Research affiliated to staff at the Mater Misericordiae University Hospital

Recent Submissions

  • Editorial: Cardiovascular Adjustments and Adaptations to Exercise: From the Athlete to the Patient.

    Crisafulli, Antonio; Piepoli, Massimo F; Thijssen, Dick; Bassareo, Pier Paolo (2020-02-27)
  • Fertility-sparing treatment in early endometrial cancer: current state and future strategies.

    Obermair, Andreas; Baxter, Eva; Brennan, Donal J; McAlpine, Jessica N; Muellerer, Jennifer J; Amant, Frédéric; van Gent, Mignon D J M; Coleman, Robert L; Westin, Shannon N; Yates, Melinda S; et al. (2020-07-08)
    Endometrial cancer (EC) is the fifth most common cancer in women worldwide. Global estimates show rising incidence rates in both developed and developing countries. Most women are diagnosed postmenopausal, but 14-25% of patients are premenopausal and 5% are under 40 years of age. Established risk factors include age and hyperestrogenic status associated with nulliparity, obesity, and metabolic syndrome. Standard treatment for EC, which involves total hysterectomy and bilateral salpingo-oophorectomy, has excellent survival outcomes, particularly for low-grade endometrioid tumors. However, it leads to permanent loss of fertility among women who wish to preserve their reproductive potential. With current trends of reproductive-age women delaying childbearing, rising EC incidence rates, and a growing epidemic of obesity, particularly in developed countries, research on conservative non-surgical treatment approaches remains a top priority. Fertility-sparing treatment predominantly involves the use of oral progestins and levonorgestrel-releasing intrauterine devices, which have been shown to be feasible and safe in women with early stage EC and minimal or no myometrial invasion. However, data on the efficacy and safety of conservative management strategies are primarily based on retrospective studies. Randomized clinical trials in younger women and high-risk obese patients are currently underway. Here, we have presented a comprehensive review of the current literature on conservative, fertility-sparing approaches, defining the optimal candidates and evaluating tumor characteristics, reproductive and oncologic outcomes, and ongoing clinical trials. We have also summarized current guidelines and recommendations based on the published literature.
  • Time taken from primary care referral to a specialist centre diagnosis of idiopathic pulmonary fibrosis: an opportunity to improve patient outcomes?

    Brereton, Christopher J; Wallis, Timothy; Casey, Michelle; Fox, Lynn; Pontopiddan, Katarina; Laws, Diane; Graves, Jennifer; Titmuss, Vanessa; Kearney, Sarah; Evans, Sian; et al. (2020-07-20)
    For patients with IPF, length of time in healthcare systems prior to review in an ILD clinic reflects disease severity and may impact upon patient outcome https://bit.ly/2TkO26r.
  • Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database.

    Nguengang Wakap, Stéphanie; Lambert, Deborah M; Olry, Annie; Rodwell, Charlotte; Gueydan, Charlotte; Lanneau, Valérie; Murphy, Daniel; Le Cam, Yann; Rath, Ana (2019-09-16)
    Rare diseases, an emerging global public health priority, require an evidence-based estimate of the global point prevalence to inform public policy. We used the publicly available epidemiological data in the Orphanet database to calculate such a prevalence estimate. Overall, Orphanet contains information on 6172 unique rare diseases; 71.9% of which are genetic and 69.9% which are exclusively pediatric onset. Global point prevalence was calculated using rare disease prevalence data for predefined geographic regions from the 'Orphanet Epidemiological file' (http://www.orphadata.org/cgi-bin/epidemio.html). Of the 5304 diseases defined by point prevalence, 84.5% of those analysed have a point prevalence of <1/1 000 000. However 77.3-80.7% of the population burden of rare diseases is attributable to the 4.2% (n = 149) diseases in the most common prevalence range (1-5 per 10 000). Consequently national definitions of 'Rare Diseases' (ranging from prevalence of 5 to 80 per 100 000) represent a variable number of rare disease patients despite sharing the majority of rare disease in their scope. Our analysis yields a conservative, evidence-based estimate for the population prevalence of rare diseases of 3.5-5.9%, which equates to 263-446 million persons affected globally at any point in time. This figure is derived from data from 67.6% of the prevalent rare diseases; using the European definition of 5 per 10 000; and excluding rare cancers, infectious diseases, and poisonings. Future registry research and the implementation of rare disease codification in healthcare systems will further refine the estimates.
  • Clinical and surgical outcomes of patients with peritoneal mesothelioma discussed at a monthly national multidisciplinary team video-conference meeting.

    Brandl, A; Westbrook, S; Nunn, S; Arbuthnot-Smith, E; Mulsow, J; Youssef, H; Carr, N; Tzivanakis, A; Dayal, S; Mohamed, F; et al. (2020-01-30)
    Background: Peritoneal mesothelioma (PM) is a rare primary neoplasm of the peritoneum with an increasing incidence worldwide. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promise as a treatment strategy. A national PM multidisciplinary team (national PM MDT) video-conference meeting was established in the UK and Ireland in March 2016, aiming to plan optimal treatment, record outcomes and provide evidence for the benefits of centralization. This article reports on the activities and outcomes of the first 2·5 years. Methods: Between March 2016 and December 2018, patients with PM, referred to peritoneal malignancy centres in Basingstoke, Birmingham, Manchester and Dublin, were discussed by the national PM MDT via video-conference. The MDT was composed of surgeons, radiologists, specialist nurses and pathologists. Patients were considered for CRS and HIPEC if considered fit for surgery and if radiological imaging suggested that complete surgical cytoreduction could be achieved. Morbidity and mortality following surgery were analysed. Survival analysis following MDT discussion was conducted. Results: A total of 155 patients (M : F ratio 0·96) with a mean(s.d.) age of 57(17) years were discussed. To date, 22 (14·2 per cent) have had CRS and HIPEC; the median Peritoneal Cancer Index for the surgical group was 17·0. Complete cytoreduction was achieved in 19 patients. Clavien-Dindo grade I-II complications occurred in 16 patients; there was no grade III-IV morbidity or 30-day in-hospital mortality. The median follow-up for the whole cohort was 18·7 months, and the 2-year survival rate from time of first review at the national PM MDT was 68·3 per cent. Conclusion: The centralized national PM MDT was effective at selecting patients suitable for CRS and HIPEC, reporting a good outcome from patient selection.
  • Feasibility, Acceptability, and Clinical Effectiveness of a Technology-Enabled Cardiac Rehabilitation Platform (Physical Activity Toward Health-I): Randomized Controlled Trial.

    Claes, Jomme; Cornelissen, Véronique; McDermott, Clare; Moyna, Niall; Pattyn, Nele; Cornelis, Nils; Gallagher, Anne; McCormack, Ciara; Newton, Helen; Gillain, Alexandra; et al. (2020-02-04)
    A convenience sample of 120 CVD patients (mean 61.4 years, SD 13.5 years; 22 women) was included. The PATHway system was deployed in the homes of 60 participants. System use decreased over time and system usability was average with a score of 65.7 (SD 19.7; range 5-100). Moderate-to-vigorous intensity PA increased in PW (PW: 127 [SD 58] min to 141 [SD 69] min, UC: 146 [SD 66] min to 143 [SD 71] min; Pinteraction=.04; effect size of 0.42), while diastolic blood pressure (PW: 79 [SD 11] mmHg to 79 [SD 10] mmHg, UC: 78 [SD 9] mmHg to 83 [SD 10] mmHg; Pinteraction=.004; effect size of -0.49) and cardiovascular risk score (PW: 15.9% [SD 10.4%] to 15.5% [SD 10.5%], UC: 14.5 [SD 9.7%] to 15.7% [SD 10.9%]; Pinteraction=.004; effect size of -0.36) remained constant, but deteriorated in UC.
  • Can routine perioperative haemodynamic parameters predict postoperative morbidity after major surgery?

    Bonnet, Jean-Francois; Buggy, Eleanor; Cusack, Barbara; Sherwin, Aislinn; Wall, Tom; Fitzgibbon, Maria; Buggy, Donal J (2020-03-24)
    Postoperative morbidity occurs in 10-15% of patients undergoing major noncardiac surgery. Predicting patients at higher risk of morbidity may help to optimize perioperative prevention. Preoperative haemodynamic parameters, systolic arterial pressure (SAP) < 100 mmHg, pulse pressure (PP) > 62 mmHg or < 53 mmHg, and heart rate (HR) > 87 min-1 are associated with increased postoperative morbidity. We evaluated the correlation between these and other routine haemodynamic parameters, measured intraoperatively, with postoperative morbidity. Postoperative morbidity was measured using the Comprehensive Complication Index (CCI) and length of stay (LOS). Additionally we correlated CCI with the cardiac risk biomarker, preoperative NT-ProBNP.
  • Idiopathic pulmonary arterial hypertension and co-existing lung disease: is this a new phenotype?

    Peacock, Andrew J; Ling, Yi; Johnson, Martin K; Kiely, David G; Condliffe, Robin; Elliot, Charlie A; Gibbs, J Simon R; Howard, Luke S; Pepke-Zaba, Joanna; Sheares, Karen K K; et al. (2020-03-30)
    Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients (IPAH lung disease ) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease (IPAH no lung disease ). Patients with 'IPAH lung disease ' have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with 'IPAH no lung disease '. We described the outcome of the cohort of patients with 'IPAH no lung disease ' in a previous paper. Here, we have compared incident 'IPAH lung disease ' patients with 'IPAH no lung disease ' patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001-2009. Compared with 'IPAH no lung disease ' (n = 355), 'IPAH lung disease ' patients (n = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in 'IPAH lung disease ' and 'IPAH no lung disease '. However, survival of 'IPAH lung disease ' was lower than 'IPAH no lung disease ' (one year survival: 72% compared with 93%). This survival was significantly worse in 'IPAH lung disease ' even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. 'IPAH lung disease ' patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with 'IPAH no lung disease ' patients. This suggests that 'IPAH lung disease ' are a separate phenotype and should not be lumped with 'IPAH no lung disease ' in clinical trials of Group 1 pulmonary arterial hypertension.
  • Towards the automatic detection of skin lesion shape asymmetry, color variegation and diameter in dermoscopic images.

    Ali, Abder-Rahman; Li, Jingpeng; O'Shea, Sally Jane (2020-06-16)
    Asymmetry, color variegation and diameter are considered strong indicators of malignant melanoma. The subjectivity inherent in the first two features and the fact that 10% of melanomas tend to be missed in the early diagnosis due to having a diameter less than 6mm, deem it necessary to develop an objective computer vision system to evaluate these criteria and aid in the early detection of melanoma which could eventually lead to a higher 5-year survival rate. This paper proposes an approach for evaluating the three criteria objectively, whereby we develop a measure to find asymmetry with the aid of a decision tree which we train on the extracted asymmetry measures and then use to predict the asymmetry of new skin lesion images. A range of colors that demonstrate the suspicious colors for the color variegation feature have been derived, and Feret's diameter has been utilized to find the diameter of the skin lesion. The decision tree is 80% accurate in determining the asymmetry of skin lesions, and the number of suspicious colors and diameter values are objectively identified.
  • Neurological manifestations and implications of COVID-19 pandemic.

    Tsivgoulis, Georgios; Palaiodimou, Lina; Katsanos, Aristeidis H; Caso, Valeria; Köhrmann, Martin; Molina, Carlos; Cordonnier, Charlotte; Fischer, Urs; Kelly, Peter; Sharma, Vijay K; et al. (2020-06-09)
    The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China and rapidly spread worldwide, with a vast majority of confirmed cases presenting with respiratory symptoms. Potential neurological manifestations and their pathophysiological mechanisms have not been thoroughly established. In this narrative review, we sought to present the neurological manifestations associated with coronavirus disease 2019 (COVID-19). Case reports, case series, editorials, reviews, case-control and cohort studies were evaluated, and relevant information was abstracted. Various reports of neurological manifestations of previous coronavirus epidemics provide a roadmap regarding potential neurological complications of COVID-19, due to many shared characteristics between these viruses and SARS-CoV-2. Studies from the current pandemic are accumulating and report COVID-19 patients presenting with dizziness, headache, myalgias, hypogeusia and hyposmia, but also with more serious manifestations including polyneuropathy, myositis, cerebrovascular diseases, encephalitis and encephalopathy. However, discrimination between causal relationship and incidental comorbidity is often difficult. Severe COVID-19 shares common risk factors with cerebrovascular diseases, and it is currently unclear whether the infection per se represents an independent stroke risk factor. Regardless of any direct or indirect neurological manifestations, the COVID-19 pandemic has a huge impact on the management of neurological patients, whether infected or not. In particular, the majority of stroke services worldwide have been negatively influenced in terms of care delivery and fear to access healthcare services. The effect on healthcare quality in the field of other neurological diseases is additionally evaluated.
  • Towards the automatic detection of skin lesion shape asymmetry, color variegation and diameter in dermoscopic images.

    Ali, Abder-Rahman; Li, Jingpeng; O'Shea, Sally Jane (2020-06-16)
    Asymmetry, color variegation and diameter are considered strong indicators of malignant melanoma. The subjectivity inherent in the first two features and the fact that 10% of melanomas tend to be missed in the early diagnosis due to having a diameter less than 6mm, deem it necessary to develop an objective computer vision system to evaluate these criteria and aid in the early detection of melanoma which could eventually lead to a higher 5-year survival rate. This paper proposes an approach for evaluating the three criteria objectively, whereby we develop a measure to find asymmetry with the aid of a decision tree which we train on the extracted asymmetry measures and then use to predict the asymmetry of new skin lesion images. A range of colors that demonstrate the suspicious colors for the color variegation feature have been derived, and Feret's diameter has been utilized to find the diameter of the skin lesion. The decision tree is 80% accurate in determining the asymmetry of skin lesions, and the number of suspicious colors and diameter values are objectively identified.
  • Lysosomal Acid Lipase Deficiency: Therapeutic Options.

    Pastores, Gregory M; Hughes, Derralynn A (2020-02-11)
    Lysosomal acid lipase (LAL) deficiency is a metabolic (storage) disorder, encompassing a severe (Wolman disease) and attenuated (Cholesterol ester storage disease) subtype; both inherited as autosomal recessive traits. Cardinal clinical features include the combination of hepatic dysfunction and dyslipidemia, as a consequence of cholesteryl esters and triglyceride accumulation, predominately in the liver and vascular and reticuloendothelial system. Significant morbidity can arise, due to liver failure and/or atherosclerosis; in part related to the severity of the underlying gene defect and corresponding enzyme deficiency. Diagnosis is based on demonstration of decreased LAL enzyme activity, complemented by analysis of the cognate gene defects. Therapeutic options include dietary manipulation and the use of lipid-lowering drugs. Sebelipase alfa, a recombinant enzyme replacement therapy, has garnered regulatory approval, following demonstration of improvements in disease-relevant markers and clinical benefit in clinical trials, which included increased survival in the most severe cases.
  • Investigation of the long-term yield of auditing for conformity with the ISO 15189:2012 quality standard in a hospital pathology laboratory.

    Green, Alastair David; Kavanagh-Wright, Lucille; Lee, Graham Robert (2020-03-04)
    Introduction: Pathology laboratories are increasingly seeking accreditation to quality standards to assure Quality of Service (QoS). However, there is little data available regarding the value of this in laboratories with well-established Quality Management Systems (QMS). Moreover, critics of accreditation claim it redirects resources toward trivial issues. Our objective was to investigate the value of auditing for conformity with the ISO 15189:2012 standard in such laboratories. Design: and Methods: In total, 483 Audit-Identified Non-Conformities (AINCs) were documented within our department since transitioning to an ISO 15189:2012 compliant QMS. The potential consequences of these were assessed by three clinical laboratorians who assigned them into categories based on their likely impact. These were: Unlikely (no clear consequences); Possible (potential for poor QoS/harm); and Probable (Likely to cause poor QoS/harm). Additionally, total numbers/severity of Real-Time Non-Conformities (RTNCs) detected outside of auditing were examined to provide additional insight into the effects of accreditation on QoS. Results: According to majority decision: 395 (81.8%) of AINCs were classified Unlikely, 88 (18.2%) were Possible, and none were Probable. The relative proportion of Unlikely AINCs also rose over time. Total numbers and severity of RTNCs dropped in the short-term following transition to an ISO 15189:2012 QMS, but steadily rose thereafter. Conclusions: Our data suggest auditing for conformity with ISO 15189:2012 standards may be effective in attaining accreditation, but may have diminishing returns in the long-term once the QMS is established, unless there is continual improvement in the audit process to promote better use of resources.
  • Correction to: Core Rehabilitation Outcome Set for Single Sided Deafness (CROSSSD) study: protocol for an international consensus on outcome measures for single sided deafness interventions using a modified Delphi survey.

    Katiri, Roulla; Hall, Deborah A; Buggy, Nora; Hogan, Nicholas; Horobin, Adele; van de Heyning, Paul; Firszt, Jill B; Bruce, Iain A; Kitterick, Pádraig T (2020-03-17)
    Following the publication of our article [1], the authors have notified us of a typo in the third bullet point of the Consensus Criteria section.
  • Beta-Hemolytic Streptococcal Infective Endocarditis: Characteristics and Outcomes From a Large, Multinational Cohort.

    Fernández Hidalgo, Núria; Gharamti, Amal A; Aznar, María Luisa; Almirante, Benito; Yasmin, Mohamad; Fortes, Claudio Querido; Plesiat, Patrick; Doco-Lecompte, Thanh; Rizk, Hussein; Wray, Dannah; et al. (2020-04-10)
    Among 1336 definite cases of streptococcal IE, 823 were caused by VGS and 147 by BHS. Patients with BHS IE had a lower prevalence of native valve (P < .005) and congenital heart disease predisposition (P = .002), but higher prevalence of implantable cardiac device predisposition (P < .005). Clinically, they were more likely to present acutely (P < .005) and with fever (P = .024). BHS IE was more likely to be complicated by stroke and other systemic emboli (P < .005). The overall in-hospital mortality of BHS IE was significantly higher than that of VGS IE (P = .001). In univariate analysis, variables associated with in-hospital mortality for BHS IE were age (odds ratio [OR], 1.044; P = .004), prosthetic valve IE (OR, 3.029; P = .022), congestive heart failure (OR, 2.513; P = .034), and stroke (OR, 3.198; P = .009).
  • A Phase II Trial of Cabozantinib in Hormone Receptor-Positive Breast Cancer with Bone Metastases.

    Xu, Jing; Higgins, Michaela J; Tolaney, Sara M; Come, Steven E; Smith, Matthew R; Fornier, Monica; Mahmood, Umar; Baselga, Jose; Yeap, Beow Y; Chabner, Bruce A; et al. (2020-06-18)
    Background: We assessed the antitumor activity of cabozantinib, a potent multireceptor oral tyrosine kinase inhibitor, in patients with hormone receptor-positive breast cancer with bone metastases. Patients and methods: In this single-arm multicenter phase II study, patients received an initial starting dose of 100 mg, later reduced to 60 mg, per day. The primary endpoint was the bone scan response rate. Secondary endpoints included objective response rate by RECIST, progression-free survival (PFS), and overall survival (OS). Results: Of 52 women enrolled, 20 (38%) experienced a partial response on bone scan and 6 (12%) had stable disease. Prior to the first repeat bone scan at 12 weeks, 19 (35%) patients discontinued study treatment because of early clinical progression or unacceptable toxicity. RECIST evaluation based on best overall response by computed tomography revealed stable disease in extraosseous tissues in 26 patients (50%) but no complete or partial responses. In 25 patients with disease control on bone scan at 12 weeks, only 3 (12%) patients developed extraosseous progression. The median PFS was 4.3 months, and median OS was 19.6 months. The most common grade 3 or 4 toxicities were hypertension (10%), anorexia (6%), diarrhea (6%), fatigue (4%), and hypophosphatemia (4%). Conclusion: Bone scans improved in 38% of patients with metastatic hormone receptor-positive breast cancer and remained stable in an additional 12% for a minimum duration of 12 weeks on cabozantinib. Further investigations should assess the activity of cabozantinib in combination with other hormonal and other breast cancer therapies and determine whether bone scan responses correlate with meaningful antitumor effects. ClinicalTrials.gov identifier. NCT01441947 IMPLICATIONS FOR PRACTICE: Most patients with metastatic hormone receptor-positive (HR+) breast cancer have bone involvement, and many have bone-only disease, which is difficult to evaluate for response. This phase II single-arm study evaluated the clinical activity of the small molecule MET/RET/VEGFR2 inhibitor cabozantinib in patients with metastatic HR+ breast cancer with bone metastases. This study met its primary endpoint, and cabozantinib treatment resulted in a significant bone scan response rate correlating with improved survival. This is the first study to use bone scan response as a primary endpoint in breast cancer. The results support further study of cabozantinib in HR+ breast cancer.
  • COVID-19 and Congenital Heart Disease: Results from a Nationwide Survey.

    Sabatino, Jolanda; Ferrero, Paolo; Chessa, Massimo; Bianco, Francesco; Ciliberti, Paolo; Secinaro, Aurelio; Oreto, Lilia; Avesani, Martina; Bucciarelli, Valentina; Calcaterra, Giuseppe; et al. (2020-06-08)
    This is a multi-centre, observational, nationwide survey, involving high-volume Italian CHD centres. COVID-19 diagnosis was defined as either "clinically suspected" or "confirmed", where a severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) test had been performed and was positive. Cardiovascular comorbidities were observed among adult patients-atrial fibrillation (seven; 9%), hypertension (five; 7%), obesity (seven; 9%) and diabetes (one; 1%)-but were absent among children. Cardiovascular complications were mainly observed in the "confirmed" COVID-19+ group, consisting of heart failure (9%), palpitations/arrhythmias (3%), stroke/TIA (3%) and pulmonary hypertension (3%). Cardiovascular symptoms such as chest pain (1%), myocardial injury (1%) and pericardial effusion (1%) were also recorded. On the contrary, CHD patients from the clinically suspected COVID-19 group presented no severe symptoms or complications.
  • Psychosocial effects of whole-body MRI screening in adult high-risk pathogenic mutation carriers: a case-controlled study (SIGNIFY).

    Bancroft, Elizabeth K; Saya, Sibel; Brown, Emma; Thomas, Sarah; Taylor, Natalie; Rothwell, Jeanette; Pope, Jennifer; Chamberlain, Anthony; Page, Elizabeth; Benafif, Sarah; et al. (2019-11-12)
    Germline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms.
  • Core Rehabilitation Outcome Set for Single Sided Deafness (CROSSSD) study: protocol for an international consensus on outcome measures for single sided deafness interventions using a modified Delphi survey.

    Katiri, Roulla; Hall, Deborah A; Buggy, Nora; Hogan, Nicholas; Horobin, Adele; van de Heyning, Paul; Firszt, Jill B; Bruce, Iain A; Kitterick, Pádraig T (2020-03-04)
    Background: Single-sided deafness (SSD) describes the presence of a unilateral severe to profound sensorineural hearing loss. SSD disrupts spatial hearing and understanding speech in background noise. It has functional, psychological and social consequences. Potential options for rehabilitation include hearing aids and auditory implants. Benefits and harms of these interventions are documented inconsistently in the literature, using a variety of outcomes ranging from tests of speech perception to quality of life questionnaires. It is therefore difficult to compare interventions when rehabilitating SSD. The Core Rehabilitation Outcome Set for Single Sided Deafness (CROSSSD) study is an international initiative that aims to develop a minimum set of core outcomes for use in future trials of SSD interventions. Methods/design: The CROSSSD study adopts an international two-round online modified Delphi survey followed by a stakeholder consensus meeting to identify a patient-centred core outcome domain set for SSD based on what is considered critical and important for assessing whether an intervention for SSD has worked. Discussion: The resulting core outcome domain set will act as a minimum standard for reporting in future clinical trials and could have further applications in guiding the use of outcome measures in clinical practice. Standardisation will facilitate comparison of research findings.
  • Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

    Schottlaender, Lucia V; Abeti, Rosella; Jaunmuktane, Zane; Macmillan, Carol; Chelban, Viorica; O'Callaghan, Benjamin; McKinley, John; Maroofian, Reza; Efthymiou, Stephanie; Athanasiou-Fragkouli, Alkyoni; et al. (2020-03-05)
    Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.

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