• Draft Genome Sequence of an Isolate of Extensively Drug-Resistant Mycobacterium tuberculosis from Nepal.

      Gautam, Sanjay S; Leong, Kelvin W C; Pradhan, Manoj; Singh, Y Ibotomba; Rajbhandari, Sagar K; Ghimire, Gokarna R; Adhikari, Krishna; Shrestha, Uma; Chaudhary, Raina; Ghimire, Gyanendra; et al. (2020-01-23)
      Extensively drug-resistant (XDR) Mycobacterium tuberculosis has become a challenge to the treatment of tuberculosis (TB) in several countries, including Nepal. Here, we report for the first time the draft genome sequence of an isolate of XDR-TB collected in Nepal and describe single-nucleotide variations associated with its extensively drug-resistant phenotype.
    • Impact of Chronic Obstructive Pulmonary Disease on Incidence, Microbiology and Outcome of Ventilator-Associated Lower Respiratory Tract Infections.

      Rouzé, Anahita; Boddaert, Pauline; Martin-Loeches, Ignacio; Povoa, Pedro; Rodriguez, Alejandro; Ramdane, Nassima; Salluh, Jorge; Houard, Marion; Nseir, Saad (2020-01-23)
      Objectives: To determine the impact of chronic obstructive pulmonary disease (COPD) on incidence, microbiology, and outcomes of ventilator-associated lower respiratory tract infections (VA-LRTI). Methods: Planned ancillary analysis of TAVeM study, including 2960 consecutive adult patients who received invasive mechanical ventilation (MV) > 48 h. COPD patients (n = 494) were compared to non-COPD patients (n = 2466). The diagnosis of ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP) was based on clinical, radiological and quantitative microbiological criteria. Results: No significant difference was found in VAP (12% versus 13%, p = 0.931), or VAT incidence (13% versus 10%, p = 0.093) between COPD and non-COPD patients. Among patients with VA-LRTI, Escherichia coli and Stenotrophomonas maltophilia were significantly more frequent in COPD patients as compared with non-COPD patients. However, COPD had no significant impact on multidrug-resistant bacteria incidence. Appropriate antibiotic treatment was not significantly associated with progression from VAT to VAP among COPD patients who developed VAT, unlike non-COPD patients. Among COPD patients, patients who developed VAT or VAP had significantly longer MV duration (17 days (9-30) or 15 (8-27) versus 7 (4-12), p < 0.001) and intensive care unit (ICU) length of stay (24 (17-39) or 21 (14-40) versus 12 (8-19), p < 0.001) than patients without VA-LRTI. ICU mortality was also higher in COPD patients who developed VAP (44%), but not VAT(38%), as compared to no VA-LRTI (26%, p = 0.006). These worse outcomes associated with VA-LRTI were similar among non-COPD patients. Conclusions: COPD had no significant impact on incidence or outcomes of patients who developed VAP or VAT.
    • Cannabinoids in the Older Person: A Literature Review.

      Beedham, William; Sbai, Magda; Allison, Isabel; Coary, Roisin; Shipway, David (2020-01-13)
      Introduction: Medical cannabinoids have received significant mainstream media attention in recent times due to an evolving political and clinical landscape. Whilst the efficacy of cannabinoids in the treatment of some childhood epilepsy syndromes is increasingly recognized, medical cannabinoids may also have potential clinical roles in the treatment of older adults. Prescribing restrictions for medical cannabinoids in certain jurisdictions (including the UK) has recently been relaxed. However, few geriatricians have the detailed knowledge or awareness of the potential risks or rewards of utilizing cannabinoids in the older person; even fewer geriatricians have direct experience of using these drugs in their own clinical practice. Older persons are more likely to suffer from medical illness representing potential indications for medical cannabinoids (e.g., pain); equally they may be more vulnerable to any adverse effects. Aim: This narrative literature review aims to provide a brief introduction for the geriatrician to the potential indications, evidence-base, contra-indications and side effects of medical cannabinoids in older people. Methods: A search was conducted of CENTRAL, Medline, Embase, CINAHL and psycINFO, Cochrane and Web of Science databases. Reference lists were hand searched. Abstracts and titles were screened, followed by a full text reading of relevant articles. Results: 35 studies were identified as relevant for this narrative review. Conclusions: Cannabinoids demonstrate some efficacy in the treatment of pain and chemotherapy-related nausea; limited data suggest potential benefits in the treatment of spasticity and anxiety. Risks of cannabinoids in older patients appear to be moderate, and their frequency comparable to other analgesic drug classes. However, the quality of research is weak, and few older patients have been enrolled in cannabinoid studies. Dedicated research is needed to determine the efficiency and safety of cannabinoids in older patients.
    • Difficult Airway Society guidelines for awake tracheal intubation (ATI) in adults.

      Ahmad, I; El-Boghdadly, K; Bhagrath, R; Hodzovic, I; McNarry, A F; Mir, F; O'Sullivan, E P; Patel, A; Stacey, M; Vaughan, D (2019-11-14)
      Awake tracheal intubation has a high success rate and a favourable safety profile but is underused in cases of anticipated difficult airway management. These guidelines are a comprehensive document to support decision making, preparation and practical performance of awake tracheal intubation. We performed a systematic review of the literature seeking all of the available evidence for each element of awake tracheal intubation in order to make recommendations. In the absence of high-quality evidence, expert consensus and a Delphi study were used to formulate recommendations. We highlight key areas of awake tracheal intubation in which specific recommendations were made, which included: indications; procedural setup; checklists; oxygenation; airway topicalisation; sedation; verification of tracheal tube position; complications; management of unsuccessful awake tracheal intubation; post-tracheal intubation management; consent; and training. We recognise that there are a range of techniques and regimens that may be effective and one such example technique is included. Breaking down the key practical elements of awake tracheal intubation into sedation, topicalisation, oxygenation and performance might help practitioners to plan, perform and address complications. These guidelines aim to support clinical practice and help lower the threshold for performing awake tracheal intubation when indicated.
    • Unmet needs in the international neuroendocrine tumor (NET) community: Assessment of major gaps from the perspective of patients, patient advocates and NET health care professionals.

      Leyden, Simone; Kolarova, Teodora; Bouvier, Catherine; Caplin, Martyn; Conroy, Siobhan; Davies, Phillipa; Dureja, Sugandha; Falconi, Massimo; Ferolla, Piero; Fisher, George; et al. (2019-10-25)
      Due to the increasing incidence and prevalence of neuroendocrine tumors (NETs), there is a need to assess any gaps in awareness and care. A survey was undertaken in 2017 to identify perceived unmet needs from the perspectives of patients/families, patient advocates and health care professionals (HCPs). The survey consisted of 33-37 questions (depending on type of respondent) across four areas: information, care, treatments and research. In total, 443 participants from 26 countries responded: 338 patients/families, 35 advocates and 70 HCPs. Perceived unmet needs regarding provision of information at diagnosis differed between groups. While 59% of HCPs believed they provided sufficient information, informational needs were mostly/fully met for only 30% of patients and 18% of advocates. Additionally, 91% of patients and 97% of advocates felt that patients had to search for information themselves. Availability of Gallium-68-Dotatate PET/CT scan was limited for the majority of patients (patients: 73%; advocates: 85%; HCP: 86%), as was access to treatments, particularly peptide receptor radionuclide therapy (patients: 42%; advocates: 95%; HCPs: 77%). All groups felt that standards of care, including psychological needs and diagnosis of mental health, were not fully met. Although about two-thirds of patients were managed by a multidisciplinary team, 14% of patients reportedly did not have enough contact. All groups supported more patient involvement in research; patients and advocates prioritized improvement in diagnosis and HCPs focused on clinical trials. This survey revealed significant unmet needs but differing perceptions regarding these among the groups. There is a need for investigation and collaboration to improve standards of care for NET patients.
    • Prophylactic, preemptive, and curative treatment for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a position statement from an international expert group.

      Mohty, Mohamad; Malard, Florent; Abecasis, Manuel; Aerts, Erik; Alaskar, Ahmed S; Aljurf, Mahmoud; Arat, Mutlu; Bader, Peter; Baron, Frederic; Basak, Grzegorz; et al. (2019-10-01)
      Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). While SOS/VOD may resolve within a few weeks in the majority of patients with mild-to-moderate disease, the most severe forms result in multiorgan dysfunction and are associated with a high mortality rate (>80%). Therefore, careful surveillance may allow early detection of SOS/VOD, particularly as the licensed available drug is proven to be effective and reduce mortality. The aim of this work is to propose an international consensus guideline for the treatment and prevention of SOS/VOD in adult patients, on behalf of an international expert group.
    • Results from a multicenter, noninterventional registry study for multiple myeloma patients who received stem cell mobilization regimens with and without plerixafor.

      Morris, Curly; Chabannon, Christian; Masszi, Tamas; Russell, Nigel; Nahi, Hareth; Kobbe, Guido; Krejci, Marta; Auner, Holger W; Pohlreich, David; Hayden, Patrick; et al. (2019-09-18)
      Plerixafor plus granulocyte-colony stimulating factor (G-CSF) enhances the mobilization of hematopoietic stem cells (HSCs) for collection and subsequent autologous hematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma (MM). This international, multicenter, noninterventional registry study (NCT01362972), evaluated long-term outcomes for MM patients who received plerixafor versus other mobilization regimens. The comparisons were: G-CSF + plerixafor (G-CSF + P) versus G-CSF-; G-CSF + P versus G-CSF + chemotherapy (G-CSF + C); and G-CSF + P + C versus G-CSF + C. Propensity score matching was used to balance groups. Primary outcome measures were progression free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR) after transplantation. After propensity matching, 77 versus 41 patients in the G-CSF + P versus G-CSF cohorts, 129 versus 129 in the G-CSF + P versus G-CSF + C cohorts, and 117 versus 117 in the G-CSF + P + C versus G-CSF + C cohorts were matched, respectively. Propensity score matching resulted in a smaller sample size and imbalances were not completely overcome. For both PFS and OS, the upper limits of the hazard ratio 95% confidence intervals exceeded prespecified boundaries; noninferiority was not demonstrated. CIR rates were higher in the plerixafor cohorts. G-CSF + P remains an option for the mobilization of HSCs in poor mobilizers with MM with no substantial differences in PFS, OS, and CIR in comparison with other regimens.
    • Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study.

      Nyberg, Tommy; Frost, Debra; Barrowdale, Daniel; Evans, D Gareth; Bancroft, Elizabeth; Adlard, Julian; Ahmed, Munaza; Barwell, Julian; Brady, Angela F; Brewer, Carole; et al. (2019-09-06)
      Background: BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. Objective: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. Design, setting, and participants: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively). Outcome measurements and statistical analysis: Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. Results and limitations: Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. Conclusions: The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers.
    • A Geospatial Analysis of Adult Major Trauma Transit Time in Dublin

      Kelly, O.; O'Reilly, M; Collins, N. (Irish Medical Journal, 2019-09)
      To estimate ambulance transit time of Major Trauma patients from scene to Emergency Department (ED) in order to inform future trauma network design.
    • The co-design, implementation and evaluation of a serious board game 'PlayDecide patient safety' to educate junior doctors about patient safety and the importance of reporting safety concerns.

      Ward, Marie; Ní Shé, Éidín; De Brún, Aoife; Korpos, Christian; Hamza, Moayed; Burke, Elaine; Duffy, Ann; Egan, Karen; Geary, Una; Holland, Catherine; et al. (2019-06-25)
      A serious game based on the PlayDecide framework was co-designed and implemented in two large urban acute teaching hospitals. To evaluate the educational value of the game voting on the position statements was recorded at the end of each game by a facilitator who also took notes after the game of key themes that emerged from the discussion. A sample of players were invited on a voluntary basis to take part in semi-structured interviews after playing the game using Flanagan's Critical Incident Technique. A paper-based questionnaire on 'Safety Concerns' was developed and administered to assess pre-and post-playing the game reporting behaviour. Dissemination workshops were held with senior clinicians to promote more inclusive leadership behaviours and responsiveness to junior doctors raising of safety concerns from senior clinicians.
    • Management of bone health in patients with cancer: a survey of specialist nurses.

      Drudge-Coates, Lawrence; van Muilekom, Erik; de la Torre-Montero, Julio C; Leonard, Kay; van Oostwaard, Marsha; Niepel, Daniela; Jensen, Bente Thoft (2019-06-15)
      Background: Patients with cancer can experience bone metastases and/or cancer treatment-induced bone loss (CTIBL), and the resulting bone complications place burdens on patients and healthcare provision. Management of bone complications is becoming increasingly important as cancer survival rates improve. Advances in specialist oncology nursing practice benefit patients through better management of their bone health, which may improve quality of life and survival. Methods: An anonymised online quantitative survey asked specialist oncology nurses about factors affecting their provision of support in the management of bone metastases and CTIBL. Results: Of 283 participants, most stated that they worked in Europe, and 69.3% had at least 8 years of experience in oncology. The most common areas of specialisation were medical oncology, breast cancer and/or palliative care (20.8-50.9%). Awareness of bone loss prevention measures varied (from 34.3% for alcohol intake to 77.4% for adequate calcium intake), and awareness of hip fracture risk factors varied (from 28.6% for rheumatoid arthritis to 74.6% for age > 65 years). Approximately one-third reported a high level of confidence in managing bone metastases (39.9%) and CTIBL (33.2%). International or institution guidelines were used by approximately 50% of participants. Common barriers to better specialist care and treatment were reported to be lack of training, funding, knowledge or professional development. Conclusion: This work is the first quantitative analysis of reports from specialist oncology nurses about the management of bone metastases and CTIBL. It indicates the need for new nursing education initiatives with a focus on bone health management.
    • 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.
    • 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.
    • Is Eminectomy Effective in the Management of Chronic Closed Lock?

      Shah, Ketan; Brown, Andrew Nicholas; Clark, Robert; Israr, Mohammed; Starr, Donald; Stassen, Leo F A (2019-04-05)
      Purpose: This study assesses the effectiveness of eminectomy in the management of chronic closed lock, refractory to conservative medical management in the largest multi-centred study of its kind in the UK, with a cohort of 167 patients. Temporomandibular mandibular joint disorder affects 30% of adults in the UK. Chronic closed lock is a well-documented sub-type. Method: A retrospective study of patients with refractory closed lock was carried out, where conservative management had been implemented for a minimum of 6 months. Refractory patients were offered eminectomy at three separate centres over a period from 1995 to 2011. The primary variable was the inter-incisal distance (IID). Other variables included pain, clicking and nerve damage pre- and post-operatively. Results: There were 167 patients across all three centres, 81% of which were female. The mean IID was 23 mm pre-operatively and 37 mm post-operatively. There was a statistically significant association with the primary predictor variable, yielding a p value of < 0.05. Clicking resolved completely post-operatively in 84 patients (58%). Pain subjectively improved in 56% cases. Conclusion: Eminectomy is a safe and effective surgical procedure and has a role to play as a second-line surgical option in the management of closed lock after more conservative medical options have failed.
    • 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 (www.raids-fp7.eu), 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.
    • Development and relative validation of a short food frequency questionnaire for assessing dietary intakes of non-alcoholic fatty liver disease patients.

      Bredin, Carla; Naimimohasses, Sara; Norris, Suzanne; Wright, Ciara; Hancock, Neil; Hart, Kathryn; Moore, J Bernadette (2019-02-25)
      Fifty-five patients completed both the SFFQ and the 4DDD within 30 weeks; 42 (76%) were diagnosed with simple steatosis, whereas 13 (24%) had biopsy-proven steatohepatitis; the majority were overweight or obese, with a median (25th; 75th percentile) BMI of 33.2 kg/m2 (29.3; 36.0). Reported energy intakes were well below EER with a median intake of 73% of requirements, suggesting widespread under-reporting. Significant correlations were observed between sugar (r = 0.408, P = 0.002), fat (r = 0.44, P = 0.001), fruits (r = 0.51, P = 0.0001) and vegetables (r = 0.40, P = 0.0024) measurements by the SFFQ and 4DDD. Bland Altman plots with regression analysis demonstrated broad comparability with the 4DDD for intakes of fat (bias - 13.8 g/day) and sugar (bias  + 12.9 g/day).
    • Current advances in the treatment of giant cell arteritis: the role of biologics.

      Low, Candice; Conway, Richard (Therapeutic Advances in Musculoskeletal Disease, 2019-01-01)
      Giant cell arteritis (GCA) is the most common form of systemic vasculitis. It is a potentially severe disease with 25% of patients suffering vision loss or stroke. Our treatment paradigm is based on glucocorticoids. Glucocorticoids are required in high doses for prolonged periods and subsequently are associated with a significant amount of treatment-related morbidity. Alternative treatment options are urgently needed to minimize these glucocorticoid adverse events. Many other agents, such as methotrexate and tumour necrosis factor alpha inhibitors have been used in GCA, with limited or no evidence of benefit. Our emerging understanding of the pathogenic processes involved in GCA has led to an increased interest in the use of biologic agents to treat the disease. Two randomized controlled trials have recently reported dramatic effects of the use of the interleukin-6 targeted biologic tocilizumab in GCA, with significant increases in remission rates and decreases in glucocorticoid burden. While encouraging, longer-term and additional outcomes are awaited to clarify the exact positioning of tocilizumab in the treatment approach. Emerging data for other biologic agents, particularly abatacept and ustekinumab, are also encouraging but less well advanced. We are at the dawn of a new era in GCA treatment, but uncertainties and opportunities abound.
    • National Medicines Information Centre VOLUME 24 NUMBER 4 2018

      National Medicines Information Centre (National Medicines Information Centre St James Hospital, 2018-08)
      Newsletter of the National Medicines Information Centre
    • National Medicines Information Centre VOLUME 24 NUMBER 3 2018

      National Medicines Information Centre (National Medicines Information Centre St James Hospital, 2018-08)
      Newsletter of the National Medicines Information Centre
    • Transcriptome level analysis in Rett syndrome using human samples from different tissues.

      Shovlin, Stephen; Tropea, Daniela (Orphanet Journal of Rare Diseases, 2018-07-11)
      The mechanisms of neuro-genetic disorders have been mostly investigated in the brain, however, for some pathologies, transcriptomic analysis in multiple tissues represent an opportunity and a challenge to understand the consequences of the genetic mutation. This is the case for Rett Syndrome (RTT): a neurodevelopmental disorder predominantly affecting females that is characterised by a loss of purposeful movements and language accompanied by gait abnormalities and hand stereotypies. Although the genetic aetiology is largely associated to Methyl CpG binding protein 2 (MECP2) mutations, linking the pathophysiology of RTT and its clinical symptoms to direct molecular mechanisms has been difficult. One approach used to study the consequences of MECP2 dysfunction in patients, is to perform transcriptomic analysis in tissues derived from RTT patients or Induced Pluripotent Stem cells. The growing affordability and efficiency of this approach has led to a far greater understanding of the complexities of RTT syndrome but is also raised questions about previously held convictions such as the regulatory role of MECP2, the effects of different molecular mechanisms in different tissues and role of X Chromosome Inactivation in RTT. In this review we consider the results of a number of different transcriptomic analyses in different patients-derived preparations to unveil specific trends in differential gene expression across the studies. Although the analyses present limitations- such as the limited sample size- overlaps exist across these studies, and they report dysregulations in three main categories: dendritic connectivity and synapse maturation, mitochondrial dysfunction, and glial cell activity. These observations have a direct application to the disorder and give insights on the altered mechanisms in RTT, with implications on potential diagnostic criteria and treatments.