performance and CPU executions as the computational load increases for high accuracy evaluation of statistical significance. CONCLUSION: Emerging âomicsâ technologies are constantly increasing the volume of data and information to be processed in all areas of biomedical research. Embracing the multicore functionality of GPUs represents a major avenue of local accelerated computing. cudaMap will make a strong contribution in the discovery of candidate therapeutics by enabling speedy execution of heavy duty connectivity mapping tasks, which are increasingly required in modern cancer research. cudaMap is open source and can be freely downloaded from http://purl.oclc.org/NET/cudaMap
Connectivity mapping using a combined gene signature from multiple colorectal cancer datasets identified candidate drugs including existing chemotherapies
BACKGROUND: While the discovery of new drugs is a complex, lengthy and costly process, identifying new uses for existing drugs is a cost-effective approach to therapeutic discovery. Connectivity mapping integrates gene expression profiling with advanced algorithms to connect genes, diseases and small molecule compounds and has been applied in a large number of studies to identify potential drugs, particularly to facilitate drug repurposing. Colorectal cancer (CRC) is a commonly diagnosed cancer with high mortality rates, presenting a worldwide health problem. With the advancement of high throughput omics technologies, a number of large scale gene expression profiling studies have been conducted on CRCs, providing multiple datasets in gene expression data repositories. In this work, we systematically apply gene expression connectivity mapping to multiple CRC datasets to identify candidate therapeutics to this disease. RESULTS: We developed a robust method to compile a combined gene signature for colorectal cancer across multiple datasets. Connectivity mapping analysis with this signature of 148 genes identified 10 candidate compounds, including irinotecan and etoposide, which are chemotherapy drugs currently used to treat CRCs. These results indicate that we have discovered high quality connections between the CRC disease state and the candidate compounds, and that the gene signature we created may be used as a potential therapeutic target in treating the disease. The method we proposed is highly effective in generating quality gene signature through multiple datasets; the publication of the combined CRC gene signature and the list of candidate compounds from this work will benefit both cancer and systems biology research communities for further development and investigations
Durability performance of structural concrete made with coarse recycled concrete aggregates
There is often a poor perception of the durability of concrete made with recycled concrete aggregates (RCA), as well as concerns regarding performance variability and contamination of the source material. Additional research regarding the addition of RCA in structural concrete is therefore required to more clearly determine the limits of its suitability.
The influence of RCA on the mechanical properties of concrete has been well investigated; the effect on durability however, is less well understood. Chloride ions can be particularly detrimental to the durability of reinforced concrete and BS 8500 currently allows RCA in strength classes up to C40/50 for structures unlikely to be exposed to de-icing salts and marine environments during their design life. This research investigated the effect of coarse RCA in combination with supplementary cementitious materials on the resistance to chloride ingress of concrete in terms of surface resistivity, sorptivity and rapid chloride migration testing. Compressive cube testing was conducted to determine compliance with characteristic and target mean strengths.
The results indicate that a higher replacement of natural aggregates with RCA causes a reduction in the resistance to water and chloride ingress, possibly due to the higher water absorption characteristics of the RCA. PFA and GGBS reduced the rate of water and chloride ingress compared to Portland cement concretes for all coarse RCA increments tested
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