• Acute complicated appendicitis caused by an ingested toothpick - A case report.

      Lloyd, A J; Abd Elwahab, S M; Boland, M R; Elfadul, A; Hill, A D K; Power, C (2022-02-25)
      Introduction and importance: Acute appendicitis is one of the most common presentations to the emergency department, particularly in young adults. A combination of clinical suspicion, inflammatory blood markers and imaging modalities such as ultrasound and CT are used for its definitive diagnosis. Early detection and intervention are paramount to reduce morbidity and mortality. Laparoscopic appendicectomy is the current gold standard in the management of appendicitis, especially if complicated according to EAES guidelines. There are few documented cases in the literature of acute appendicitis secondary to foreign body ingestion. On account of this, there are currently no guidelines for its management. Our literature review highlights the importance of surgical management of foreign body acute appendicitis. Case presentation: This case report describes the rare presentation of acute complicated appendicitis caused by an ingested toothpick in a 64 year old woman. The patient was admitted with a 3 day history of lower abdominal pain, localizing to the right iliac fossa with raised inflammatory markers. CT imaging reported acute complicated appendicitis. Laparoscopic appendicectomy was performed during which a toothpick was seen protruding through the appendiceal wall. Post operatively the patient was treated with IV antibiotics for 5 days prior to discharge. Clinical discussion: Due to the rare nature of foreign body appendicitis there are no specific guidelines on the respective surgical approach. A literature review showed that in the setting of foreign body appendicitis, surgical intervention is paramount with no scope for conservative management.
    • Outcomes of colonoscopy with non-anesthesiologist-administered propofol (NAAP): an equivalence trial.

      Alburquerque, Marco; Smarrelli, Antonella; Montesinos, Julio Chevarria; Carreño, Sergi Ortega; Fernandez, Ana Zaragoza; García, Alba Vargas; Frontado, Cesar Ledezma; Vidal, Lluís; Francesch, Montserrat Figa; Lladó, Ferrán González-Huix (2021-06-17)
      Background and study aims  Efficacy and safety of NAAP for gastrointestinal endoscopy have been widely documented, although there is no information about the outcomes of colonoscopy when the endoscopist supervises the sedation. In this context, the aim of this trial was to determine the equivalence of adenoma detection rate (ADR) in colorectal cancer (CRC) screening colonoscopies performed with non-anesthesiologist-administered propofol (NAAP) and performed with monitored anesthesia care (MAC). Patients and methods  This was a single-blind, non-randomized controlled equivalence trial that enrolled adults from a national CRC screening program (CRCSP). Patients were blindly assigned to undergo either colonoscopy with NAAP or MAC. The main outcome measure was the ADR in CRCSP colonoscopies performed with NAAP. Results  We included 315 patients per group. The median age was 59.76 ± 5.81 years; 40.5 % of patients were women. The cecal intubation rate was 97 %, 81.8 % of patients had adequate bowel preparation, withdrawal time was > 6 minutes in 98.7 %, and the median global exploration time was 24.25 ± 8.86 minutes (range, 8-70 minutes). The ADR was 62.9 % and the complication rate (CR) was 0.6 %. Analysis by intention-to-treat showed an ADR in the NAAP group of 64.13 % compared with 61.59 % in the MAC group, a difference (δADR) of 2.54 %, 95 %CI: -0.10 to 0.05. Analysis by per-protocol showed an ADR in the NAAP group of 62.98 %, compared with 61.94 % in the MAC group, δADR: 1.04 %, 95 %CI: -0.09 to 0.07. There was no difference in CR (NAAP: 0,63 vs. MAC: 0.63); P  = 1.0. Conclusions  ADR in colorectal cancer screening colonoscopies performed with NAAP was equivalent to that in those performed with MAC. Similarly, there was no difference in complication rates.
    • Differential Binding of Autoantibodies to MOG Isoforms in Inflammatory Demyelinating Diseases.

      Schanda, Kathrin; Peschl, Patrick; Lerch, Magdalena; Seebacher, Barbara; Mindorf, Swantje; Ritter, Nora; Probst, Monika; Hegen, Harald; Di Pauli, Franziska; Wendel, Eva-Maria; et al. (2021-06-15)
      Objective: To analyze serum immunoglobulin G (IgG) antibodies to major isoforms of myelin oligodendrocyte glycoprotein (MOG-alpha 1-3 and beta 1-3) in patients with inflammatory demyelinating diseases. Methods: Retrospective case-control study using 378 serum samples from patients with multiple sclerosis (MS), patients with non-MS demyelinating disease, and healthy controls with MOG alpha-1-IgG positive (n = 202) or negative serostatus (n = 176). Samples were analyzed for their reactivity to human, mouse, and rat MOG isoforms with and without mutations in the extracellular MOG Ig domain (MOG-ecIgD), soluble MOG-ecIgD, and myelin from multiple species using live cell-based, tissue immunofluorescence assays and ELISA. Results: The strongest IgG reactivities were directed against the longest MOG isoforms alpha-1 (the currently used standard test for MOG-IgG) and beta-1, whereas the other isoforms were less frequently recognized. Using principal component analysis, we identified 3 different binding patterns associated with non-MS disease: (1) isolated reactivity to MOG-alpha-1/beta-1 (n = 73), (2) binding to MOG-alpha-1/beta-1 and at least one other alpha, but no beta isoform (n = 64), and (3) reactivity to all 6 MOG isoforms (n = 65). The remaining samples were negative (n = 176) for MOG-IgG. These MOG isoform binding patterns were associated with a non-MS demyelinating disease, but there were no differences in clinical phenotypes or disease course. The 3 MOG isoform patterns had distinct immunologic characteristics such as differential binding to soluble MOG-ecIgD, sensitivity to MOG mutations, and binding to human MOG in ELISA. Conclusions: The novel finding of differential MOG isoform binding patterns could inform future studies on the refinement of MOG-IgG assays and the pathophysiologic role of MOG-IgG.
    • Prediction of caregiver quality of life in amyotrophic lateral sclerosis using explainable machine learning.

      Antoniadi, Anna Markella; Galvin, Miriam; Heverin, Mark; Hardiman, Orla; Mooney, Catherine (2021-06-10)
      Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative, fatal and currently incurable disease. People with ALS need support from informal caregivers due to the motor and cognitive decline caused by the disease. This study aims to identify caregivers whose quality of life (QoL) may be impacted as a result of caring for a person with ALS. In this study, we worked towards the identification of the predictors of a caregiver's QoL in addition to the development of a model for clinical use to alert clinicians when a caregiver is at risk of experiencing low QoL. The data were collected through the Irish ALS Registry and via interviews on several topics with 90 patient and caregiver pairs at three time-points. The McGill QoL questionnaire was used to assess caregiver QoL-the MQoL Single Item Score measures the overall QoL and was selected as the outcome of interest in this work. The caregiver's existential QoL and burden, as well as the patient's depression and employment before the onset of symptoms were the features that had the highest impact in predicting caregiver quality of life. A small subset of features that could be easy to collect was used to develop a second model to use it in a clinical setting. The most predictive features for that model were the weekly caregiving duties, age and health of the caregiver, as well as the patient's physical functioning and age of onset.
    • Endovascular balloon-assisted liquid embolisation of soft tissue vascular malformations: technical feasibility and safety.

      Lamanna, Anthony; Maingard, Julian; Florescu, Grace; Kok, Hong Kuan; Ranatunga, Dinesh; Barras, Christen; Lee, Michael J; Brooks, Duncan Mark; Jhamb, Ashu; Chandra, Ronil V; et al. (2021-06-08)
      Purpose: Arteriovenous malformations (AVMs) are abnormal communications between arteries and veins without an intervening capillary system. The best endovascular treatment option for these is unclear and may involve multiple staged procedures using a variety of embolic materials. We report our initial experience using a modified version of a previously published neurointerventional technique to treat soft tissue AVMs with single-stage curative intent. Materials and methods: Soft tissue AVMs treated endovascularly using either sole arterial or combined arterial and venous balloon-assisted techniques with liquid embolic agents were retrospectively identified over a 3.5 year period (January 2017 to June 2020)) at two centres. Clinical, pre-operative radiological, procedural technical and post treatment details were recorded. Results: Seven patients were treated for symptomatic soft tissue arteriovenous malformations. These AVMs were located in the peripheral limbs (five), tongue (one) and uterus (one). Curative treatment was achieved in 6/7 patients with one patient requiring a second treatment approximately 1 year later. A variety of liquid embolisation agents (LEAs) including sclerosants and polymers were used. Clinical success rate was 100% following treatment. One patient experienced expected temporary post-operative tongue swelling requiring tracheostomy occurred following embolisation of the lingual AVM. A minor complication in a second patient was due to an access site haematoma developed following treatment of the hand AVM requiring surgical intervention. No long-term sequelae or additional complications were observed. Conclusion: Endovascular arterial and venous balloon assisted LEA embolization of soft tissue AVMs with curative intent is feasible. This technique may provide an alternative treatment option for achieving durable occlusion for complex soft tissue AVMs.
    • Coding practice in national and regional kidney biopsy registries.

      Dendooven, Amélie; Peetermans, Han; Helbert, Mark; Nguyen, Tri Q; Marcussen, Niels; Nagata, Michio; Gesualdo, Loreto; Perkowska-Ptasinska, Agnieszka; Capusa, Cristina; López-Gómez, Juan M; et al. (2021-05-24)
      Background: Kidney biopsy registries all over the world benefit research, teaching and health policy. Comparison, aggregation and exchange of data is however greatly dependent on how registration and coding of kidney biopsy diagnoses are performed. This paper gives an overview over kidney biopsy registries, explores how these registries code kidney disease and identifies needs for improvement of coding practice. Methods: A literature search was undertaken to identify biopsy registries for medical kidney diseases. These data were supplemented with information from personal contacts and from registry websites. A questionnaire was sent to all identified registries, investigating age of registries, scope, method of coding, possible mapping to international terminologies as well as self-reported problems and suggestions for improvement. Results: Sixteen regional or national kidney biopsy registries were identified, of which 11 were older than 10 years. Most registries were located either in Europe (10/16) or in Asia (4/16). Registries most often use a proprietary coding system (12/16). Only a few of these coding systems were mapped to SNOMED CT (1), older SNOMED versions (2) or ERA-EDTA PRD (3). Lack of maintenance and updates of the coding system was the most commonly reported problem. Conclusions: There were large gaps in the global coverage of kidney biopsy registries. Limited use of international coding systems among existing registries hampers interoperability and exchange of data. The study underlines that the use of a common and uniform coding system is necessary to fully realize the potential of kidney biopsy registries.
    • Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer.

      Mezynski, M Janusz; Farrelly, Angela M; Cremona, Mattia; Carr, Aoife; Morgan, Clare; Workman, Julie; Armstrong, Paul; McAuley, Jennifer; Madden, Stephen; Fay, Joanna; et al. (2021-05-01)
      Background: Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods: Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results: Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM-1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions: PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.
    • Decline in subarachnoid haemorrhage volumes associated with the first wave of the COVID-19 pandemic.

      Nguyen, Thanh N; Haussen, Diogo C; Qureshi, Muhammad M; Yamagami, Hiroshi; Fujinaka, Toshiyuki; Mansour, Ossama Y; Abdalkader, Mohamad; Frankel, Michael; Qiu, Zhongming; Taylor, Allan; et al. (2021-03-26)
      Background: During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study's objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines. Methods: We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March-31 May 2020. The prior 1-year control period (1 March-31 May 2019) was obtained to account for seasonal variation. Findings: There was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI -24.3% to -20.7%, p<0.0001). Embolisation of ruptured aneurysms declined with 1170-1035 procedures, respectively, representing an 11.5% (95%CI -13.5% to -9.8%, p=0.002) relative drop. Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations, a 24.9% relative decline (95% CI -28.0% to -22.1%, p<0.0001). A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1% (95% CI 32.3% to 50.6%, p=0.008) despite a decrease in SAH admissions in this tertile. Interpretation: There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction.
    • Resistance to Cell Death in Mucinous Colorectal Cancer-A Review.

      O'Connell, Emer; Reynolds, Ian Sean; McNamara, Deborah A; Burke, John P; Prehn, Jochen (2021-03-19)
      Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10-15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite instability and the CpG island methylator phenotype. Mutations of the APC gene and p53 mutations which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for BCL-2 proteins, including BCL-XL, in preventing apoptosis in mucinous CRC has been explored to a limited extent. Additional mechanisms opposing cell death include altered death receptor expression and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. While the presence of MUC2 is associated with an immunosuppressive environment, the tumor immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment.
    • Effect of routinely assessing and addressing depression and diabetes distress using patient-reported outcome measures in improving outcomes among adults with type 2 diabetes: a systematic review protocol.

      McMorrow, Rita; Hunter, Barbara; Hendrieckx, Christel; Kwasnicka, Dominika; Cussen, Leanne; Ho, Felicia Ching Siew; Speight, Jane; Emery, Jon; Manski-Nankervis, Jo-Anne (2021-03-15)
      Introduction: Type 2 diabetes is a global health priority. People with diabetes are more likely to experience mental health problems relative to people without diabetes. Diabetes guidelines recommend assessment of depression and diabetes distress during diabetes care. This systematic review will examine the effect of routinely assessing and addressing depression and diabetes distress using patient-reported outcome measures in improving outcomes among adults with type 2 diabetes. Methods and analysis: MEDLINE, Embase, CINAHL Complete, PsycInfo, The Cochrane Library and Cochrane Central Register of Controlled Trials will be searched using a prespecified strategy using a prespecified Population, Intervention, Comparator, Outcomes, Setting and study design strategy. The date range of the search of all databases will be from inception to 3 August 2020. Randomised controlled trials, interrupted time-series studies, prospective and retrospective cohort studies, case-control studies and analytical cross-sectional studies published in peer-reviewed journals in the English language will be included. Two review authors will independently screen abstracts and full texts with disagreements resolved by a third reviewer, if required, using Covidence software. Two reviewers will undertake risk of bias assessment using checklists appropriate to study design. Data will be extracted using prespecified template. A narrative synthesis will be conducted, with a meta-analysis, if appropriate.
    • Development of a Novel Weighted Ranking Method for Immunohistochemical Quantification of a Heterogeneously Expressed Protein in Gastro-Esophageal Cancers.

      Richards, Cathy E; Sheehan, Katherine M; Kay, Elaine W; Hedner, Charlotta; Borg, David; Fay, Joanna; O'Grady, Anthony; Hill, Arnold D K; Jirström, Karin; Hopkins, Ann M (2021-03-13)
      High expression of Junctional Adhesion Molecule-A (JAM-A) has been linked with poor prognosis in several cancers, including breast cancers overexpressing the human epidermal growth factor receptor-2 (HER2). Furthermore, JAM-A expression has been linked with regulating that of HER2, and associated with the development of resistance to HER2-targeted therapies in breast cancer patients. The purpose of this study was to establish a potential relationship between JAM-A and HER2 in HER2-overexpressing gastro-esophageal (GE) cancers. Interrogation of gene expression datasets revealed that high JAM-A mRNA expression was associated with poorer survival in HER2-positive gastric cancer patients. However, high intra-tumoral heterogeneity of JAM-A protein expression was noted upon immunohistochemical scoring of a GE cancer tissue microarray (TMA), precluding a simple confirmation of any relationship between JAM-A and HER2 at protein level. However, in a test-set of 25 full-face GE cancer tissue sections, a novel weighted ranking system proved effective in capturing JAM-A intra-tumoral heterogeneity and confirming statistically significant correlations between JAM-A/HER2 expression. Given the growing importance of immunohistochemistry in stratifying cancer patients for the receipt of new targeted therapies, this may sound a cautionary note against over-relying on cancer TMAs in biomarker discovery studies of heterogeneously expressed proteins. It also highlights a timely need to develop validated mechanisms of capturing intra-tumoral heterogeneity to aid in future biomarker/therapeutic target development for the benefit of cancer patients.
    • Novel case of a scleroderma-mimicking syndrome associated with gastrointestinal stromal tumour.

      Butt, Zaran Ahmad; Ng, Wan Lin; Osman, Kamal; Howard, Donough (2021-03-04)
      We report a case of a 54-year-old man who developed an atypical systemic syndrome involving Raynaud's phenomenon, pulmonary fibrosis and skin thickening. These features were initially suggestive of newly diagnosed scleroderma. However, he displayed atypical clinical features of same, antinuclear antibody was negative and symptoms were refractory to various immunosuppressive therapies. CT imaging revealed a gastric mass, which later proved to be a gastrointestinal stromal tumour (GIST). Resection of the GIST leads to minimal symptomatic improvement. Surveillance imaging 1 year later revealed metastatic deposits. He was subsequently initiated on imatinib therapy, which led to a rapid improvement in fibrotic changes within weeks. While there have been previous descriptions of paraneoplastic fibrotic disorders, this is the first description of a scleroderma mimic in the setting of a GIST. It highlights an important potential overlap in the pathogenesis of these disease processes and the potential efficacy of tyrosine kinase inhibitors for scleroderma-like fibrotic disorders.
    • One year of procarbazine lomustine and vincristine is poorly tolerated in low grade glioma: a real world experience in a national neuro-oncology centre.

      Keogh, Rachel J; Aslam, Razia; Hennessy, Maeve A; Coyne, Zac; Hennessy, Bryan T; Breathnach, Oscar S; Grogan, Liam; Morris, Patrick G (2021-02-08)
      Background: Following optimal local therapy, adjuvant Procarbazine, Lomustine and Vincristine (PCV) improves overall survival (OS) in low-grade glioma (LGG). However, 1 year of PCV is associated with significant toxicities. In the pivotal RTOG 9802 randomised control trial, approximately half of the patients discontinued treatment after 6 months. As patients on clinical trials may be fitter, we aimed to further explore the tolerability of PCV chemotherapy in routine clinical practice. Methods: We conducted a retrospective study between 2014 and 2018 at a National Neuro-Oncology centre. Patients who had received PCV during this time period were included. The primary objective was to assess tolerability of treatment. Secondary objectives included evaluation of treatment delays, dose modifications and toxicities. Results: Overall, 41 patients were included, 24 (58%) were male and 21 (51%) aged ≥40 years. 38 (93%) underwent surgical resection and all patients received adjuvant radiotherapy prior to chemotherapy. The median number of cycles completed was 3,2,4 for procarbazine, lomustine and vincristine respectively. Only 4 (10%) completed all 6 cycles of PCV without dose modifications. There was a universal decline in dose intensity as cycles of chemotherapy progressed. Dose intensity for cycle 1 versus cycle 6 respectively: procarbazine (98% versus 46%), lomustine (94% versus 48%) and vincristine (93% versus 50%). Haematological toxicities were common. Six (14%) patients experienced Grade III-IV thrombocytopaenia and 13 (31%) experienced Grade III-IV neutropaenia. Conclusion: Toxicities are frequently observed with the PCV regimen in clinical practice. It might be preferable to adjust doses from the start of chemotherapy to improve tolerability or consider alternative chemotherapy, particularly in older patients with LGG.
    • Self-reported interpersonal and educational/vocational difficulties in young adults with a history of transient psychotic experiences: findings from a population-based study.

      Coughlan, Helen; Walton-Ball, Erin; Carey, Eleanor; Healy, Colm; O'Regan-Murphy, Grace; Uidhir, Aoife Nic; Clarke, Mary C; Cannon, Mary (2021-01-11)
      Background: Psychotic experiences (PEs) are not uncommon in young people and are associated with both psychopathology and compromised global functioning. Although psychotic experiences are transient (short-lived, self-resolving and non-recurring) for most people who report them, few studies have examined the association between early transient PEs and later functioning in population samples. Additionally, studies using self-report measures of interpersonal and educational/ vocational difficulties are lacking. The aim of this study was to examine the relationship between transient psychotic experiences and self-reported interpersonal and educational/vocational difficulties in adolescence and young adulthood. Methods: Participants were 103 young people from a longitudinal population-based study cohort of mental health in Ireland. They attended for baseline clinical interviews in childhood (age 11-13) and were followed up in young adulthood (age 19-25). Participants who reported psychotic experiences at baseline but not at follow-up were classified as having transient psychotic experiences. Data from both time-points were used to examine the association between transient psychotic experiences and self-reported interpersonal and educational/ vocational difficulties in young adulthood using poisson regression modelling. Results: Young people with a history of transient psychotic experiences reported significantly higher interpersonal (adj IRR: 1.83, 95%ileCI: 1.10-3.02, p = .02) and educational/vocational (adj IRR: 2.28, 95%ileCI: 1.43-3.64, p = .001) difficulties during adolescence. However, no significant differences in interpersonal (adj IRR: 0.49, 95%ileCI: 0.10-2.30, p = .37) or educational/vocational (adj IRR: 0.88, 95%ileCI: 0.37-2.08, p = .77) difficulties were found in young adulthood. Self-reported interpersonal and educational/vocational difficulties in young people both with and without a history of transient psychotic experiences decreased between adolescence and young adulthood. Conclusions: Young people with transient psychotic experiences have increased interpersonal and educational/vocational difficulties in adolescence but these may not persist into the young adult years. This finding indicates that early psychotic experiences may not confer high risk for long-term interpersonal or educational/vocational deficits among young people who experience these phenomena transiently.
    • Mucinous Adenocarcinoma of the Rectum: A Whole Genome Sequencing Study.

      Reynolds, Ian S; Thomas, Valentina; O'Connell, Emer; Fichtner, Michael; McNamara, Deborah A; Kay, Elaine W; Prehn, Jochen H M; Burke, John P; Furney, Simon J (2020-08-26)
      The average number of SNVs, InDels and SVs in the cohort was 16,600, 1,855, and 120, respectively. A single case was MSI-H. KRAS mutations were found in 70% of cases while TP53 was mutated in only 40% of cases. CNA gain was identified on chromosomes 7, 8, 12, 13, and 20 while CNA loss was found on chromosomes 4, 8, 17, and 18 corresponding to oncogenes and tumor suppressor genes, respectively. Overall mucinous rectal cancers are more likely to be MSI-H and to have KRAS, BRAF, and PIK3CA mutations when compared to rectal adenocarcinoma NOS. Microbial analysis demonstrated an abundance of Fusobacterium nucleatum in tumor samples compared to normal tissue.
    • Targeting IgG Autoantibodies for Improved Cytotoxicity of Bactericidal Permeability Increasing Protein in Cystic Fibrosis.

      McQuillan, Karen; Gargoum, Fatma; Murphy, Mark P; McElvaney, Oliver J; McElvaney, Noel G; Reeves, Emer P (2020-07-17)
      In people with cystic fibrosis (PWCF), inflammation with concurrent infection occurs from a young age and significantly influences lung disease progression. Studies indicate that neutrophils are important effector cells in the pathogenesis of CF and in the development of anti-neutrophil cytoplasmic autoantibodies (ANCA). ANCA specific for bactericidal permeability increasing protein (BPI-ANCA) are detected in people with CF, and correlate with infection with Pseudomonas aeruginosa. The aim of this study was to determine the signaling mechanism leading to increased BPI release by CF neutrophils, while identifying IgG class BPI-ANCA in CF airways samples as the cause for impaired antimicrobial activity of BPI against P. aeruginosa. Plasma and/or bronchoalveolar lavage fluid (BAL) was collected from PWCF (n = 40), CF receiving ivacaftor therapy (n = 10), non-CF patient cohorts (n = 7) and healthy controls (n = 38). Plasma and BAL BPI and BPI-ANCA were measured by ELISA and GTP-bound Rac2 detected using an in vitro assay. The antibacterial effect of all treatments tested was determined by colony forming units enumeration. Levels of BPI are significantly increased in plasma (p = 0.007) and BALF (p < 0.0001) of PWCF. The signaling mechanism leading to increased degranulation and exocytosis of BPI by CF neutrophils (p = 0.02) involved enhancement of Rac2 GTP-loading (p = 0.03). The full-length BPI protein was detectable in all CF BAL samples and patients displayed ANCA with BPI specificity. IgG class autoantibodies were purified from CF BAL complexed to BPI (n=5), with IgG autoantibody cross-linking of antigen preventing BPI induced P. aeruginosa killing (p < 0.0001). Results indicate that the immune-mediated diminished antimicrobial defense, attributed to anti-BPI-IgG, necessitates the formation of a drug/immune complex intermediate that can maintain cytotoxic effects of BPI towards Gram-negative pathogens, with the potential to transform the current treatment of CF airways disease.
    • Technical outcome of atlantoaxial transarticular screw fixation without supplementary posterior construct for rheumatoid arthritis.

      Thomas, Philip; Amoo, Michael; Horan, Jack; Husien, Mohammed Ben; Cawley, Derek; Nagaria, Jabir; Bolger, Ciaran (2020-07-11)
      Background: transarticular screw (TAS) fixation without a supplementary posterior construct, even in rheumatoid arthritis (RA) patients, provides sufficient stability with acceptable clinical results. Here, we present our experience with 15 RA patients who underwent atlantoaxial (AA) TAS fixation without utilizing a supplementary posterior fusion. Methods: To treat AA instability, all 15 RA patients underwent C1-C2 TAS fixation without a supplementary posterior construct. Patients were followed for at least 24 months. Pre- and postoperative sagittal measures of C1- C2, C2-C7, and C1-C7 angles, atlanto-dens interval (ADI), posterior atlanto-dens interval (PADI), and adjacent segment (i.e., C2-C3) anterior disc height (ADH) were retrospectively recorded from lateral X-ray imaging. The presence or absence of superior migration of the odontoid (SMO), cervical subaxial subluxation, C1-C2 bony fusion, screw pull-out, and screw breakage were also noted. Results: There was little difference between the pre- and postoperative studies regarding angles measured. Following TAS fixation, the mean ADI shortened, and mean PADI lengthened. There was no difference in the mean measures of C2-C3 ADH. There was no evidence of SMO pre- or postoperatively. Two patients developed anterior subluxation at C5-C6; one of the two also developed anterior subluxation at C2-C3. All patients subsequently showed C1-C2 bony fusion without screw pull-out or breakage. Conclusion: In RA patients who have undergone C1-C2 TAS fixation, eliminating a supplementary posterior fusion resulted in adequate stability.
    • Youth mental health in the time of COVID-19.

      Power, Emmet; Hughes, S; Cotter, D; Cannon, M (2020-07-02)
      Youth mental health is a rapidly developing field with a focus on prevention, early identification, treatment innovation and service development. In this perspective piece, we discuss the effects of COVID-19 on young people's mental health. The psychosocial effects of COVID-19 disproportionately affect young people. Both immediate and longer-term factors through which young people are affected include social isolation, changes to the delivery of therapeutic services and almost complete loss of all structured occupations (school, work and training) within this population group. Longer-term mechanisms include the effects of the predicted recession on young people's mental health. Opportunities within this crisis exist for service providers to scale up telehealth and digital services that may benefit service provision for young people's mental health in the future.
    • Endovascular flow-diversion of visceral and renal artery aneurysms using dual-layer braided nitinol carotid stents.

      van Veenendaal, Penelope; Maingard, Julian; Kok, Hong Kuan; Ranatunga, Dinesh; Buckenham, Tim; Chandra, Ronil V; Lee, Michael J; Brooks, Duncan Mark; Asadi, Hamed (2020-06-28)
      Background: Visceral and renal artery aneurysms (VRAAs) are uncommon but are associated with a high mortality rate in the event of rupture. Endovascular treatment is now first line in many centres, but preservation of arterial flow may be difficult in unfavourable anatomy including wide necked aneurysms, parent artery tortuosity and proximity to arterial bifurcations. Endovascular stenting, and in particular flow-diversion, is used in neurovascular intervention to treat intracranial aneurysms but is less often utilised in the treatment of VRAAs. The CASPER stent is a low profile dual-layer braided nitinol stent designed for carotid stenting with embolic protection and flow-diversion properties. We report the novel use of the CASPER stent for the treatment of VRAAs. We present a case series describing the treatment of six patients with VRAAs using the CASPER stent. Results: Six patients with unruptured VRAAs were treated electively. There were three splenic artery aneurysms and three renalartery aneurysms. Aneurysms were treated with the CASPER stent, with or without loose aneurysm coil packing or liquid embolic depending on size and morphology. All stents were successfully deployed with no immediate or periprocedural complications. Four aneurysms completely occluded after serial imaging follow up with one case requiring repeat CASPER stenting for complete occlusion. In one patient a single aneurysm remained patent at last follow up, A single case was complicated by delated splenic infarction and surgical splenectomy.
    • Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome.

      Kempegowda, Punith; Melson, Eka; Manolopoulos, Konstantinos N; Arlt, Wiebke; O'Reilly, Michael W (2020-06-24)
      Polycystic ovary syndrome (PCOS) has been traditionally perceived as a reproductive disorder due to its most common presentation with menstrual dysfunction and infertility. However, it is now clear that women with PCOS are at increased risk of metabolic dysfunction, from impaired glucose tolerance and type 2 diabetes mellitus to nonalcoholic fatty liver disease and cardiovascular disease. PCOS is characterised by androgen excess, with cross-sectional data showing that hyperandrogenism is directly complicit in the development of metabolic complications. Recent studies have also shown that C11-oxy C19 androgens are emerging to be clinically and biochemically significant in PCOS, thus emphasising the importance of understanding the impact of both classic and C11-oxy C19 androgens on women's health. Here we discuss androgen metabolism in the context of PCOS, and dissect the role played by androgens in the development of metabolic disease through their effects on metabolic target tissues in women.