Determining the role of novel metabolic pathways in driving intracranial pressure reduction after weight loss

Idiopathic intracranial hypertension, a disease classically occurring in women with obesity, is characterised by raised intracranial pressure. Weight loss leads to reduction in intracranial pressure. Additionally, pharmacological glucagon-like peptide-1 agonism reduces cerebrospinal fluid secretion and intracranial pressure. The potential mechanisms by which weight loss reduces intracranial pressure are unknown and was the focus for this study.Meal stimulation tests (fasted plasma sample, then samples at 15, 30, 60, 90 and 120 minutes following a standardised meal) were conducted pre- and post-bariatric surgery (early (2 weeks) and late (12 months)) in patients with active idiopathic intracranial hypertension. Dynamic changes in gut neuropeptides (glucagon-like peptide-1, gastric inhibitory polypeptide, and ghrelin) and metabolites (untargeted ultra-high performance liquid chromatography-mass spectrometry) were evaluated. We determined the relationship between gut neuropeptides, metabolites, and intracranial pressure.18 idiopathic intracranial hypertension patients were included (Roux-En-Y gastric bypass n=7, gastric banding n=6, or sleeve gastrectomy n=5). At 2 weeks post-bariatric surgery, despite similar weight loss, Roux-En-Y gastric bypass had a two-fold (50%) greater reduction in intracranial pressure compared to sleeve. Increased meal stimulated glucagon-like peptide-1 secretion was observed after Roux-En-Y gastric bypass (+600 %) compared to sleeve (+319 %). There was no change in gastric inhibitory polypeptide and ghrelin. Dynamic changes in meal stimulated metabolites after bariatric surgery consistently identified changes in lipid metabolites, predominantly ceramides, glycerophospholipids and lysoglycerophospholipids, which correlated with intracranial pressure. A greater number of differential lipid metabolites were observed in the Roux-En-Y gastric bypass cohort at 2 weeks, and these also correlated with intracranial pressure.In idiopathic intracranial hypertension, we identified novel changes in lipid metabolites and meal stimulated glucagon-like peptide-1 levels following bariatric surgery which were associated with changes in intracranial pressure. Roux-En-Y gastric bypass was most effective at reducing intracranial pressure despite analogous weight loss to gastric sleeve at 2 weeks post-surgery and was associated with more pronounced changes in these metabolite pathways. We suggest that these novel perturbations in lipid metabolism and glucagon-like peptide-1 secretion are mechanistically important in driving reduction in intracranial pressure following weight loss in patients with idiopathic intracranial hypertension. Therapeutic targeting of these pathways, for example with glucagon-like peptide-1 agonist infusion, could represent a therapeutic strategy

Clinical Methods and Design for a Phase II Randomised Control Trial to Assess the Efficacy and Safety of an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor (AZD4017) in Idiopathic Intracranial Hypertension: IIH:DT

Background: Idiopathic intracranial hypertension (IIH) is a condition with few effective management options. So far, there have been no randomized controlled trials evaluating new treatments in IIH.Objectives: The purpose of this paper is to outline the trial design for the Idiopathic Intracranial Hypertension Drug Trial (IIH:DT), assessing an innovative medical treatment in IIH and the rationale for the chosen trial methodology.Methods: IIH:DT is a phase II double-blind randomized placebo-controlled trial recruiting 30 female participants with active IIH (intracranial pressure >25cm H2 O and papilledema). Participants are randomized in a 1:1 ratio to 12 weeks of either AZD4017, an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, or a matching placebo. They receive either 400 mg of AZD4017 or placebo twice daily. Participants are followed up at Weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16 postrandomization. The primary outcome is to examine the effect of AZD4017 on intracranial pressure, measured by lumbar puncture, over 12 weeks. Secondary outcome measures include IIH symptoms, visual function, papilledema, headache measures, safety, and tolerability. Cerebrospinal fluid, serum, plasma, urine, and adipose tissue are also taken for exploratory outcomes.Results: All participants were recruited between April 2014 and August 2016.Conclusions: IIH:DT is the first phase II double-blind randomized placebo-controlled trial assessing the efficacy and safety of the novel pharmacological intervention, AZD4017, for the treatment of IIH.Trial Registration: Clinicaltrials.gov NCT02017444; https://clinicaltrials.gov/ct2/show/NCT02017444 (Archived by WebCite at http://www.webcitation.org/6tVHesN6s

Topiramate is more effective than acetazolamide at lowering intracranial pressure

BACKGROUND The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats. METHODS We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate. RESULTS At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999). CONCLUSION Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest

Investigating harms of testing for ovarian cancer – psychological outcomes and cancer conversion rates in women with symptoms of ovarian cancer:A cohort study embedded in the multicentre ROCkeTS prospective diagnostic study

Objective: To investigate psychological correlates in women referred with suspected ovarian cancer via the fast‐track pathway, explore how anxiety and distress levels change at 12 months post‐testing, and report cancer conversion rates by age and referral pathway. Design: Single‐arm prospective cohort study. Setting: Multicentre. Secondary care including outpatient clinics and emergency admissions. Population: A cohort of 2596 newly presenting symptomatic women with a raised CA125 level, abnormal imaging or both. Methods: Women completed anxiety and distress questionnaires at recruitment and at 12 months for those who had not undergone surgery or a biopsy within 3 months of recruitment. Main outcome measures: Anxiety and distress levels measured using a six‐item short form of the State–Trait Anxiety Inventory (STAI‐6) and the Impact of Event Scale – Revised (IES‐r) questionnaire. Ovarian cancer (OC) conversion rates by age, menopausal status and referral pathway. Results: Overall, 1355/2596 (52.1%) and 1781/2596 (68.6%) experienced moderate‐to‐severe distress and anxiety, respectively, at recruitment. Younger age and emergency presentations had higher distress levels. The clinical category for anxiety and distress remained unchanged/worsened in 76% of respondents at 12 months, despite a non‐cancer diagnosis. The OC rates by age were 1.6% (95% CI 0.5%–5.9%) for ag

Lee Silverman Voice Treatment versus NHS Speech and Language Therapy versus control for dysarthria in Parkinson’s disease (PD COMM):a UK, multicentre, pragmatic, randomised controlled trial

Objectives: We aimed to assess the clinical effectiveness of two speech and language therapy (SLT) approaches versus no speech and language therapy for dysarthria in people with Parkinson’s disease. Design: This was a pragmatic, UK-wide, multicentre, three-arm, parallel group, unblinded, randomised controlled trial. Participants were randomly assigned using minimisation in a 1:1:1 ratio to Lee Silverman Voice Treatment (LSVT LOUD®), NHS SLT, or no SLT. Analyses were based on the intention to treat principle.Setting: The speech and language therapy interventions were delivered in outpatient or home settings.Participants: Between September 2016 and March 2020, 388 people with Parkinson’s disease and dysarthria were randomised into the trial: 130 to LSVT LOUD®, 129 to NHS SLT, and 129 to no SLT.Interventions: Lee Silverman Voice Treatment (LSVT LOUD®) consisted of four, face-to-face or remote, 50-minute sessions each week delivered over 4 weeks. Home-based practice activities were set for up to 5 to 10 minutes daily on treatment days and 15 minutes twice daily on non-treatment days. NHS Speech and language therapy (NHS SLT) dosage was determined by the local therapist in response to individual participants’ needs. Prior research suggested that NHS SLT participants would receive an average of one session per week over 6 to 8 weeks. Local practices for NHS SLT were accepted, except for those within the LSVT LOUD® protocol. Main outcome measures: The primary outcome was the self-reported Voice Handicap Index (VHI) total score at 3 months.Results: People randomised to LSVT LOUD® reported lower VHI scores at 3 months post-randomisation than those who were randomised to no SLT (-8·0 points (99%CI: -13·3 to -2·6); p = 0·0001). There was no evidence of a difference in VHI scores between NHS SLT and no SLT (1·7 points; (99%Cl: -3·8 to 7·1); p = 0·43). Patients randomised to LSVT LOUD® also reported lower VHI scores than those randomised to NHS SLT (-9·6 points; (99%CI: -14·9 to -4·4); p &lt; 0.0001). There were 93 adverse events (predominately vocal strain) in the LSVT LOUD® group, 46 in the NHS SLT group, and none in the no SLT group. There were no serious adverse events. Conclusions: LSVT LOUD® was more effective at reducing the participant reported impact of voice problems than no SLT and NHS SLT. NHS SLT showed no evidence of benefit compared to no SLT. Trial registration: The completed trial registration is ISRCTN12421382. Funding: NIHR HTA Programme, project number HTA 10/135/02. <br/

Lee Silverman Voice Treatment versus NHS Speech and Language Therapy versus control for dysarthria in Parkinson’s disease (PD COMM):a UK, multicentre, pragmatic, randomised controlled trial

Objectives: We aimed to assess the clinical effectiveness of two speech and language therapy (SLT) approaches versus no speech and language therapy for dysarthria in people with Parkinson’s disease. Design: This was a pragmatic, UK-wide, multicentre, three-arm, parallel group, unblinded, randomised controlled trial. Participants were randomly assigned using minimisation in a 1:1:1 ratio to Lee Silverman Voice Treatment (LSVT LOUD®), NHS SLT, or no SLT. Analyses were based on the intention to treat principle.Setting: The speech and language therapy interventions were delivered in outpatient or home settings.Participants: Between September 2016 and March 2020, 388 people with Parkinson’s disease and dysarthria were randomised into the trial: 130 to LSVT LOUD®, 129 to NHS SLT, and 129 to no SLT.Interventions: Lee Silverman Voice Treatment (LSVT LOUD®) consisted of four, face-to-face or remote, 50-minute sessions each week delivered over 4 weeks. Home-based practice activities were set for up to 5 to 10 minutes daily on treatment days and 15 minutes twice daily on non-treatment days. NHS Speech and language therapy (NHS SLT) dosage was determined by the local therapist in response to individual participants’ needs. Prior research suggested that NHS SLT participants would receive an average of one session per week over 6 to 8 weeks. Local practices for NHS SLT were accepted, except for those within the LSVT LOUD® protocol. Main outcome measures: The primary outcome was the self-reported Voice Handicap Index (VHI) total score at 3 months.Results: People randomised to LSVT LOUD® reported lower VHI scores at 3 months post-randomisation than those who were randomised to no SLT (-8·0 points (99%CI: -13·3 to -2·6); p = 0·0001). There was no evidence of a difference in VHI scores between NHS SLT and no SLT (1·7 points; (99%Cl: -3·8 to 7·1); p = 0·43). Patients randomised to LSVT LOUD® also reported lower VHI scores than those randomised to NHS SLT (-9·6 points; (99%CI: -14·9 to -4·4); p &lt; 0.0001). There were 93 adverse events (predominately vocal strain) in the LSVT LOUD® group, 46 in the NHS SLT group, and none in the no SLT group. There were no serious adverse events. Conclusions: LSVT LOUD® was more effective at reducing the participant reported impact of voice problems than no SLT and NHS SLT. NHS SLT showed no evidence of benefit compared to no SLT. Trial registration: The completed trial registration is ISRCTN12421382. Funding: NIHR HTA Programme, project number HTA 10/135/02. <br/

Methods Used in Economic Evaluations of Chronic Kidney Disease Testing — A Systematic Review

Background: The prevalence of chronic kidney disease (CKD) is high in general populations around the world. Targeted testing and screening for CKD are often conducted to help identify individuals that may benefit from treatment to ameliorate or prevent their disease progression. Aims: This systematic review examines the methods used in economic evaluations of testing and screening in CKD, with a particular focus on whether test accuracy has been considered, and how analysis has incorporated issues that may be important to the patient, such as the impact of testing on quality of life and the costs they incur. Methods: Articles that described model-based economic evaluations of patient testing interventions focused on CKD were identified through the searching of electronic databases and the hand searching of the bibliographies of the included studies. Results: The initial electronic searches identified 2,671 papers of which 21 were included in the final review. Eighteen studies focused on proteinuria, three evaluated glomerular filtration rate testing and one included both tests. The full impact of inaccurate test results was frequently not considered in economic evaluations in this setting as a societal perspective was rarely adopted. The impact of false positive tests on patients in terms of the costs incurred in re-attending for repeat testing, and the anxiety associated with a positive test was almost always overlooked. In one study where the impact of a false positive test on patient quality of life was examined in sensitivity analysis, it had a significant impact on the conclusions drawn from the model. Conclusion: Future economic evaluations of kidney function testing should examine testing and monitoring pathways from the perspective of patients, to ensure that issues that are important to patients, such as the possibility of inaccurate test results, are properly considered in the analysis

Antidepressants for the prevention of depression following first-episode psychosis (ADEPP): study protocol for a multi-centre, double-blind, randomised controlled trial

Background: Depressive episodes are common after first-episode psychosis (FEP), affecting more than 40% of people, adding to individual burden, poor outcomes, and healthcare costs. If the risks of developing depression were lower, this could have a beneficial effect on morbidity and mortality, as well as improving outcomes. Sertraline is a selective serotonin reuptake inhibitor and a common first-line medication for the treatment of depression in adults. It has been shown to be safe when co-prescribed with antipsychotic medication, and there is evidence that it is an effective treatment for depression in established schizophrenia. We present a protocol for a multi-centre, double-blind, randomised, placebo-controlled clinical trial called ADEPP that aims to investigate the efficacy and cost-effectiveness of sertraline in preventing depression after FEP. Methods: The recruitment target is 452 participants between the ages of 18 and 65 years who are within 12 months of treatment initiation for FEP. Having provided informed consent, participants will be randomised to receive either 50 mg of sertraline daily or matched placebo for 6 months, in addition to treatment as usual. The primary outcome measure will be a comparison of the number of new cases of depression between the treatment and placebo arms over the 6-month intervention phase. Secondary outcomes include suicidal behaviour, anxiety, rates of relapse, functional outcome, quality of life, and resource use. Discussion: The ADEPP trial will test whether the addition of sertraline following FEP is a clinically useful, acceptable, and cost-effective way of improving outcomes following FEP. Trial registration: ISRCTN12682719 registration date 24/11/2020