Correlation between large rearrangements and patient phenotypes in NF1 deletion syndrome: an update and review.

About 5-10% of neurofibromatosis type 1 (NF1) patients exhibit large genomic germline deletions that remove the NF1 gene and its flanking regions. The most frequent NF1 large deletion is 1.4 Mb, resulting from homologous recombination between two low copy repeats. This "type-1" deletion is associated with a severe clinical phenotype in NF1 patients, with several phenotypic manifestations including learning disability, a much earlier development of cutaneous neurofibromas, an increased tumour risk, and cardiovascular malformations. NF1 adjacent co-deleted genes could act as modifier loci for the specific clinical manifestations observed in deleted NF1 patients. Furthermore, other genetic modifiers (such as CNVs) not located at the NF1 locus could also modulate the phenotype observed in patients with large deletions. In this study, we analysed 22 NF1 deletion patients by genome-wide array-CGH with the aim (1) to correlate deletion length to observed phenotypic features and their severity in NF1 deletion syndrome, and (2) to identify whether the deletion phenotype could also be modulated by copy number variations elsewhere in the genome. We then review the role of co-deleted genes in the 1.4 Mb interval of type-1 deletions, and their possible implication in the main clinical features observed in this high-risk group of NF1 patients.

National UK guidelines for the management of paediatric craniopharyngioma.

Although rare, craniopharyngiomas constitute up to 80% of tumours in the hypothalamic-pituitary region in childhood. Despite being benign, the close proximity of these tumours to the visual pathways, hypothalamus, and pituitary gland means that both treatment of the tumour and the tumour itself can cause pronounced long-term neuroendocrine morbidity against a background of high overall survival. To date, the optimal management strategy for these tumours remains undefined, with practice varying between centres. In light of these discrepancies, as part of a national endeavour to create evidence-based and consensus-based guidance for the management of rare paediatric endocrine tumours in the UK, we aimed to develop guidelines, which are presented in this Review. These guidelines were developed under the auspices of the UK Children's Cancer and Leukaemia Group and the British Society for Paediatric Endocrinology and Diabetes, with the oversight and endorsement of the Royal College of Paediatrics and Child Health using Appraisal of Guidelines for Research & Evaluation II methodology to standardise care for children and young people with craniopharyngiomas.

Fat in the Fossa and the Sphenoid Sinus: A Simple and Effective Solution to CSF Leaks in Transsphenoidal Surgery. Cohort Study and Systematic Review.

Objectives Cerebrospinal fluid (CSF) leak following endoscopic transsphenoidal surgery (TSS) remains a challenge and is associated with high morbidity. We perform a primary repair with f at in the pituitary f ossa and further fat in the s phenoid sinus (FFS). We compare the efficacy of this FFS technique with other repair methods and perform a systematic review. Design, Patients, and Methods This is a retrospective analysis of patients undergoing standard TSS from 2009 to 2020, comparing the incidence of significant postoperative CSF rhinorrhea (requiring intervention) using the FFS technique compared with other intraoperative repair strategies. Systematic review of current repair methods described in the literature was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Results In all, there were 439 patients, with 276 patients undergoing multilayer repair, 68 patients FFS repair, and 95 patients no repair. No significant differences were observed in baseline demographics between the groups. Postoperative CSF leak requiring intervention was significantly lower in the FFS repair group (4.4%) compared with the multilayer (20.3%) and no repair groups (12.6%, p < 0.01). This translated to fewer reoperations (2.9% FFS vs. 13.4% multilayer vs. 8.4% no repair, p < 0.05), fewer lumbar drains (2.9% FFS vs. 15.6% multilayer vs. 5.3% no repair, p < 0.01), and shorter hospital stay (median days: 4 [3-7] FFS vs. 6 (5-10) multilayer vs. 5 (3-7) no repair, p < 0.01). Risk factors for postoperative leak included female gender, perioperative lumbar drain, and intraoperative leak. Conclusion Autologous fat on fat graft for standard endoscopic transsphenoidal approach effectively reduces the risk of significant postoperative CSF leak with reduced reoperation and shorter hospital stay.

Toward the fabrication of a 5-µm-resolution Wolter microscope for the National Ignition Facility (invited).

Advancements in computer-controlled polishing, metrology, and replication have led to an x-ray mirror fabrication process that is capable of producing high-resolution Wolter microscopes. We present the fabrication and test of a nickel-cobalt replicated full-shell x-ray mirror that was electroformed from a finely figured and polished mandrel. This mandrel was designed for an 8-m source-to-detector-distance microscope, with 10× magnification, and was optimized to reduce shell distortions that occur within 20 mm of the shell ends. This, in combination with an improved replication tooling design and refined bath parameters informed by a detailed COMSOL Multiphysics® model, has led to reductions in replication errors in the mirrors. Mandrel surface fabrication was improved by implementing a computer-controlled polishing process that corrected the low-frequency mandrel figure error and achieved <2.0 nm RMS convergence error. X-ray tests performed on a pair of mirror shells replicated from the mandrel have demonstrated <10 µm full-width at half-maximum (FWHM) spatial resolution. Here, we discuss the development process, highlight results from metrology and x-ray testing, and define a path for achieving a program goal of 5 µm FWHM resolution.

Prognostic factors and surgical outcomes of spontaneous spinal epidural haematoma: a systematic review and meta-analysis.

Spontaneous spinal epidural haematoma (SSEH) is a rare disease defined as blood accumulation within the vertebral epidural space without a cause identified, which can lead to severe neurological deficits. We aim to provide a comprehensive understanding of the prognostic factors affecting surgical outcomes in true SSEH and propose a critical time frame for operative management. A systematic literature search was performed and registered, using OVID Medline and EMBASE, in line with the PRISMA guidelines. Relevant demographic, clinical, surgical, and outcome data were extracted. The ASIA scale was uniformly used throughout our systematic review. Statistical analysis was performed via logistic regression. Of the 1179 articles examined, we included 181 studies involving 295 adult patients surgically treated for SSEH. SSEH were most commonly found in the cervicothoracic spine, with 2-4 spinal segments most commonly involved. Multivariable logistic regression model showed that the following factors were statistically significant in the post-operative outcome: operation type (P = 0.024), pre-operative neurologic status (P < 0.001), use of warfarin (P = 0.039), and operative interval (P = 0.006). Our retrospective analysis confirms the reversibility of severe neurological deficits after surgical intervention, with a prognosis of post-operative outcomes determined by the use of warfarin, pre-operative ASIA grade, and above all surgical evacuation within 12 h.

Spontaneous rupture of malignant papillary craniopharyngioma with CSF seeding and metastatic deposits: A case report and literature review.

Introduction: Craniopharyngiomas are benign tumours mainly confined to the cranial cavity in the suprasellar region. Research Question and Case Description: We present a rare case of an aggressive papillary craniopharyngioma with disseminated spinal intradural disease. A 67-year-old woman presented with a 4-month history of headache, visual disturbance, acute confusion and radicular leg pain. Previous history of breast carcinoma (ER â€‹+ â€‹PR â€‹+ â€‹HER2-) was noted. The importance of histological diagnosis prior to treatment of sellar or suprasellar lesions with atypical or aggressive features is explored. Materials and methods: MRI demonstrated a partly solid and partly cystic pituitary mass lesion in the sellar and suprasellar region with chiasmal compression and hypothalamic involvement. The sella was mildly enlarged and there were no calcifications. Whole neuraxis MRI revealed intradural deposits involving the ventricular system, spinal cord and conus. Within a month, the lesion rapidly increased in size. The patient underwent a craniotomy and transventricular resection of the sellar and suprasellar mass. Cranial lesion histology favoured papillary craniopharyngioma, confirmed by BRAF V600 mutation. Lumbar puncture CSF cytology confirmed craniopharyngioma with BRAF mutation and no evidence of metastatic breast cancer. Results: The patient remained confused postoperatively without focal neurological deficit and underwent palliative whole brain radiotherapy. She died 4 months later. A review of the literature identified 29 reports of ruptured craniopharyngioma. Discussion and Conclusion: Ruptured craniopharyngioma presents with a suprasellar mass and drop lesions in the spinal canal, characteristics radiologically indistinguishable from metastatic disease. The importance of histological diagnoses in directing the management of these cases is highlighted.

Prognostic factors for surgically managed intramedullary spinal cord tumours: a single-centre case series.

PURPOSE: Intramedullary spinal cord tumours (IMSCTs) are comparatively rare neoplasms. We present a single-centre clinical case series of adult patients with surgically managed IMSCTs. METHODS: We performed a retrospective analysis of electronic patient records in the time period spanning July 2010 to July 2021. All adult patients that had undergone surgical management for IMSCTs were eligible for inclusion. Baseline and post-operative clinical and radiological characteristics, along with follow-up data, were assessed. We also performed a literature review with a focus on surgical outcomes for IMSCTs. RESULTS: Sixty-six patients matched our selection criteria, with a median age of 42 years (range 23-85). Thirty-four ependymomas, 17 haemangioblastomas, 12 astrocytomas, 2 lymphomas and 1 teratoma were included. Statistical analysis yielded several significant findings: IMSCTs spanning a greater number of vertebral levels are significantly associated with poor McCormick outcomes (p = 0.03), presence of gait disturbance before surgery is significantly associated with poor outcome for both post-operative McCormick and Nurick scores (p = 0.007), and radicular pain present pre-operatively is significantly associated with a good post-operative McCormick score (p = 0.045). Haemangioblastomas are significantly more likely to have a clear intra-operative dissection plane compared to ependymomas and astrocytomas (p = 0.009). However, astrocytomas have a significantly higher prevalence of good McCormick outcomes compared to ependymomas and haemangioblastomas (p = 0.03). CONCLUSION: Histological diagnosis, cranio-caudal extent of the tumour and the presence or absence of baseline deficits-such as gait impairment and radicular pain-are significant in determining neurological outcomes after surgery for IMSCTs.

Do All Notochordal Lesions Require Proton Beam Radiotherapy? A Proposed Reclassification of Ecchordosis Physaliphora as Benign Notochord Cell Tumor.

Objectives Ecchordosis physaliphora (EP) is a benign notochord lesion of the clivus arising from the same cell line as chordoma, its malignant counterpart. Although usually asymptomatic, it can cause spontaneous cerebrospinal fluid (CSF) rhinorrhea. Benign notochordal cell tumor (BNCT) is considered another indolent, benign variant of chordoma. Although aggressive forms of chordoma require maximal safe resection followed by proton beam radiotherapy, BNCT and EP can be managed with close imaging surveillance without resection or radiotherapy. However, while BNCT and EP can be distinguished from more aggressive forms of chordoma, differentiating the two is challenging as they are radiologically and histopathologically identical. This case series aims to characterize the clinicopathological features of EP and to propose classifying EP and BNCT together for the purposes of clinical management. Design Case series. Setting Tertiary referral center, United Kingdom. Participants Patients with suspected EP from 2015 to 2019. Main Outcome Measures Diagnosis of EP. Results Seven patients with radiological suspicion of EP were identified. Five presented with CSF rhinorrhea and two were asymptomatic. Magnetic resonance imaging features consistently showed T1-hypointense, T2-hyperintense nonenhancing lesions. Diagnosis was made on biopsy for patients requiring repair and radiologically where no surgery was indicated. The histological features of EP included physaliphorous cells of notochordal origin (positive epithelial membrane antigen, S100, CD10, and/or MNF116) without mitotic activity. Conclusion EP is indistinguishable from BNCT. Both demonstrate markers of notochord cell lines without malignant features. Their management is also identical. We therefore propose grouping EP with BNCT. Close imaging surveillance is required for both as progression to chordoma remains an unquantified risk.

Systematic Review Comparing Open versus Endoscopic Surgery in Clival Chordomas and a 10-Year Single-Center Experience.

Objectives Chordomas are rare, slow-growing, and osteo-destructive tumors of the primitive notochord. There is still contention in the literature as to the optimal management of chordoma. We conducted a systematic review of the surgical management of chordoma along with our 10-year institutional experience. Design A systematic search of the literature was performed in October 2020 by using MEDLINE and EMBASE for articles relating to the surgical management of clival chordomas. We also searched for all adult patients surgically treated for primary clival chordomas at our institute between 2009 and 2019. Participants Only articles describing chordomas arising from the clivus were included in the analysis. For our institution experience, only adult primary clival chordoma cases were included. Main Outcome Measures Patients were divided into endoscopic or open surgery. Rate of gross total resection (GTR), recurrence, and complications were measured. Results Our literature search yielded 24 articles to include in the study. Mean GTR rate among endoscopic cases was 51.9% versus 41.7% for open surgery. Among the eight cases in our institutional experience, we found similar GTR rates between endoscopic and open surgery. Conclusion Although there is clear evidence in the literature that endoscopic approaches provide better rates of GTR with fewer overall complications compared to open surgery. However, there are still situations where endoscopy is not viable, and thus, open surgery should still be considered if required.

Pituitary apoplexy in an adolescent male with macroprolactinoma presenting as middle cerebral artery territory infarction.

Pituitary apoplexy typically presents with acute headache, vomiting, visual disturbance, and confusion. Herein, we report a rare presentation of ischemic stroke due to pituitary apoplexy. A 16.5-year-old male presented with reduced Glasgow Coma Scale (GCS) score, slurred speech, right-sided hemiparesis, and bitemporal hemianopia. Magnetic resonance imaging of the brain showed a large hemorrhagic sellar/suprasellar mass and an area of cortical T2/FLAIR hyperintensity with corresponding diffusion restriction in the middle cerebral artery territory. Computed tomography (CT) intracranial angiogram showed luminal occlusion of the clinoid and ophthalmic segments of both internal carotid arteries (ICAs, left>right) due to mass pressure effect. Biochemical investigations confirmed hyperprolactinemia and multiple pituitary hormone deficiencies. Stress-dose hydrocortisone was commenced with cabergoline, followed by urgent endoscopic transsphenoidal debulking of the tumor (subsequent histology showing prolactinoma). Postoperative CT angiogram showed improved caliber of ICAs. Intensive neurorehabilitation was implemented and resulted in complete recovery of motor and cognitive deficits. At the last assessment (18.8 years), the patient remained on complete anterior pituitary hormone replacement without cabergoline. Pituitary apoplexy is a medical emergency requiring prompt recognition and treatment and should be suspected in patients presenting with sudden, severe headache; nausea; or visual disturbance and meningism. Ischemic stroke is a rare manifestation of pituitary apoplexy in the pediatric population.

ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis.

A Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes (SMARCB1/LZTR1) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2. These genes together account for 70-85% of familial schwannomatosis and 30-40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12-14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours and/or functional loss especially with SMARCB1-related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients' psychosocial needs should be assessed annually as well as review of pain/pain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.

Endocrinological aspects of pituitary adenoma surgery in Europe.

Hormone-secreting adenomas are treated in many neurosurgical centers within Europe. The goal of the survey is to understand variance in practice management of pituitary tumors amongst neurosurgical centers. A list of departments performing pituitary surgery was created. The survey consisted of 58 questions. This study focuses on neurosurgical care of hormone-secreting adenomas. For analysis, the departments were divided into four subgroups: academic/non-academic, high-volume/low-volume, "mainly endoscopic/mainly microscopic practice" and geographical regions. Data from 254 departments from 34 countries were obtained. Most centers surgically treat 1-5 hormone-secreting adenomas per year. In prolactinomas this is the case in 194 centers, (76.4%), in GH-secreting adenomas: 133 centers, (52.4%), ACTH-secreting adenomas: 172 centers, (69.8%). Surgery as a primary treatment of prolactinomas is considered in 64 centers (25.2%). In 47 centers (18.8%), GH-secreting microadenomas are often treated pharmacologically first. Debulking surgery for an invasive GH-secreting adenoma in which hormonal remission is not a realistic goal of the surgery and the patient has no visual deficit surgery is always or mostly indicated in 156 centers (62.9%). Routine postoperative hydrocortisone replacement therapy is administered in 147 centers (58.6%). Our survey shows that in most centers, few hormone-secreting adenomas are treated per year. In about 25% of the centers, prolactinoma surgery may be regarded as first-line treatment; in about 20% of the centers, medical treatment is the first-line treatment for GH-secreting adenomas. Pretreatment for ACTH-secreting adenomas is routinely used in 21% of centers. This survey may serve as plea for neurosurgical care centralization of hormone-secreting adenomas.

Pituitary Adenoma Surgery Survey: Neurosurgical Centers and Pituitary Adenomas.

Objective: Pituitary adenoma surgery has evolved rapidly in recent decades. This study aims to determine current practice across a wide range of European neurosurgical centers. Methods: A list of eligible departments performing pituitary adenoma surgery was created. The survey consisted of 58 questions. For analysis, the departments were divided into four subgroups: academic/nonacademic, high-volume/low-volume, "mainly endoscopic/mainly microscopic practice," and geographical regions. Results: Data from 254 departments from 34 countries were obtained. In 108 centers (42.5%), <30 pituitary adenomas were operated per year. Twenty (7.9%) centers performed >100 adenoma surgeries per year. Number of neurosurgeons performing endonasal surgeries are as follows: 1 in 24.9% of centers and 2 in 49.8% of centers. All residents assisted endonasal surgeries in 126 centers (49.8%). In 28 centers (21.1%), all residents performed endonasal surgery under supervision during residency. In 141 centers (56.8%), the endoscopic approach was used in >90% of the surgeries. Regular pituitary board (either weekly or once a month) meetings were held in 147 centers (56.3%). Nonfunctioning adenomas represent >70% of pituitary caseload in 149 centers (58.7%). Conclusions: In our survey, most centers perform less than 100 surgeries for pituitary adenomas. In most centers, pituitary surgeries are performed by one or two neurosurgeons. Residents have a limited exposure to this type of surgery, and the formal pituitary board is not a standard. Nonfunctioning adenomas make up most of surgically treated adenomas. This study can serve as a benchmark for further analyses of pituitary adenoma centers in Europe.

Experimental and computational study of pulsatile flow characteristics in Romanesque and gothic aortic arch models.

Romanesque and Gothic are two types of deformed aortic arch geometries after surgical repair of coarctation of the aorta. The abnormal arch geometry and hemodynamics are associated with late systemic hypertension, aortic aneurysms, and other cardiovascular complications. To understand the fluid dynamic signatures of such flow, a combined experimental and computational fluid dynamic (CFD) study has been conducted to quantitatively compare the main (axial) and secondary flow characteristics. In the experiments, a pulsatile flow simulator was used to generate the pulsatile flow conditions. Phase-locked planar and tomographic particle image velocimetry techniques were employed to quantitatively study the flow fields. Three-dimensional CFD simulations were also performed and compared with the experimental data. The results show that in the Romanesque arch, the flow first accelerates along the inner wall and then becomes more uniform in the cross-section after the peak systole. A pair of wall vortices and Dean-type vortices develop during the systolic phase. The coherent structures are continuously extended into the descending aorta and persist throughout the cycle. In comparison, the Gothic arch exhibits a highly skewed velocity distribution with high velocity around the arch apex. The sharp curvature causes flow separation, jet impingement, and stagnant flow near the top. The coherent structures in the Gothic arch are less continuous in the descending aorta, which also differ from those observed in the Romanesque model. The distinct flow characteristics of the Gothic arch lead to more temporal and spatial variations of wall shear stress in the descending aorta, implying hemodynamic risks for aortic complications.

What is the current clinical practice in pituitary adenoma surgery in Europe? European Pituitary Adenoma Surgery Survey (EU-PASS) results-technical part.

Pituitary adenoma surgery has evolved rapidly in recent decades, changing clinical practice markedly and raising new challenges. There is no current consensus or guidelines for perioperative care that includes possible complication management. This study aims to determine current practice across European neurosurgical centres. We created a list of eligible departments performing pituitary adenoma surgery based on cooperation with EANS, national neurosurgical societies, and personal communication with local neurosurgeons. We contacted the chairpersons from each department and asked them (or another responsible neurosurgeon) to fill out the survey. The survey consisted of 58 questions. For further analysis, departments were divided into subgroups: "academic"/ "non-academic centre", "high-volume"/"low-volume", "mainly endoscopic"/ "mainly microscopic"/ "mixed practise", and by geographical regions. Data from 254 departments from 34 countries were obtained. The average time to complete the survey was 18 min. Notably, the endoscopic approach is the predominant surgical approach in Europe, used in 56.8% of the centres. In routine cases without intraoperative cerebrospinal fluid leak, high-volume centres are less pedantic with sellar closure when compared with low-volume centres (p < 0.001). On the other hand, when a postoperative cerebrospinal fluid leak occurs, high-volume centres are more active and indicate early reoperation (p = 0.013). Less than 15% of the participating centres perform early postoperative MRI scans. Marked variation was noted among different groups of respondents and some contentious issues are discussed. Such information can encourage useful debate about the reasons for the variations seen and perhaps help develop standardised protocols to improve patient outcomes. A future research focus is to compare European results with other regions.

Neurosurgical Approaches to the Skull Base: A Guide for the Radiologist.

Skull base surgery relies on the assessment of detailed neuroimaging studies to assist with surgical planning. We review typical neuroimaging features associated with common neurosurgical skull base approaches, highlighting relevant imaging anatomy and pertinent postoperative imaging appearances.

Surgical Management of Spinal Chordoma: A Systematic Review and Single-Center Experience.

OBJECTIVE: Chordoma is a rare neoplasm of the neuraxis derived from remnants of the primitive notochord. The importance of wide margins and use of adjuvant therapy in spinal chordomas are still contentious points in the management of spinal chordomas. We conducted a systematic review of the surgical management of spinal chordomas alongside our 10-year institutional experience. METHODS: A systematic search of the literature was performed in November 2020 using Embase and MEDLINE for articles regarding the surgical management of chordomas arising from the mobile spine and sacrum. We also searched for all adult patients who were surgically managed for spinal chordomas at our institute between 2010 and 2020. In both the systematic review and our institutional case series, data on adequacy of resection, use of adjuvant therapy, complications, recurrence (local or metastatic), and survival outcomes were collected. RESULTS: We identified and analyzed 42 articles, yielding 1531 patients, from which the overall gross total or wide resection rate was 54.9%. Among the 8 cases in our institutional experience (4 sacral, 3 cervical, and 1 lumbar), we achieved gross total resection in 50% of initial operations. The recurrence rate was 25% in our gross total resection group and 50% where initial resection was subtotal. Of patients, 75% had no evidence of recurrence at most recent follow-up. CONCLUSIONS: Albeit difficult at times because of the proximity to neurovascular tissue, achieving a wide resection followed by adjuvant therapy for spinal chordomas is of great importance. Multidisciplinary discussion is valuable to ensure the best outcome for the patient.

D-MannosE to prevent Recurrent urinary tract InfecTions (MERIT): protocol for a randomised controlled trial.

INTRODUCTION: Recurrent urinary tract infections (RUTIs) have a significant negative impact on quality of life and healthcare costs. To date, daily prophylactic antibiotics are the only treatment which have been shown to help prevent RUTIs. D-mannose is a type of sugar which is believed to inhibit bacterial adherence to uroepithelial cells, and is already being used by some women in an attempt to prevent RUTIs. There is currently insufficient rigorous evidence on which to base decisions about its use. The D-mannose to prevent recurrent urinary tract infections (MERIT) study will evaluate whether D-mannose is clinically and cost-effective in reducing frequency of infection and symptom burden for women presenting to UK primary care with RUTI. METHODS AND ANALYSIS: MERIT will be a two-arm, individually randomised, double blind placebo controlled, pragmatic trial. Participants will be randomised to take D-mannose powder or placebo powder daily for 6 months. The primary outcome will be the number of medical attendances attributable to symptoms of RUTI. With 508 participants we will have 90% power to detect a 50% reduction in the chance of a further clinically suspected UTI, assuming 20% lost to follow-up. Secondary outcomes will include: number of days of moderately bad symptoms of UTI; time to next consultation; number of clinically suspected UTIs; number of microbiologically proven UTIs; number of antibiotic courses for UTI; quality of life and healthcare utilisation related to UTI. A within trial economic evaluation will be conducted to examine cost-effectiveness of D-mannose in comparison with placebo. A nested qualitative study will explore participants' experiences and perceptions of recruitment to, and participation in a study requiring a daily treatment. ETHICS AND DISSEMINATION: Ethical approval has been obtained from South West-Central Bristol Research Ethics Committee. Publication of the MERIT study is anticipated to occur in 2021. TRIAL REGISTRATION NUMBER: ISRCTN 13283516.