Home-monitoring for neovascular age-related macular degeneration in older adults within the UK: the MONARCH diagnostic accuracy study.

Background: Most neovascular age-related macular degeneration treatments involve long-term follow-up of disease activity. Home monitoring would reduce the burden on patients and those they depend on for transport, and release clinic appointments for other patients. The study aimed to evaluate three home-monitoring tests for patients to use to detect active neovascular age-related macular degeneration compared with diagnosing active neovascular age-related macular degeneration by hospital follow-up. Objectives: There were five objectives: Estimate the accuracy of three home-monitoring tests to detect active neovascular age-related macular degeneration. Determine the acceptability of home monitoring to patients and carers and adherence to home monitoring. Explore whether inequalities exist in recruitment, participants' ability to self-test and their adherence to weekly testing during follow-up. Provide pilot data about the accuracy of home monitoring to detect conversion to neovascular age-related macular degeneration in fellow eyes of patients with unilateral neovascular age-related macular degeneration. Describe challenges experienced when implementing home-monitoring tests. Design: Diagnostic test accuracy cohort study, stratified by time since starting treatment. Setting: Six United Kingdom Hospital Eye Service macular clinics (Belfast, Liverpool, Moorfields, James Paget, Southampton, Gloucester). Participants: Patients with at least one study eye being monitored by hospital follow-up. Reference standard: Detection of active neovascular age-related macular degeneration by an ophthalmologist at hospital follow-up. Index tests: KeepSight Journal: paper-based near-vision tests presented as word puzzles. MyVisionTrack®: electronic test, viewed on a tablet device. MultiBit: electronic test, viewed on a tablet device. Participants provided test scores weekly. Raw scores between hospital follow-ups were summarised as averages. Results: Two hundred and ninety-seven patients (mean age 74.9 years) took part. At least one hospital follow-up was available for 317 study eyes, including 9 second eyes that became eligible during follow-up, in 261 participants (1549 complete visits). Median testing frequency was three times/month. Estimated areas under receiver operating curves were < 0.6 for all index tests, and only KeepSight Journal summary score was significantly associated with the lesion activity (odds ratio = 3.48, 95% confidence interval 1.09 to 11.13, p = 0.036). Older age and worse deprivation for home address were associated with lower participation (χ2 = 50.5 and 24.3, respectively, p < 0.001) but not ability or adherence to self-testing. Areas under receiver operating curves appeared higher for conversion of fellow eyes to neovascular age-related macular degeneration (0.85 for KeepSight Journal) but were estimated with less precision. Almost half of participants called a study helpline, most often due to inability to test electronically. Limitations: Pre-specified sample size not met; participants' difficulties using the devices; electronic tests not always available. Conclusions: No index test provided adequate test accuracy to identify lesion diagnosed as active in follow-up clinics. If used to detect conversion, patients would still need to be monitored at hospital. Associations of older age and worse deprivation with study participation highlight the potential for inequities with such interventions. Provision of reliable electronic testing was challenging. Future work: Future studies evaluating similar technologies should consider: Independent monitoring with clear stopping rules based on test performance. Deployment of apps on patients' own devices since providing devices did not reduce inequalities in participation and complicated home testing. Alternative methods to summarise multiple scores over the period preceding a follow-up. Trial registration: This trial is registered as ISRCTN79058224. Funding: This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/97/02) and is published in full in Health Technology Assessment; Vol. 28, No. 32. See the NIHR Funding and Awards website for further award information.

Treatment for neovascular age-related macular degeneration, the most common cause of sight loss in those over 50 years, involves regular eye injections and frequent follow-up appointments. This is inconvenient for patients and causes capacity issues in the hospital eye service. Finding tests that could be undertaken at home that could detect if a further injection and hospital appointment was required or not would increase capacity to see those at highest risk of sight loss and also reduce the burden on patients and their carers. We investigated three different visual function tests, one paper-based and two applications on an iPod Touch_TM tablet (Apple, Cupertino, CA, USA). We wanted to see if they could detect an increase in disease activity that would require treatment, compared to the decision by a retinal specialist at a traditional hospital eye outpatient visit based on clinical examination and retinal imaging. To encourage those without a smartphone or home internet to participate, we provided both an iPod Touch and Mobile Wireless-Fidelity device with a mobile contract. None of the tests performed well enough to safely monitor patients at home. Those who were willing to participate tended to be younger, had previous experience of using smartphones, sending e-mail and internet access and were more well-off than those who chose not to participate. Some participants also experienced difficulties with the devices provided and successfully uploading the data which were not related to the extent of previous information technology experience. There were also significant technical challenges for the research team. The study helpline was used heavily, considerably more than we anticipated. These tests are not ready to be used in this context. Future studies involving mobile health technology need to carefully consider how to reach those unlikely to participate and provide sufficient technical support to support long-term follow-up.

Acceptability of Home Monitoring for Neovascular Age-Related Macular Degeneration Reactivation: A Qualitative Study.

This study formed part of a diagnostic test accuracy study to quantify the ability of three index home monitoring (HM) tests (one paper-based and two digital tests) to identify reactivation in Neovascular age-related macular degeneration (nAMD). The aim of the study was to investigate views about acceptability and explore adherence to weekly HM. Semi-structured interviews were held with 98 patients, family members, and healthcare professionals. A thematic approach was used which was informed by theories of technology acceptance. Various factors influenced acceptability including a patient's understanding about the purpose of monitoring. Training and ongoing support were regarded as essential for overcoming unfamiliarity with digital technology. Findings have implications for implementation of digital HM in the care of older people with nAMD and other long-term conditions.

Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres.

BACKGROUND: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). METHODS: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. DISCUSSION: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. TRIAL REGISTRATIONS: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).

Home-Monitoring Vision Tests to Detect Active Neovascular Age-Related Macular Degeneration.

Importance: Most neovascular age-related macular degeneration (nAMD) treatments involve long-term follow-up of disease activity. Home-monitoring would reduce the burden on patients and their caregivers and release clinic capacity. Objective: To evaluate 3 vision home-monitoring tests for patients to use to detect active nAMD compared with diagnosing active nAMD at hospital follow-up during the after-treatment monitoring phase. Design, Setting, and Participants: This was a diagnostic test accuracy study wherein the reference standard was detection of active nAMD by an ophthalmologist at hospital follow-up. The 3 home-monitoring tests evaluated included the following: (1) the KeepSight Journal (KSJ [International Macular and Retinal Foundation]), which contains paper-based near-vision tests presented as word puzzles, (2) the MyVisionTrack (mVT [Genentech]) vision-monitoring mobile app, viewed on an Apple mobile operating system-based device, and (3) the MultiBit (MBT [Visumetrics]) app, viewed on an Apple mobile operating system-based device. Participants were asked to test weekly; mVT and MBT scores were transmitted automatically, and KSJ scores were returned to the research office every 6 months. Raw scores between hospital follow-ups were summarized as averages. Patients were recruited from 6 UK hospital eye clinics and were 50 years and older with at least 1 eye first treated for active nAMD for at least 6 months or longer to a maximum of 42 months before approach. Participants were stratified by time since starting treatment. Study data were analyzed from May to September 2021. Exposures: The KSJ, mVT, and MBT were compared with the reference standard (in-hospital ophthalmologist examination). Main Outcomes and Measures: Estimated area under receiver operating characteristic curve (AUROC). The study had 90% power to detect a difference of 0.06, or 80% power to detect a difference of 0.05, if the AUROC for 2 tests was 0.75. Results: A total of 297 patients (mean [SD] age, 74.9 [6.6] years; 174 female [58.6%]) were included in the study. At least 1 hospital follow-up was available for 312 study eyes in 259 participants (1549 complete visits). Median (IQR) home-monitoring testing frequency was 3 (1-4) times per month. Estimated AUROC was less than 0.6 for all home-monitoring tests, and only the KSJ summary score was associated with lesion activity (odds ratio, 3.48; 95% CI, 1.09-11.13; P = .04). Conclusions and Relevance: Results suggest that no home-monitoring vision test evaluated provided satisfactory diagnostic accuracy to identify active nAMD diagnosed in hospital eye service follow-up clinics. Implementing any of these evaluated tests, with ophthalmologists only reviewing test positives, would mean most active lesions were missed, risking unnecessary sight loss.

Inequalities in Uptake and Use of Digital Applications for Home-Monitoring of Neovascular Age-Related Macular Degeneration in an Elderly Visually Impaired Population: The MONARCH Study.

Purpose: To describe inequalities in the Monitoring for Neovascular Age-related Macular Degeneration Reactivation at Home (MONARCH) diagnostic test accuracy study for: recruitment; participants' ability to self-test; and adherence to testing using digital applications during follow-up. Methods: Home-monitoring vision tests included two tests implemented as software applications (apps: MyVisionTrack and MultiBit) on an iPod Touch device. Patients were provided with all hardware required to participate (iPod and MIFI device) and trained to use the apps. Regression models estimated associations of age, sex, Index of Multiple Deprivation, strata of time since first diagnosis, and baseline visual acuity at study entry on outcomes of willingness to participate, ability to perform tests, and adherence to weekly testing. Results: A minority of patients who were approached were willing-in-principle to participate. Increasing age was associated with being unwilling-in-principle to participate. Patients from the most deprived areas had a 47% decrease in odds of being willing compared to those from the middle quintile deprived areas (odds ratio, 0.53; 95% confidence interval = 0.32, 0.88). Increasing age and worse deprivation were not consistently associated either with ability to self-monitor with the index tests, or adherence to weekly testing. Conclusions: Associations of increasing age and worse deprivation index were associated with unwillingness-in-principle to participate despite the provision of hardware' highlighting the potential for inequality with interventions of the kind evaluated. Translational Relevance: The clear evidence of inequalities in participation should prompt future research on ways to encourage adoption of mobile health technologies by underserved populations.

Descriptive study of the challenges when implementing an app for patients with neovascular age-related macular degeneration to monitor their vision at home.

OBJECTIVES: Remote monitoring of health has the potential to reduce the burden to patients of face-to-face appointments and make healthcare more efficient. Apps are available for patients to self-monitor vision at home, for example, to detect reactivation of age-related macular degeneration (AMD). Describing the challenges when implementing apps for self-monitoring of vision at home was an objective of the MONARCH study to evaluate two vision-monitoring apps on an iPod Touch (Multibit and MyVisionTrack). DESIGN: Diagnostic Test Accuracy study. SETTING: Six UK hospitals. METHODS: The study provides an example of the real-world implementation of such apps across health sectors in an older population. Challenges described include the following: (1) frequency and reason for incoming calls made to a helpline and outgoing calls made to participants; (2) frequency and duration of events responsible for the tests being unavailable; and (3) other technical and logistical challenges. RESULTS: Patients (n=297) in the study were familiar with technology; 252/296 (85%) had internet at home and 197/296 (67%) had used a smartphone. Nevertheless, 141 (46%) called the study helpline, more often than anticipated. Of 435 reasons for calling, all but 42 (10%) related to testing with the apps or hardware, which contributed to reduced adherence. The team made at least one call to 133 patients (44%) to investigate why data had not been transmitted. Multibit and MyVisionTrack apps were unavailable for 15 and 30 of 1318 testing days for reasons which were the responsibility of the app providers. Researchers also experienced technical challenges with a multiple device management system. Logistical challenges included regulations for transporting lithium-ion batteries and malfunctioning chargers. CONCLUSIONS: Implementation of similar technologies should incorporate a well-resourced helpline and build in additional training time for participants and troubleshooting time for staff. There should also be robust evidence that chosen technologies are fit for the intended purpose. TRIAL REGISTRATION NUMBER: ISRCTN79058224.

Evaluating atezolizumab in patients with urinary tract squamous cell carcinoma (AURORA): study protocol for a single arm, open-label, multicentre, phase II clinical trial.

BACKGROUND: Bladder and urinary tract cancers account for approximately 21,000 new diagnoses and 5,000 deaths annually in the UK. Approximately 90% are transitional cell carcinomas where advanced disease is treated with platinum based chemotherapy and PD-1/PD-L1 directed immunotherapy. Urinary tract squamous cell carcinoma (UTSCC) accounts for about 5% of urinary tract cancers overall making this a rare disease. We have yet to establish definitive systemic treatment options for advanced UTSCC. Preliminary translational data, from UTSCC patient tumour samples, indicate high PD-L1 expression and tumour infiltrating lymphocytes in a proportion of cases. Both of these features are associated with differential gene expression consistent with a tumour/immune microenvironment predicted to be susceptible to immune checkpoint directed immunotherapy which we will evaluate in the AURORA trial. METHODS: AURORA is a single arm, open-label, multicentre,UK phase II clinical trial. 33 patients will be recruited from UK secondary care sites. Patients with UTSCC, suitable for treatment with palliative intent, will receive atezolizumab PD-L1 directed immunotherapy (IV infusion, 1680 mg, every 28 days) for one year if tolerated. Response assessment, by cross sectional imaging will occur every 12 weeks. AURORA uses a Simon's 2-stage optimal design with best overall objective response rate (ORR, by RECIST v1.1) at a minimum of 12 weeks from commencing treatment as the primary endpoint. Secondary endpoints will include overall survival, progression-free survival, duration of response, magnitude of response using waterfall plots of target lesion measurements, quality of life using the EORTC QLQ-C30 tool, safety and tolerability (CTCAE v5) and evaluation of potential biomarkers of treatment response including PD-L1 expression. Archival tumour samples and blood samples will be collected for translational analyses. DISCUSSION: If this trial shows atezolizumab to be safe and effective it may lead to a future late phase randomised controlled trial in UTSCC. Ultimately, we hope to provide a new option for treatment for such patients. TRIAL REGISTRATIONS: EudraCT Number: 2021-001995-32 (issued 8th September 2021); ISRCTN83474167 (registered 11 May 2022); NCT05038657 (issued 9th September 2021).

Patient Acceptability of Home Monitoring for Neovascular Age-Related Macular Degeneration Reactivation: A Qualitative Study.

Neovascular age-related macular degeneration (nAMD) is a chronic, progressive condition and the commonest cause of visual disability in older adults. This study formed part of a diagnostic test accuracy study to quantify the ability of three index home monitoring (HM) tests (one paper-based and two digital tests) to identify reactivation in nAMD. The aim of this qualitative research was to investigate patients' or participants' views about acceptability and explore adherence to weekly HM. Semi-structured interviews were held with 78/297 participants (26%), with close family members (n = 11) and with healthcare professionals involved in training participants in HM procedures (n = 9) (n = 98 in total). A directed thematic analytical approach was applied to the data using a deductive and inductive coding framework informed by theories of technology acceptance. Five themes emerged related to: 1. The role of HM; 2. Suitability of procedures and instruments; 3. Experience of HM; 4. Feasibility of HM in usual practice; and 5. Impediments to patient acceptability of HM. Various factors influenced acceptability including a patient's understanding about the purpose of monitoring. While initial training and ongoing support were regarded as essential for overcoming unfamiliarity with use of digital technology, patients viewed HM as relatively straightforward and non-burdensome. There is a need for further research about how use of performance feedback, level of support and nature of tailoring might facilitate further the implementation of routinely conducted HM. Home monitoring was acceptable to patients and they recognised its potential to reduce clinic visits during non-active treatment phases. Findings have implications for implementation of digital HM in the care of older people with nAMD and other long-term conditions.

The COVID-19 Pandemic and Ophthalmic Care: A Qualitative Study of Patients with Neovascular Age-Related Macular Degeneration (nAMD).

Concerns have been expressed about the relationship between reduced levels of health care utilisation and the COVID-19 pandemic. This study aimed to elicit and explore the views of patients with neovascular age-related macular degeneration (nAMD) regarding the COVID-19 pandemic and their ophthalmic care. Semi-structured telephone interviews were conducted with thirty-five patients with nAMD taking part in a larger diagnostic accuracy study of home-monitoring tests. Participants were recruited using maximum variation sampling to capture a range of key characteristics including age, gender and time since initial treatment. Transcribed interview data were analysed using a deductive and inductive thematic approach. Three themes emerged from the analysis: i. access to eye clinic care. ii. COVID-19-mitigating factors and care delivery and iii. social and personal circumstances. Participants reported anxieties about cancelled or delayed appointments, limited communication from clinic-based services about appointments, and the impact of this on their ongoing care. Despite these concerns, there was apprehension about attending appointments due to infection risk and a perception that nAMD patients are a 'high risk' group. Views of those who attended clinics during the study period were, however, positive, with social distancing and infection control measures providing reassurance. These findings contribute to our understanding about experiences of patients with nAMD during the COVID-19 pandemic and may have potential implications for future planning of care services in similar circumstances. Innovative approaches may be required to address issues related to access to care, including concerns about delayed or cancelled appointments.

Monitoring for neovascular age-related macular degeneration (AMD) reactivation at home: the MONARCH study.

AIMS: This study aims to quantify the diagnostic test-accuracy of three visual function self-monitoring tests for detection of active disease in patients with neovascular age-related macular degeneration (nAMD) when compared with usual care. An integrated qualitative study will investigate the acceptability of these home-based testing strategies. METHODS: All consenting participants are provided with an equipment pack containing an iPod touch with two vision test applications installed and a paper journal of reading tests. Participants self-monitor their vision at home each week with all three tests for 12-18 months. Usual care continues over this period. Key eligibility criteria are: age ≥50 years; at least one eye with AMD with ≥6-≤42 months since first AMD treatment; and vision not worse than Snellen 6/60, LogMAR 1.04 or 33 letters. The primary outcome, and reference standard, is diagnosis of active disease during usual care monitoring in the Hospital Eye Service. Secondary outcomes include duration of study participation, ability of participants to do the tests, adherence to weekly testing and acceptability of the tests to participants. CONCLUSIONS: Recruitment is in progress at five NHS centres. Challenges in procuring equipment, setting up the devices and transporting devices containing lithium batteries to participating sites delayed the start of recruitment. The study will describe the performance of the tests self-administered at home in detecting active disease compared to usual care monitoring. It will also describe the feasibility of the NHS implementing patient-administered electronic tests or similar applications at home for monitoring health.

Laparoscopically assisted versus open oesophagectomy for patients with oesophageal cancer-the Randomised Oesophagectomy: Minimally Invasive or Open (ROMIO) study: protocol for a randomised controlled trial (RCT).

INTRODUCTION: Surgery (oesophagectomy), with neoadjuvant chemo(radio)therapy, is the main curative treatment for patients with oesophageal cancer. Several surgical approaches can be used to remove an oesophageal tumour. The Ivor Lewis (two-phase procedure) is usually used in the UK. This can be performed as an open oesophagectomy (OO), a laparoscopically assisted oesophagectomy (LAO) or a totally minimally invasive oesophagectomy (TMIO). All three are performed in the National Health Service, with LAO and OO the most common. However, there is limited evidence about which surgical approach is best for patients in terms of survival and postoperative health-related quality of life. METHODS AND ANALYSIS: We will undertake a UK multicentre randomised controlled trial to compare LAO with OO in adult patients with oesophageal cancer. The primary outcome is patient-reported physical function at 3 and 6 weeks postoperatively and 3 months after randomisation. Secondary outcomes include: postoperative complications, survival, disease recurrence, other measures of quality of life, spirometry, success of patient blinding and quality assurance measures. A cost-effectiveness analysis will be performed comparing LAO with OO. We will embed a randomised substudy to evaluate the safety and evolution of the TMIO procedure and a qualitative recruitment intervention to optimise patient recruitment. We will analyse the primary outcome using a multi-level regression model. Patients will be monitored for up to 3 years after their surgery. ETHICS AND DISSEMINATION: This study received ethical approval from the South-West Franchay Research Ethics Committee. We will submit the results for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN10386621.

Repeated daily administration of increasing doses of lipopolysaccharide provides a model of sustained inflammation-induced depressive-like behaviour in mice that is independent of the NLRP3 inflammasome.

Mounting preclinical evidence has implicated the NLRP3 inflammasome in depression-related behaviours elicited by chronic stress or acute lipopolysaccharide (LPS) challenge. However, the relevance of acute LPS as a model of depression has been questioned and behavioural time-courses of its effects can be inconsistent. The aims of this study were (1) to develop a novel protocol for repeated daily LPS administration and (2) to use this model to assess the involvement of NLRP3 inflammasome signalling in sustained inflammation-induced depressive-like behaviour in adult C57BL/6J mice deficient in NLRP3. Acute LPS (0.83mg/kg; i.p.) induced sickness behaviour evident as hypolocomotor activity. However, there was no significant increase in depressive-like behaviour in the forced swim test 24h post-administration. Interestingly, depressive-like behaviours were observed in the female urine sniffing test and in the sucrose preference test at 24h, but not 48h, post-administration of acute LPS. To mimic a period of sustained inflammation, 3-day repeated increasing LPS doses (0.1, 0.42 and 0.83mg/kg; i.p.) was compared to constant LPS doses (0.83mg/kg; i.p.). Sickness behaviour was seen in response to increasing doses, but tolerance developed to repeated constant doses of LPS. Furthermore, 3-day increasing doses of LPS resulted in a significant increase in immobility time in the forced swim test, consistent with depressive-like behaviour. When NLRP3-/- mice received this 3-day increasing dose regimen of LPS, sickness behaviours were attenuated compared to wild-type mice. The behaviour in the forced swim test was not significantly altered in NLRP3-/- mice. We propose that this increasing repeated dosing LPS model of inflammation-induced depressive-like behaviour may better model the sustained inflammation observed in depression and may provide a more translationally relevant paradigm to study the inflammatory mechanisms that contribute to depression.

Defensive eye-blink startle responses in a human experimental model of anxiety.

Inhalation of low concentrations of carbon dioxide (CO2) triggers anxious behaviours in rodents via chemosensors in the amygdala, and increases anxiety, autonomic arousal and hypervigilance in healthy humans. However, it is not known whether CO2 inhalation modulates defensive behaviours coordinated by this network in humans. We examined the effect of 7.5% CO2 challenge on the defensive eye-blink startle response. A total of 27 healthy volunteers completed an affective startle task during inhalation of 7.5% CO2 and air. The magnitude and latency of startle eye-blinks were recorded whilst participants viewed aversive and neutral pictures. We found that 7.5% CO2 increased state anxiety and raised concurrent measures of skin conductance and heart rate (HR). CO2 challenge did not increase startle magnitude, but slowed the onset of startle eye-blinks. The effect of CO2 challenge on HR covaried with its effects on both subjective anxiety and startle latency. Our findings are discussed with reference to startle profiles during conditions of interoceptive threat, increased cognitive load and in populations characterised by anxiety, compared with acute fear and panic.

Lesions of the dorsomedial striatum impair formation of attentional set in rats.

Behavioural flexibility refers to the ability to rapidly adapt to novel situations and it has been suggested that the frontal lobe and basal ganglia are implicated in various components of adjusting to changes in environmental contingencies. Behavioural flexibility can be assessed using attentional set-shifting tasks, in which performance is impaired after damage to the prefrontal cortex. The present study explores the downstream contribution of the prefrontal projection zone in the dorsomedial striatum (DMS) to attentional set shifting. Rats were tested in two set-shifting tasks following quinolinic acid injections bilaterally into the DMS. When tested in a rodent version of the set-shifting task, rats with a DMS lesion displayed a greater number of errors during the reversal stages of the task than sham lesion controls but the nature of the errors did not differ between the two groups. Interestingly, when the rats were tested in a modified version of the set-shifting task, directly designed for measuring the formation of an attentional set, sham lesion controls displayed a pronounced shift-cost, evident of successful set-formation. In contrast, rats with DMS lesions failed to form an attentional set, showing no performance cost when a shift of attention was required. These results support previous reports of the importance of the DMS in behavioural flexibility but also suggest that this region is vital for the formation of set, possibly by extrapolating different perceptions into a unified representation of a dimension.