Self-management strategies for people with epilepsy: An overview of reviews.

OBJECTIVE: This overview of systematic reviews aimed to appraise evidence regarding self-management strategies on health-related quality of life, self-efficacy, medication compliance, seizure status and psychosocial outcomes compared to usual care for people with epilepsy. METHODS: Databases were searched until September 2022 using MeSH terms included OVID Medline, Embase and Cochrane. Following application of eligibility criteria, data were extracted and quality of articles was assessed using the AMSTAR2 checklist. A narrative synthesis of evidence included certainty of evidence evaluated using a Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: The 12 selected reviews contained three meta-analyses and 91 unique primary studies. One review considered only epilepsy with intellectual disability and three considered paediatrics. Interventions included technologically-based interventions, small group discussion, or counselling and educational programs. There was high certainty evidence to suggest self-management is associated with improvement in health-related quality of life and moderate certainty evidence to suggest improvement in depression symptoms. There was low certainty evidence to suggest a modest reduction in negative health events and a minimal increase in the satisfaction with life. There was no evidence of benefit favouring self-management on measures of adherence epilepsy self-management, perception of self-efficacy, medication adherence or seizure status. SIGNIFICANCE: Despite high certainty evidence to suggest that self-management strategies for people with epilepsy improve health-related quality of life, benefits have not been demonstrated for outcomes that would be expected to be associated with these improvements, such as seizure status. These results provide support for self-management strategies to supplement usual care for people with epilepsy.

Impact of epilepsy surgery on quality of life: Systematic review and meta-analysis.

Improved quality of life (QoL) is an important outcome goal following epilepsy surgery. This study aims to quantify change in QoL for adults with drug-resistant epilepsy (DRE) who undergo epilepsy surgery, and to explore clinicodemographic factors associated with these changes. We conducted a systematic review and meta-analysis using Medline, Embase, and Cochrane Central Register of Controlled Trials. All studies reporting pre- and post-epilepsy surgery QoL scores in adults with DRE via validated instruments were included. Meta-analysis assessed the postsurgery change in QoL. Meta-regression assessed the effect of postoperative seizure outcomes on postoperative QoL as well as change in pre- and postoperative QoL scores. A total of 3774 titles and abstracts were reviewed, and ultimately 16 studies, comprising 1182 unique patients, were included. Quality of Life in Epilepsy Inventory-31 item (QOLIE-31) meta-analysis included six studies, and QOLIE-89 meta-analysis included four studies. Postoperative change in raw score was 20.5 for QOLIE-31 (95% confidence interval [CI] = 10.9-30.1, I2 = 95.5) and 12.1 for QOLIE-89 (95% CI = 8.0-16.1, I2 = 55.0%). This corresponds to clinically meaningful QOL improvements. Meta-regression demonstrated a higher postoperative QOLIE-31 score as well as change in pre- and postoperative QOLIE-31 score among studies of cohorts with higher proportions of patients with favorable seizure outcomes. At an individual study level, preoperative absence of mood disorders, better preoperative cognition, fewer trials of antiseizure medications before surgery, high levels of conscientiousness and openness to experience at the baseline, engagement in paid employment before and after surgery, and not being on antidepressants following surgery were associated with improved postoperative QoL. This study demonstrates the potential for epilepsy surgery to provide clinically meaningful improvements in QoL, as well as identifies clinicodemographic factors associated with this outcome. Limitations include substantial heterogeneity between individual studies and high risk of bias.

Recognition and epileptology of protracted CLN3 disease.

OBJECTIVE: This study was undertaken to analyze phenotypic features of a cohort of patients with protracted CLN3 disease to improve recognition of the disorder. METHODS: We analyzed phenotypic data of 10 patients from six families with protracted CLN3 disease. Haplotype analysis was performed in three reportedly unrelated families. RESULTS: Visual impairment was the initial symptom, with onset at 5-9 years, similar to classic CLN3 disease. Mean time from onset of visual impairment to seizures was 12 years (range = 6-41 years). Various seizure types were reported, most commonly generalized tonic-clonic seizures; focal seizures were present in four patients. Progressive myoclonus epilepsy was not seen. Interictal electroencephalogram revealed mild background slowing and 2.5-3.5-Hz spontaneous generalized spike-wave discharges. Additional interictal focal epileptiform discharges were noted in some patients. Age at death for the three deceased patients was 31, 31, and 52 years. Molecular testing revealed five individuals were homozygous for c.461-280_677 + 382del966, the "common 1-kb" CLN3 deletion. The remaining individuals were compound heterozygous for various combinations of recurrent pathogenic CLN3 variants. Haplotype analysis demonstrated evidence of a common founder for the common 1-kb deletion. Dating analysis suggested the deletion arose approximately 1500 years ago and thus did not represent cryptic familial relationship in this Australian cohort. SIGNIFICANCE: We highlight the protracted phenotype of a disease generally associated with death in adolescence, which is a combined focal and generalized epilepsy syndrome with progressive neurological deterioration. The disorder should be suspected in an adolescent or adult patient presenting with generalized or focal seizures preceded by progressive visual loss. The common 1-kb deletion has been typically associated with classic CLN3 disease, and the protracted phenotype has not previously been reported with this genotype. This suggests that modifying genetic factors may be important in determining this somewhat milder phenotype and identification of these factors should be the subject of future research.

Comorbidities in newly diagnosed epilepsy: Pre-existing health conditions are common and complex across age groups.

OBJECTIVES: People with epilepsy have a higher prevalence of medical and psychiatric comorbidities compared to the general population. Comorbidities are associated with poor epilepsy outcomes, and there have been recommendations for screening and early identification to improve clinical management. Data from 'First Seizure Clinics' (FSCs) with expert epileptological review can inform about disorders already present at the point of diagnosis of epilepsy or unprovoked seizures. Here, we aimed to describe pre-existing conditions with a focus on psychiatric, substance use, cardiac, neurological, and cancer health domains. METHODS: We included 1383 adults who received a new diagnosis of epilepsy or unprovoked seizures at Austin Hospital (AH) or Royal Melbourne Hospital (RMH) (Australia) FSCs from 2000 to 2010. Data were audited from FSC records, primarily detailed interviews undertaken by epileptologists. Logistic regression examined age distribution and other risk factors. RESULTS: The median age at FSC presentation was 37 years (IQR 26-53, range 18-94). Pre-existing conditions were reported by 40 %; from 32 % in the youngest group (18-30 years) to 53 % in the oldest (65+ years). Psychiatric (18 %) and substance use (16 %) disorders were most common, with higher prevalence among patients 18 to 65 years of age compared to those older than 65 years (p < 0.001). Cardiac, neurological, or cancer conditions were reported by 3-6 %, most often amongst those older than 65 years (p < 0.01). Eight percent (n = 112) reported disorders in >1 health domain. The commonest combination was a psychiatric condition with substance use disorder. Of the sixty-two patients reporting this combination, 61 were ≤65 years of age. CONCLUSIONS: Pre-existing health conditions are present in a substantial proportion of patients diagnosed with epilepsy or unprovoked seizures. Disorders are highest amongst elders, but one-third of younger adults also reported positive histories. These are predominantly psychiatric and/or substance use disorders, conditions strongly associated with poor outcomes in the general population. These findings inform post-diagnosis planning and management, as well as research examining post-diagnostic outcomes and associations between comorbidities and epilepsy.

An innovative model of access and triage to reduce waiting in an outpatient epilepsy clinic: an intervention study.

BACKGROUND: Delayed access to outpatient care may negatively impact on health outcomes. We aimed to evaluate implementation of the Specific Timely Appointments for Triage (STAT) model of access in an epilepsy clinic to reduce a long waitlist and waiting time. METHODS: This study is an intervention study using pre-post comparison and an interrupted time series analysis to measure the effect of implementation of the STAT model to an epilepsy clinic. Data were collected over 28 months to observe the number of patients on the waitlist and the waiting time over three time periods: 12 months prior to implementation of STAT, ten months during implementation and six months post-intervention. STAT combines one-off backlog reduction with responsive scheduling that protects time for new appointments based on historical data. The primary outcomes were the number of patients on the waitlist and the waiting time across the three time periods. Secondary outcomes evaluated pre- and post-intervention changes in number of appointments offered weekly, non-arrival and discharge rates. RESULTS: A total of 938 patients were offered a first appointment over the study period. The long waitlist was almost eliminated, reducing from 616 during the pre-intervention period to 11 post-intervention (p = 0.002), but the hypothesis that waiting time would decrease was not supported. The interrupted time series analysis indicated a temporary increase in waiting time during the implementation period but no significant change in slope or level in the post- compared to the pre-intervention period. Direct comparison of the cohort of patients seen in the pre- and post-intervention periods suggested an increase in median waiting time following the intervention (34 [IQR 25-86] to 46 [IQR 36-61] days (p = 0.001)), but the interquartile range reduced indicating less variability in days waited and more timely access for the longest waiters. CONCLUSIONS: The STAT model was implemented in a specialist epilepsy outpatient clinic and reduced a large waitlist. Reductions in the waitlist were achieved with little or no increase in waiting time. The STAT model provides a framework for an alternative way to operate outpatient clinics that can help to ensure that all people referred are offered an appointment in a timely manner.

Precipitation as a Possible Risk Factor for Development of Lyme Nephritis in Dogs.

To determine whether increased precipitation in the months before diagnosis is predictive of Lyme nephritis in dogs, a symmetrical bidirectional case-crossover study was performed on 87 dogs with presumptive Lyme nephritis. Cases were geographically linked to the nearest precipitation monitoring station, and monthly total precipitation for the 4 mo preceding diagnosis was compared to monthly total precipitation 1 yr before and 1 yr after. Breeds affected included Labrador retrievers (n = 31), mixed-breed dogs (n = 19), and golden retrievers (n = 10), with a possible seasonal bimodal peak in spring and fall. In age-adjusted analysis, each additional inch of precipitation 3 mo before diagnosis was associated with an increase in the odds of developing Lyme nephritis (odds ratio 1.13, 95% confidence interval 1.01-1.25). The results suggest that increased precipitation is a possible risk factor for Lyme nephritis in dogs. These findings may provide useful information for the accurate diagnosis of dogs with protein-losing nephropathy and may guide future studies of risk factors for Lyme nephritis. The methodology employed here reinforces the concept that case-crossover designs have utility beyond acute exposures and outcomes and offer an attractive alternative for studies in companion animals.

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.

OBJECTIVE: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. METHODS: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. RESULTS: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. INTERPRETATION: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284.

The effect of epilepsy surgery on productivity: A systematic review and meta-analysis.

OBJECTIVES: An important but understudied benefit of resective epilepsy surgery is improvement in productivity; that is, people's ability to contribute to society through participation in the workforce and in unpaid roles such as carer duties. Here, we aimed to evaluate productivity in adults with drug-resistant epilepsy (DRE) pre- and post-resective epilepsy surgery, and to explore the factors that positively influence productivity outcomes. METHODS: We conducted a systematic review and meta-analysis using four electronic databases: Medline (Ovid), EMBASE (Ovid), EBM Reviews - Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library. All studies over the past 30 years reporting on pre- and post-resective epilepsy surgical outcomes in adults with DRE were eligible for inclusion. Meta-analysis was performed to assess the post-surgery change in employment outcomes. RESULTS: A total of 1005 titles and abstracts were reviewed. Seventeen studies, comprising 2056 unique patients, were suitable for the final quantitative synthesis and meta-analysis. Resective epilepsy surgery resulted in a 22% improvement in overall productivity (95% confidence interval [CI]: 1.07-1.40). The factors associated with increased post-surgery employment risk ratios were lower pre-surgical employment in the workforce (relative risk ratio [RRR] =0.34; 95% CI: 0.15-0.74), shorter follow-up duration (RRR = 0.95; 95% CI: 0.90-0.99), and lower mean age at time of surgery (RRR= 0.97; 95% CI: 0.94-0.99). The risk of bias of the included studies was assessed using Risk Of Bias In Non-randomised Studies - of Interventions and was low for most variables except "measurement of exposure." SIGNIFICANCE: There is clear evidence that resective surgery in eligible surgical DRE patients results in improved productivity. Future work may include implementing a standardized method for collecting and reporting productivity in epilepsy cohorts and focusing on ways to reprioritize health care resource allocation to allow suitable candidates to access surgery earlier. This will ultimately benefit individuals with DRE, their families, our communities, and the wider health care system.

PIGN encephalopathy: Characterizing the epileptology.

OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

Pet-owner perceptions of laparoscopy in an urban hybrid veterinary practice.

OBJECTIVE: To investigate owner perceptions of laparoscopic surgery, including attitudes towards paying more for minimally invasive surgery (MIS). STUDY DESIGN: Randomized cross-sectional prospective survey. SAMPLE POPULATION: One hundred owners presenting at a combined general and specialty practice. METHODS: Participants were interviewed using a survey tool to assess prior knowledge of laparoscopic procedures, attitude for or against these procedures, reasons for this attitude, and whether they would pay more for the procedures. Demographic data were collected. RESULTS: Fifty-five percent of owners had previous knowledge of laparoscopy. Ninety-two percent of owners would choose laparoscopy over an open procedure for their pet. Reasons given for preferring laparoscopy: less postoperative pain (66.3%), shorter length of hospitalization (26.1%), better cosmesis (20.1%), perception of lower cost (15.2%), faster return to function (14.1%), length of anesthesia (5.4%), and other reasons (26.1%). Ninety-one percent of owners were willing to pay more for MIS. Among owners who indicated they would be willing to pay more, owners presenting with dogs were 2.5 times more likely to be willing to pay at least $1000 more than owners presenting with cats. CONCLUSION: The majority of owners surveyed at a large hybrid hospital in an urban setting choose laparoscopic over open procedures and were willing to pay more for them. CLINICAL SIGNIFICANCE: The results highlight the importance of client and veterinarian education regarding the options of MIS for pets, as owners who are informed may prefer referral for the procedures. The financial investment to build a MIS practice may be justified.

Associations between styloid process sheath CT sizes and age, body weight, and breed in horses.

The styloid process sheath (SPS) is a part of the tympanic temporal bone and an incomplete bony sleeve surrounding the styloid process, tympanohyoid cartilage, and dorsal part of the stylohyoid bone. In horses undergoing head CT, we observed a range of SPS sizes and questioned whether differences were early features of temporohyoid osteoarthropathy (THO) or normal anatomic variations associated with age, body weight, sex, or breed. We hypothesized that SPS sizes were positively correlated with age and body weight, but not with sex or breed. Using a convenience population of horses that underwent head CT at our institution (2008-2017), regardless of THO status, we investigated these hypotheses in a retrospective cross-sectional study. The sample comprised 102 horses. The median SPS height was larger medially (4.3 mm) than laterally (2.4 mm) and the median width was 11.1 mm: no difference was detected between sides. Geldings had a significantly larger median SPS width (11.6 mm) than stallions (8.7 mm; P < 0.05) and mares (10.0 mm; P < 0.05). No association was detected between SPS sizes and body weight and breed. Univariate and multivariate analyses initially found significant associations between SPS heights and age. Secondary analyses performed following removal of outliers and horses <2-years old found similar but less pronounced results (annual increase in SPS heights decreased from 3.2-3.8% to 0.9-2.6%). Most associations were insignificant when investigated by age group, but the annual rate of increased size might be faster in older horses. Excessive SPS enlargement was theorized as an essential component of THO.

What is the effect of delays in access to specialist epilepsy care on patient outcomes? A systematic review and meta-analysis.

OBJECTIVE: To determine the association between delays in access to specialist epilepsy care and patient outcomes. METHODS: Three databases were searched using eligibility criteria related to the concepts of timely access, epilepsy, and clinical outcome. Comparative data on patient outcomes by time to treatment was required for inclusion. Studies were selected independently by two researchers who reviewed title/abstract, then full text articles. Data were extracted and risk of bias was evaluated. Results were synthesized in random effects model meta-analyses, and strength of the body of evidence was evaluated. Descriptive analysis was conducted for studies not included in meta-analyses. RESULTS: Thirty-five studies, reported in 40 papers, were included. The studies investigated impact of delays in diagnosis, commencement of medication, or surgery for children and adults. Early diagnosis and access to specialist neurology care was associated with improvements in seizure status, development, and/or intelligence quotients. Meta-analyses provided low to high certainty evidence of increased odds of improved seizure outcome with early commencement of medication depending on follow-up period and individual risk factors. There was moderate certainty evidence that people with favorable seizure outcomes wait less time (MD 2.8 years, 95% CI 1.7-3.9) for surgery compared to those with unfavorable outcomes. SIGNIFICANCE: This review provides evidence that earlier access to specialist epilepsy care for diagnosis, commencement of medication, and surgery is associated with better patient outcomes.

Adverse events related to antiepileptic drugs.

OBJECTIVE: Adverse events (AEs) related to antiepileptic drugs (AEDs) may interfere with adequate dosing and patient adherence, leading to suboptimal seizure control, and relatedly, increased injuries, hospitalizations, and mortality. This study investigated the clinicodemographic factors associated with AEs related to AEDs as reported by the Liverpool Adverse Events Profile (LAEP), and explored the ability of LAEP to discriminate between epilepsy and psychogenic nonepileptic seizures (PNES). We hypothesized that female sex, mood disorders, AED-polytherapy, duration, and severity of epilepsy are associated with increased endorsement of AEs related to AEDs, and that endorsement of AEs related to AEDs would significantly differ between epilepsy and PNES patients. METHODS: We prospectively enrolled adult patients admitted to two inpatient video-electroencephalogram monitoring units. Clinicodemographic variables and psychometric measures of depression, anxiety, and cognitive function were recorded. Patient-reported AE endorsement was obtained using the LAEP, which was reduced to four latent domains using exploratory structural equation modeling. General linear models identified variables associated with each domain. Logistic regression determined the ability of LAEP scores to differentiate between epilepsy and PNES. RESULTS: 311 patients met inclusion criteria. Mean age was 38 years and 56% of patients were female. Network analysis demonstrated strong relationships between depression and anxiety with physical, sleep, psychiatric, and dermatological AE endorsement. Depression, female sex, and AED polytherapy were associated with greater AE endorsement. Epilepsy, compared to PNES, was associated with lower AE endorsement. Fewer prescribed AEDs and greater reported physical AE endorsement were associated with PNES diagnosis. SIGNIFICANCE: There is a strong relationship between patient-reported AEs and psychiatric symptomatology. Those with PNES paradoxically endorse greater physical AEs despite receiving fewer AEDs. Patients who endorse AEs in clinical practice should be screened for comorbid depression or anxiety and treated accordingly.

First seizure presentations in adults: beyond assessment and treatment.

Almost 10% of people will experience at least one seizure over a lifetime. Although common, first seizures are serious events and warrant careful assessment and management. First seizures may be provoked by acute or remote symptomatic factors including life-threatening metabolic derangements, drug toxicity or structural brain lesions. An unprovoked first seizure may herald the onset of epilepsy and may be accompanied by medical and psychiatric illnesses. Accidents, injuries and death associated with first seizures are likely under-reported. The cognitive and emotional impact of first seizures is often neglected. Evaluation of a patient presenting with a first seizure requires careful history-taking and early specialist assessment, however optimal management strategies have not been extensively investigated. Further, advances in technology and the role of eHealth interventions such as telemedicine may be of value in the care of patients who have experienced a first seizure. This article reviews the impact and implications of first seizures beyond the scope provided in current guidelines which tend to focus on assessment and management. It examines the effect of first seizures on the well-being of patients; assesses morbidity and premature mortality in first seizures and discusses current and future directions to optimise safety and health of people with first seizures, with a focus on adult patients. Recognition of these issues is essential to provide adequate care for people with first seizures.

Comparisons of direct and indirect utilities in adult epilepsy populations: A systematic review.

OBJECTIVE: Epilepsy is common and carries substantial morbidity, and therefore identifying cost-effective health interventions is essential. Cost-utility analysis is a widely used method for such analyses. For this, health conditions are rated in terms of utilities, which provide a standardized score to reflect quality of life. Utilities are obtained either indirectly using quality of life questionnaires, or directly from patients or the general population. We sought to describe instruments used to estimate utilities in epilepsy populations, and how results differ according to methods used. METHODS: We undertook a systematic review of studies comparing at least two instruments for obtaining utilities in epilepsy populations. MEDLINE, Embase, ScienceDirect, Cochrane Library, Google Scholar, and gray literature were searched from inception to June 2019. Mean utilities were recorded and compared for each method. RESULTS: Of the 38 unique records initially identified, eight studies met inclusion criteria. Utilities were highest for direct "tradeoff" methods, obtained via instruments including standard gamble (0.93) and time tradeoff (0.92), compared to indirect methods, obtained via instruments including EuroQoL five-dimensional form (range = 0.72-0.86) and Health Utilities Index Mark 3 (range = 0.52-0.71). Visual analog scale (VAS), a direct "nontradeoff" instrument, provided equal or lower utilities (range = 68.0-79.8) compared to indirect instruments. SIGNIFICANCE: Direct methods, with the important exception of VAS, may provide higher utilities than indirect methods. More studies are needed to identify the most appropriate utility instruments for epilepsy populations, and to investigate whether there is variation between utilities for different types of epilepsy and other patient- and disease-specific factors.

Specific timely appointments for triage to reduce wait times in a medical outpatient clinic: protocol of a pre-post study with process evaluation.

BACKGROUND: Managing demand for services is a problem in many areas of healthcare, including specialist medical outpatient clinics. Some of these clinics have long waiting lists with variation in access for referred people. A model of triage and appointment allocation has been developed and tested that has reduced waiting times by about a third in community outpatient services. This study aims to determine whether the model can be applied in the setting of a specialist medical outpatient clinic to reduce wait time from referral to first appointment. METHODS: A pre-post study will collect data before and after implementing the Specific Timely Appointments for Triage (STAT) model of access and triage. The study will incorporate a pre-implementation period of 12 months, an implementation period of up to 6 months and a post STAT-implementation period of 6 months. The setting will be the epilepsy clinic at a metropolitan health service in Melbourne. Included will be all people referred to the clinic, or currently waiting, during the allocated periods of data collection (total sample estimated n = 975). Data routinely collected by the health service and qualitative data from staff will be analysed to determine the effects of introducing the STAT model. The primary outcome will be wait time, measured by number of patients on the wait list at monthly time points and the mean number of days waited from referral to first appointment. Secondary outcomes will include patient outcomes, such as admission to hospital while waiting, and service outcomes, including rate of discharge. Analysis of the primary outcome will include interrupted time series analysis and simple comparisons of the pre and post-implementation periods. Process evaluation will include investigation of the fidelity of the intervention, adaptations required and qualitative analysis of the experiences of clinic staff. DISCUSSION: Prompt access to service and optimum patient flow is important for patients and service providers. Testing the STAT model in a specialist medical outpatient clinic will add to the evidence informing service providers and policy makers about how the active management of supply and demand in health care can influence wait times. The results from this study may be applicable to other specialist medical outpatient clinics, potentially improving access to care for many people.

The aryl hydrocarbon receptor as an antitumor target of synthetic curcuminoids in colorectal cancer.

BACKGROUND: Curcumin has proven to be a potent antitumor agent in both preclinical and clinical models of colorectal cancer (CRC). It has also been identified as a ligand of the transcription factor known as the aryl hydrocarbon receptor (AHR). Our laboratory has identified the AHR as a mechanism which contributes to both tumorigenesis in a mouse model of inflammatory CRC as well an apoptotic target in vitro. Curcumin's role as an AHR ligand may modulate its effects to induce colon cancer cell death, and this role may be enhanced via structural modification of the curcumin backbone. We sought to determine if the two piperidone analogs of curcumin, RL66 and RL118, exhibit more robust antitumor actions than their parent compound in the context of colorectal cancer in vitro. Moreover, to ascertain the ability of curcumin, RL66 and RL118 to activate the AHR and evaluate if this activation has any effect on CRC cell death. MATERIALS AND METHODS: DLD1, HCT116, LS513, and RKO colon cell lines were propagated in vitro. Natural curcumin was obtained commercially, whereas RL66 and RL118 were synthesized and characterized de novo. Multiwell fluorescent/luminescent signal detection was used to simultaneously ascertain cell viability, cell cytonecrosis, and relative amounts of apoptotic activity. AHR activity was measured with a dual luciferase reporter gene system. Stable expression of small interfering RNA interference was established in the HCT116 cell lines to create AHR "knock down" cell lines. RESULTS: Both RL66 and RL118 proved to be more potent antitumor agents than their parent compound curcumin in all cell lines tested. The majority of this cell death was due to induction of apoptosis, which occurred earlier and to a greater degree following RL66 and RL118 treatment as opposed to curcumin. Also, RL66 and RL118 were found to be activators of AHR, and a portion of their ability to cause cell death was dependent on this induction. Curcumin was found unable to activate the AHR, and levels of AHR messenger RNA did not change their effects on cell death. CONCLUSIONS: Piperidone analogs of curcumin exhibited enhanced antitumor effects in vitro as opposed to their parent compound. Even more, this enhanced cell death profile may be partially attributed to the ability of these compounds to activate the AHR. Further study of synthetic curcumin analogs as chemopreventives and chemoadjuncts in CRC is warranted. Also, more generally, the AHR may represent a potential putative target for novel anticancer agents for CRC.

The Aryl Hydrocarbon Receptor is a Repressor of Inflammation-associated Colorectal Tumorigenesis in Mouse.

OBJECTIVE: To determine the role of the aryl hydrocarbon receptor (AHR) in colitis-associated colorectal tumorigenesis. BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in United States. Chronic intestinal inflammation increases the risk for the development of CRC. We investigated the involvement of AHR, a ligand-activated transcriptional regulator, in colitis-associated colorectal tumorigenesis. METHODS: We used a mouse model of colitis-associated colorectal tumorigenesis that employs treatment with azoxymethane and dextran sodium sulfate. We examined the role of AHR using both an Ahr-deletion mouse model (Ahr) and treatment with the AHR pro-agonist indole-3-carbinol (I3C). Incidence, multiplicity, and location of tumors were visually counted. Tumors were defined as neoplasms. Intestinal inflammation was assessed by quantitative PCR for proinflammatory markers and colon length. Data were evaluated and compared using GraphPad Prism software (version 6, La Jolla, CA). RESULTS: Tumor incidence was increased 32% in Ahr null mice and tumor multiplicity was approximately increased 3-fold compared with wild-type mice (2.4 vs 7; P < 0.05). Furthermore, tumor multiplicity was reduced 92% by treatment of I3C in wild-type mice, whereas the suppressor effect of I3C was not observed in Ahr null mice (P < 0.05). CONCLUSIONS: We found that AHR plays a protective role in colitis-associated colorectal tumorigenesis. This conclusion is based on the observations that Ahr null mice showed increased number of colorectal tumors, and mice treated with I3C exhibited fewer tumors. This study supports the use of AHR agonists such as I3C as a chemopreventive therapy for IBD-associated CRC in human patients.

Indole-3-carbinol induces tumor cell death: function follows form.

BACKGROUND: Even with colonoscopy screening and preventive measures becoming more commonplace, colorectal cancer (CRC) remains the third leading cause of oncologic death in the United States as of 2014. Many chemotherapeutics exist for the treatment of colorectal cancer, though they often come with significant side effect profiles or narrow efficacy ranges in terms of patient profile. Dietary phytochemicals such as glucobrassicin and its metabolite indole-3-carbinol (I3C) have been implicated in tumor prevention in many preclinical models across a variety of gastrointestinal tumors and represent an intriguing new class of natural chemotherapeutics for CRC. I3C has been identified as a ligand of the aryl hydrocarbon receptor (AHR), and we aimed to characterize this AHR activation in relation to its cytotoxic properties. METHODS: Human colorectal cancer cell lines DLD1, HCT116, HT-29, LS513, and RKO were treated with indole-3-carbinol or vehicle. Cell viability was assessed via a fluorescent product assay, and apoptotic activity was assessed via a luminescent signal tied to a ratio of caspase-3 and caspase-7 activity. Gene expression of AHR and CYP1A1 messenger ribonucleic acid (mRNA) was measured using quantitative real-time polymerase chain reaction. Small interfering RNA stable expression lines were established on a HCT116 background using a laboratory-developed transfection protocol as published elsewhere. RESULTS: Multiple colorectal cancer cell types express increased CYP1A1 mRNA levels (a specific marker of AHR-driven activity) after treatment with I3C, characterizing I3C treatment as agonistic of this pathway. Also, I3C induced a dose-dependent decrease in cell viability as well as inducing apoptosis. Furthermore, using small interfering RNA interference to knockdown AHR responsiveness generated a significant resistance to the chemotherapeutic actions of indole-3-carbinol regarding both cell viability and apoptotic activity. CONCLUSIONS: Some degree of the cytotoxic and proapoptotic effects of indole-3-carbinol on colon cancer cells is dependent on activation of the aryl hydrocarbon receptor. This represents a novel mechanism for the molecular action of indole-3-carbinol and enhances our understanding of its effects in the context of colorectal cancer. Continued preclinical study of both indole-3-carbinol and the aryl hydrocarbon receptor pathway is warranted, which may one day lead to novel diet-derived colon cancer treatments that enlist the AHR.