Recent Submissions

  • Involving Clients to Inform Development and Implementation of Combined Type 2 Diabetes and Chronic Kidney Disease Care Using Discovery Interview Technique.

    Blanchfield, Denise; O'Connor, Laserina (Innovational Publishers, 2020-10)
    The development of chronic kidney disease in persons with Type 2 diabetes has been described as an epidemic. Standard outpatient care for these associated conditions is routinely provided separately, resulting in missed opportunities to implement preventative and early management strategies. Historically, care delivery for these combined conditions has fallen within the remit of medical professionals, evidenced by a dearth of information pertaining to the contribution of advanced practice nursing for this cohort. Clients report an uncoordinated impersonal approach to care delivery for associated conditions, however incorporating their experience is vital to the delivery of patient centered care and will be included in this study through their stories. The primary aim of this participatory action research (PAR) study is to utilize the client care stories and health-care professional perspectives to inform development and implementation of a new combined Type 2 diabetes and chronic kidney disease service in the context of advanced practice nursing. Methodology: This study adopted a PAR approach informed by patient discovery interviews and key stakeholders focus groups. Transcripts will be developed from discovery interviews and focus groups and analyzed using thematic analysis. Results: The PAR will utilize thematic analysis outcomes to inform the primary aim and clinical outcomes from combined care will be evaluated after 9 months by retrospective chart review. Conclusion: The approach adopted in this study represents a departure from traditional medically led care strategies. Outcomes may elucidate potential challenges to the development and delivery of innovative care delivery for underserved patient cohorts in the context of advanced practice nursing.
  • Beaumont Hospital and National Ambulance Service: Pathfinder Service

    Corcoran, Grace; Kenna, Lawrence; Beaumont Hospital, National Ambulance Service (Beaumont Hospital, 2020-02-26)
    Presentation on integration of ambulance service and Beaumont Hospital ED.
  • Musculoskeletal anomalies in children with Down syndrome: an observational study.

    Foley, Charlene; Killeen, Orla G (2018-11-24)
    Background: Musculoskeletal complications of Down syndrome (DS) are common but infrequently reported. The combination of ligamentous laxity and low muscle tone contributes to increased risk of a number of musculoskeletal disorders and a delay in acquisition of motor milestones. The primary aim of this study was to describe musculoskeletal anomalies reported in a national cohort of children with DS. Methods: This was an observational study. Children with DS, aged 0-21 years, were invited to attend a musculoskeletal assessment clinic conducted by a paediatric physician. Relevant musculoskeletal history and clinical findings were documented. Results: Over an 18-month period, 503 children with DS were examined (56% male). The median age was 8.1 years (0.6-19.2). Pes planus was almost universal, occurring in 91% of the cohort. A range of other musculoskeletal anomalies were observed, with inflammatory arthritis (7%) and scoliosis (4.8%) occurring most frequently after pes planus. Delay in ambulation was common; the median age to walk was 28 months (12-84). Conclusion: Children with DS are at increased risk of a number of potentially debilitating musculoskeletal problems. These conditions can present in variable manners or be completely asymptomatic. Pes planus is common; therefore, early consideration of orthotics and lifelong appropriate supportive footwear should be considered. Delayed ambulation is frequently noted. A significant proportion of children with DS have arthritis; however, despite a high prevalence, it is often missed, leading to delayed diagnosis. An annual musculoskeletal assessment for all children with DS could potentially enable early detection of problems, allowing for timely multidisciplinary team intervention and better clinical outcomes.
  • The Role of Religion in Buffering the Impact of Stressful Life Events on Depressive Symptoms in Patients with Depressive Episodes or Adjustment Disorder.

    Lorenz, Louisa; Doherty, Anne; Casey, Patricia (2019-04-08)
    Most studies into the role of religiousness in relation to depression severity have mainly found an inverse relationship between greater religiousness and lower levels of depressive symptoms. There is reason to assume that religiousness has a buffering effect on the relationship between stressful life events and depressive symptoms. The aim of this study was to investigate the role of religiousness in moderating the impact of stressors on depressive symptoms. n = 348 patients with either a depressive episode or adjustment disorder were assessed at referral to the liaison psychiatry services in three Dublin hospitals and n = 132 patients were followed up six months later. We assessed depressive symptoms, life events, social support, and religiosity, and used hierarchical and multiple linear regression for data analysis. The interaction of organised religious activity and the amount of life events was significant (β = -0.19, p = 0.001) in the cross-sectional prediction of depressive symptoms while non-organised religious activity (β = -0.23, p = 0.001) and intrinsic religiousness (β = -0.15, p = 0.033) interacted significantly with life events in the longitudinal analysis. This study demonstrated that various dimensions of religiousness buffered the impact of life events on outcome.
  • Distribution of lymph node metastases in esophageal carcinoma [TIGER study]: study protocol of a multinational observational study.

    Hagens, Eliza R C; van Berge Henegouwen, Mark I; van Sandick, Johanna W; Cuesta, Miguel A; van der Peet, Donald L; Heisterkamp, Joos; Nieuwenhuijzen, Grard A P; Rosman, Camiel; Scheepers, Joris J G; Sosef, Meindert N; et al. (2019-07-04)
    Background: An important parameter for survival in patients with esophageal carcinoma is lymph node status. The distribution of lymph node metastases depends on tumor characteristics such as tumor location, histology, invasion depth, and on neoadjuvant treatment. The exact distribution is unknown. Neoadjuvant treatment and surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy has not been reached. The aim of this study is to determine the distribution of lymph node metastases in patients with resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed. This can be the foundation for a uniform worldwide staging system and establishment of the optimal surgical strategy for esophageal cancer patients. Methods: The TIGER study is an international observational cohort study with 50 participating centers. Patients with a resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed in participating centers will be included. All lymph node stations will be excised and separately individually analyzed by pathological examination. The aim is to include 5000 patients. The primary endpoint is the distribution of lymph node metastases in esophageal and esophago-gastric junction carcinoma specimens following transthoracic esophagectomy with at least 2-field lymphadenectomy in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and (disease free) survival. Discussion: The TIGER study will provide a roadmap of the location of lymph node metastases in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and survival. Patient-tailored treatment can be developed based on these results, such as the optimal radiation field and extent of lymphadenectomy based on the primary tumor characteristics.
  • Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability.

    Verheije, Rosalind; Kupchik, Gabriel S; Isidor, Bertrand; Kroes, Hester Y; Lynch, Sally Ann; Hawkes, Lara; Hempel, Maja; Gelb, Bruce D; Ghoumid, Jamal; D'Amours, Guylaine; et al. (2018-10-05)
    Deletions on chromosome 15q14 are a known chromosomal cause of cleft palate, typically co-occurring with intellectual disability, facial dysmorphism, and congenital heart defects. The identification of patients with loss-of-function variants in MEIS2, a gene within this deletion, suggests that these features are attributed to haploinsufficiency of MEIS2. To further delineate the phenotypic spectrum of the MEIS2-related syndrome, we collected 23 previously unreported patients with either a de novo sequence variant in MEIS2 (9 patients), or a 15q14 microdeletion affecting MEIS2 (14 patients). All but one de novo MEIS2 variant were identified by whole-exome sequencing. One variant was found by targeted sequencing of MEIS2 in a girl with a clinical suspicion of this syndrome. In addition to the triad of palatal defects, heart defects, and developmental delay, heterozygous loss of MEIS2 results in recurrent facial features, including thin and arched eyebrows, short alae nasi, and thin vermillion. Genotype-phenotype comparison between patients with 15q14 deletions and patients with sequence variants or intragenic deletions within MEIS2, showed a higher prevalence of moderate-to-severe intellectual disability in the former group, advocating for an independent locus for psychomotor development neighboring MEIS2.
  • Association of synovial tissue polyfunctional T-cells with DAPSA in psoriatic arthritis.

    Wade, Sarah M; Canavan, Mary; McGarry, Trudy; Low, Candice; Wade, Siobhan C; Mullan, Ronan H; Veale, Douglas J; Fearon, Ursula (2019-01-09)
    PsA synovial tissue infiltrating CD4+ T-cells expressed higher levels of interleukin (IL)-17A, interferon gamma (IFN-γ), GM-CSF and CD161, with parallel enrichment of Th1, Th17 and exTh17 T-helper subsets (all p<0.05). Interestingly, a significant proportion of synovial T-cell subsets were triple-positive for GM-CSF, tumour necrosis factor (-TNF), -IL-17 or IFN-γ compared with matched blood (all p<0.05). Importantly, frequencies of polyfunctional T-cells correlated with DAPSA: Th1-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p<0.01), Th17-GM-CSF+/TNF+/IL-17+ (r=0.6, p<0.057) and exTh17-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p=0.0096), with no associations observed for single cytokine-producing T-cells. Following ex vivo culture of PsA synovial tissue cell suspensions, polyfunctional GM-CSF+TNFα+IL-17A+ or/IFN-γ+-producing T-cells (p<0.05), but not single cytokine-producing T-cells, were inhibited with a PDE4 inhibitor. Conclusion: These data demonstrate enrichment of polyfunctional T-cells in PsA synovial tissue which were strongly associated with DAPSA and ex vivo therapeutic response.
  • KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

    Kennedy, Joanna; Goudie, David; Blair, Edward; Chandler, Kate; Joss, Shelagh; McKay, Victoria; Green, Andrew; Armstrong, Ruth; Lees, Melissa; Kamien, Benjamin; et al. (2018-09-24)
    Purpose: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. Methods: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. Results: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. Conclusion: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
  • Reproductive health outcomes in women with psoriatic arthritis.

    Murray, Kieran; Moore, Louise; McAuliffe, Fionnuala; Veale, Douglas J (2019-02-15)
  • Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome.

    Scholl, Suzy; Popovic, Marina; de la Rochefordiere, Anne; Girard, Elodie; Dureau, Sylvain; Mandic, Aljosa; Koprivsek, Katarina; Samet, Nina; Craina, Marius; Margan, Madalin; et al. (2019-04-02)
    Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (, conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.
  • Influenza and associated co-infections in critically ill immunosuppressed patients.

    Martin-Loeches, Ignacio; Lemiale, Virginie; Geoghegan, Pierce; McMahon, Mary AISLING; Pickkers, Peter; Soares, Marcio; Perner, Anders; Meyhoff, Tine Sylvest; Bukan, Ramin Brandt; Rello, Jordi; et al. (2019-05-02)
    Background It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. Methods Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. Results Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P < 0.001). Patients with influenza plus co-infection had the highest rates of intubation and longest ICU LOS. On crude analysis, influenza infection status was associated with ICU mortality (P < 0.001) but not hospital mortality (P = 0.09). Patients with influenza plus co-infection and patients with non-influenza infection alone had similar ICU mortality (41% and 37% respectively) that was higher than patients with influenza alone or those without infection (33% and 26% respectively). A propensity score-matched analysis did not show a difference in hospital mortality attributable to influenza infection (OR = 1.01, 95%CI 0.90–1.13, P = 0.85). Age, severity scores, ARDS, and performance status were all associated with ICU, hospital, and 90-day mortality. Conclusions Category of infectious etiology of respiratory failure (influenza, non-influenza, influenza plus co-infection, and non-infectious) was associated with ICU but not hospital mortality. In a propensity score-matched analysis, influenza infection was not associated with the primary outcome of hospital mortality. Overall, influenza infection alone may not be an independent risk factor for hospital mortality in immunosuppressed patients.
  • Adipose tissue as a key player in obstructive sleep apnoea.

    Ryan, Silke; Arnaud, Claire; Fitzpatrick, Susan F; Gaucher, Jonathan; Tamisier, Renaud; Pépin, Jean-Louis (2019-06-26)
    Obstructive sleep apnoea (OSA) is a major health concern worldwide and adversely affects multiple organs and systems. OSA is associated with obesity in >60% of cases and is independently linked with the development of numerous comorbidities including hypertension, arrhythmia, stroke, coronary heart disease and metabolic dysfunction. The complex interaction between these conditions has a significant impact on patient care and mortality. The pathophysiology of cardiometabolic complications in OSA is still incompletely understood; however, the particular form of intermittent hypoxia (IH) observed in OSA, with repetitive short cycles of desaturation and re-oxygenation, probably plays a pivotal role. There is fast growing evidence that IH mediates some of its detrimental effects through adipose tissue inflammation and dysfunction. This article aims to summarise the effects of IH on adipose tissue in experimental models in a comprehensive way. Data from well-designed controlled trials are also reported with the final goal of proposing new avenues for improving phenotyping and personalised care in OSA.
  • Thinking forward: promising but unproven ideas for future intensive care.

    Marini, John J; DeBacker, Daniel; Gattinoni, Luciano; Ince, Can; Martin-Loeches, Ignacio; Singer, Pierre; Singer, Mervyn; Westphal, Martin; Vincent, Jean-Louis (2019-06-14)
    Progress toward determining the true worth of ongoing practices or value of recent innovations can be glacially slow when we insist on following the conventional stepwise scientific pathway. Moreover, a widely accepted but flawed conceptual paradigm often proves difficult to challenge, modify or reject. Yet, most experienced clinicians, educators and clinical scientists privately entertain untested ideas about how care could or should be improved, even if the supporting evidence base is currently thin or non-existent. This symposium encouraged experts to share such intriguing but unproven concepts, each based upon what the speaker considered a logical but unproven rationale. Such free interchange invited dialog that pointed toward new or neglected lines of research needed to improve care of the critically ill. In this summary of those presentations, a brief background outlines the rationale for each novel and deliberately provocative unconfirmed idea endorsed by the presenter.
  • Effect of Glyceryl Trinitrate on Hemodynamics in Acute Stroke.

    Appleton, Jason P; Woodhouse, Lisa J; Bereczki, Daniel; Berge, Eivind; Christensen, Hanne K; Collins, Rónán; Gommans, John; Ntaios, George; Ozturk, Serefnur; Szatmari, Szabolcs; et al.
    Background and Purpose- Increased blood pressure (BP), heart rate, and their derivatives (variability, pulse pressure, rate-pressure product) are associated with poor clinical outcome in acute stroke. We assessed the effects of glyceryl trinitrate (GTN) on hemodynamic parameters and these on outcome in participants in the ENOS trial (Efficacy of Nitric Oxide in Stroke). Methods- Four thousand and eleven patients with acute stroke and raised BP were randomized within 48 hours of onset to transdermal GTN or no GTN for 7 days. Peripheral hemodynamics were measured at baseline (3 measures) and daily (2 measures) during treatment. Between-visit BP variability over days 1 to 7 (as SD) was assessed in quintiles. Functional outcome was assessed as modified Rankin Scale and cognition as telephone mini-mental state examination at day 90. Analyses were adjusted for baseline prognostic variables. Data are mean difference or odds ratios with 95% CI. Results- Increased baseline BP (diastolic, variability), heart rate, and rate-pressure product were each associated with unfavorable functional outcome at day 90. Increased between-visit systolic BP variability was associated with an unfavourable shift in modified Rankin Scale (highest quintile adjusted odds ratio, 1.65; 95% CI, 1.37-1.99), worse cognitive scores (telephone mini-mental state examination: highest quintile adjusted mean difference, -2.03; 95% CI, -2.84 to -1.22), and increased odds of death at day 90 (highest quintile adjusted odds ratio, 1.57; 95% CI, 1.12-2.19). GTN lowered BP and rate-pressure product and increased heart rate at day 1 and reduced between-visit systolic BP variability. Conclusions- Increased between-visit BP variability was associated with poor functional and cognitive outcomes and increased death 90 days after acute stroke. In addition to lowering BP and rate-pressure product, GTN reduced between-visit systolic BP variability. Agents that lower BP variability in acute stroke require further study.
  • 'HepCheck Dublin': an intensified hepatitis C screening programme in a homeless population demonstrates the need for alternative models of care.

    Lambert, John S; Murtagh, Ross; Menezes, Dee; O'Carroll, Austin; Murphy, Carol; Cullen, Walter; McHugh, Tina; Avramovic, Gordana; Tinago, Willard; Van Hout, Marie Claire (2019-02-07)
    Background: Hepatitis C virus (HCV) is one of the main causes of chronic liver disease worldwide. Prevalence of HCV in homeless populations ranges from 3.9 to 36.2%. The HepCheck study sought to investigate and establish the characterisation of HCV burden among individuals who attended an intensified screening programme for HCV in homeless services in Dublin, Ireland. Methods: The HepCheck study was conducted as part of a larger European wide initiative called HepCare Europe. The study consisted of three phases; 1) all subjects completed a short survey and were offered a rapid oral HCV test; 2) a convenience sample of HCV positive participants from phase 1 were selected to complete a survey on health and social risk factors and 3) subjects were tracked along the referral pathway to identify whether they were referred to a specialist clinic, attended the specialist clinic, were assessed for cirrhosis by transient elastography (Fibroscan) and were treated for HCV. Results: Five hundred ninety-seven individuals were offered HCV screening, 73% were male and 63% reported having had a previous HCV screening. We screened 538 (90%) of those offered screening, with 37% testing positive. Among those who tested positive, 112 (56%) were 'new positives' and 44% were 'known positives'. Undiagnosed HCV was prevalent in 19% of the study sample. Active past 30-day drug use was common, along with attendance for drug treatment. Unstable accommodation was the most common barrier to attending specialist appointments and accessing treatment. Depression and anxiety, dental problems and respiratory conditions were common reported health problems. Forty-six subjects were referred to specialised services and two subjects completed HCV treatment. Conclusions: This study demonstrates that the current hospital-based model of care is inadequate in addressing the specific needs of a homeless population and emphasises the need for a community-based treatment approach. Findings are intended to inform HepCare Europe in their development of a community-based model of care in order to engage with homeless individuals with multiple co-morbidities including substance abuse, who are affected by or infected with HCV.
  • A novel multidrug-resistant PVL-negative CC1-MRSA-IV clone emerging in Ireland and Germany likely originated in South-Eastern Europe.

    Earls, Megan R; Shore, Anna C; Brennan, Gráinne I; Simbeck, Alexandra; Schneider-Brachert, Wulf; Vremerǎ, Teodora; Dorneanu, Olivia S; Slickers, Peter; Ehricht, Ralf; Monecke, Stefan; et al. (2019-01-21)
    This study investigated the recent emergence of multidrug-resistant Panton-Valentine leukocidin (PVL)-negative CC1-MRSA-IV in Ireland and Germany. Ten CC1-MSSA and 139 CC1-MRSA isolates recovered in Ireland between 2004 and 2017 were investigated. These were compared to 21 German CC1-MRSA, 10 Romanian CC1-MSSA, five Romanian CC1-MRSA and two UAE CC1-MRSA, which were selected from an extensive global database, based on similar DNA microarray profiles to the Irish isolates. All isolates subsequently underwent whole-genome sequencing, core-genome single nucleotide polymorphism (cgSNP) analysis and enhanced SCCmec subtyping. Two PVL-negative clades (A and B1) were identified among four main clades. Clade A included 20 German isolates, 119 Irish isolates, and all Romanian MRSA and MSSA isolates, the latter of which differed from clade A MRSA by 47-130 cgSNPs. Eighty-six Irish clade A isolates formed a tight subclade (A1) exhibiting 0-49 pairwise cgSNPs, 80 of which harboured a 46 kb conjugative plasmid carrying both ileS2, encoding high-level mupirocin resistance, and qacA, encoding chlorhexidine resistance. The resistance genes aadE, aphA3 and sat were detected in all clade A MRSA and the majority (8/10) of clade A MSSA isolates. None of the clade A isolates harboured any enterotoxin genes other than seh, which is universally present in CC1. Clade B1 included the remaining German isolate, 17 Irish isolates and the two UAE isolates, all of which corresponded to the Western Australia MRSA-1 (WA MRSA-1) clone based on genotypic characteristics. MRSA within clades A and B1 differed by 188 cgSNPs and clade-specific SCCmec characteristics were identified, indicating independent acquisition of the SCCmec element. This study demonstrated the existence of a European PVL-negative CC1-MRSA-IV clone that is distinctly different from the well-defined PVL-negative CC1-MRSA-IV clone, WA MRSA-1. Furthermore, cgSNP analysis revealed that this newly defined clone may have originated in South-Eastern Europe, before spreading to both Ireland and Germany.
  • Single Core Genome Sequencing for Detection of both Sensu Lato and Relapsing Fever Borrelia Species.

    Lee, Sin Hang; Healy, John Eoin; Lambert, John S (2019-05-20)
    Lyme disease, initially described as Lyme arthritis, was reported before nucleic-acid based detection technologies were available. The most widely used diagnostic tests for Lyme disease are based on the serologic detection of antibodies produced against antigens derived from a single strain of Borrelia burgdorferi. The poor diagnostic accuracy of serological tests early in the infection process has been noted most recently in the 2018 Report to Congress issued by the U.S. Department of Health and Human Services Tick-Borne Disease Working Group. Clinical Lyme disease may be caused by a diversity of borreliae, including those classified as relapsing fever species, in the United States and in Europe. It is widely accepted that antibiotic treatment of Lyme disease is most successful during this critical early stage of infection. While genomic sequencing is recognized as an irrefutable direct detection method for laboratory diagnosis of Lyme borreliosis, development of a molecular diagnostic tool for all clinical forms of borreliosis is challenging because a "core genome" shared by all pathogenic borreliae has not yet been identified. After a diligent search of the GenBank database, we identified two highly conserved segments of DNA sequence among the borrelial 16S rRNA genes. We further developed a pair of Borrelia genus-specific PCR primers for amplification of a segment of borrelial 16S rRNA gene as a "core genome" to be used as the template for routine Sanger sequencing-based metagenomic direct detection test. This study presented examples of base-calling DNA sequencing electropherograms routinely generated in a clinical diagnostic laboratory on DNA extracts of human blood specimens and ticks collected from human skin bites and from the environment. Since some of the tick samples tested were collected in Ireland, borrelial species or strains not known to exist in the United States were also detected by analysis of this 16S rRNA "core genome". We recommend that hospital laboratories located in Lyme disease endemic areas begin to use a "core genome" sequencing test to routinely diagnose spirochetemia caused by various species of borreliae for timely management of patients at the early stage of infection.
  • The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis.

    Veale, Douglas J; McGonagle, Dennis; McInnes, Iain B; Krueger, James G; Ritchlin, Christopher T; Elewaut, Dirk; Kanik, Keith S; Hendrikx, Thijs; Berstein, Gabriel; Hodge, Jennifer; et al.
    The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS.
  • Enterovirus and parechovirus meningitis in infants younger than 90 days old in the UK and Republic of Ireland: a British Paediatric Surveillance Unit study.

    Kadambari, Seilesh; Braccio, Serena; Ribeiro, Sonia; Allen, David J; Pebody, Richard; Brown, David; Cunney, Robert; Sharland, Mike; Ladhani, Shamez (2018-12-08)
    Objectives: This study aimed to prospectively collect detailed clinical information for all enterovirus (EV) and human parechovirus (HPeV) meningitis cases in infants aged <90 days in the UK and Ireland. Participants, design and setting: Prospective, active national surveillance during July 2014 to July 2015 through the British Paediatric Surveillance Unit. Reporting paediatricians completed questionnaires requesting information on clinical presentation, investigations, management and outcomes at hospital discharge and after 12 months. Main outcome measures: To describe the clinical burden of EV and HPeV meningitis in infants aged <90 days. Results: During the 13-month surveillance period, 703 cases (668 EV, incidence0.79/1,000 live- births; 35 HPeV, 0.04/1,000 live-births) were identified. The most common clinical presentations were fever (EV: 570/668(85%); HPeV: 28/35(80%)), irritability (EV: 441/668(66%); HPeV: 23/35(66%)) and reduced feeding (EV: 363/668(54%); HPeV 23/35(66%)). Features of circulatory shock were present in 27% (182/668) of EV and 43% (15/35) of HPeV cases. Overall, 11% (76/668) of EV and 23% (8/35) of HPeV cases required intensive care support. Nearly all cases (678/703, 96%) were confirmed by cerebrospinal fluid (CSF) PCR, with 52% (309/600) having normal CSF white cell count for age. Two infants with EV meningitis died (2/668, 0.3%) and four survivors (4/666, 0.6%) had long-term complications at 12 months' follow-up. Infants with HPeV meningitis survived without sequelae. Overall 189 infants had a formal hearing test and none had sensorineural hearing loss. Conclusion: The incidence of laboratory-confirmed EV/HPeV meningitis in young infants is more than twice that for bacterial meningitis. Less than 1% will develop severe neurological complications or die of their infection. Further studies are required to formally assess long-term neurodevelopmental sequelae.

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