Matching-adjusted indirect comparison of efficacy in patients with moderate-to-severe plaque psoriasis treated with ixekizumab vs. secukinumab.

BACKGROUND: Head-to-head randomized studies comparing ixekizumab and secukinumab in the treatment of psoriasis are not available. OBJECTIVES: To assess efficacy and quality of life using matching-adjusted indirect comparisons for treatment with ixekizumab vs. secukinumab. METHODS: Psoriasis Area and Severity Index (PASI) improvement of at least 75%, 90% and 100% and Dermatology Life Quality Index (DLQI) 0/1 response rates for approved dosages of ixekizumab (160 mg at Week 0, then 80 mg every two weeks for the first 12 weeks) and secukinumab (300 mg at Weeks 0, 1, 2, 3 and 4, then 300 mg every 4 weeks) treatment were compared using data from active (etanercept and ustekinumab) and placebo-controlled studies. Comparisons were made using the Bucher (BU) method and two modified versions of the Signorovitch (SG) method (SG total and SG separate). Subsequently, results based on active treatment common comparators were combined using generic inverse-variance meta-analysis. RESULTS: In the meta-analysis of studies with active comparators, PASI 90 response rates were 12·7% [95% confidence interval (CI) 5·5-19·8, P = 0·0005], 10·0% (95% CI 2·1-18·0, P = 0·01) and 11·2% (95% CI 3·2-19·1, P = 0·006) higher and PASI 100 response rates were 11·7% (95% CI 5·9-17·5, P < 0·001), 12·7% (95% CI 6·0-19·4, P < 0·001) and 13·1% (95% CI 6·3-19·9, P < 0·001) higher for ixekizumab compared with secukinumab using BU, SG total and SG separate methods. PASI 75 results were comparable when SG methods were used and favoured ixekizumab when the BU method was used. Week 12 DLQI 0/1 response rates did not differ significantly. CONCLUSIONS: Ixekizumab had higher PASI 90 and PASI 100 responses at week 12 compared with secukinumab using adjusted indirect comparisons.

Continuous dosing versus interrupted therapy with ixekizumab: an integrated analysis of two phase 3 trials in psoriasis.

BACKGROUND: Continuous treatment is recommended for patients with moderate-to-severe psoriasis; however, treatment may need to be interrupted in routine clinical practice. OBJECTIVE: To assess outcomes in patients continuously treated with ixekizumab versus those who interrupted therapy and were subsequently retreated with ixekizumab (IXE). METHODS: This analysis used data pooled from two phase 3 trials, UNCOVER-1 and UNCOVER-2. Patients were randomized to placebo (PBO), IXE every 4 (Q4W) or IXE every 2 weeks (Q2W) for 12 weeks. Patients with a static Physician's Global Assessment (sPGA) 0, 1 at Week 12 were rerandomized to IXEQ4W, IXE every 12 weeks (not presented) or PBO. We examined outcomes in patients who were continuously treated (IXEQ2W/IXEQ4W; IXEQ4W/IXEQ4W) or withdrawn (IXEQ2W/PBO; IXEQ4W/PBO), and in patients who were withdrawn and retreated with IXEQ4W for 24 weeks after disease relapse (sPGA ≥3). RESULTS: A total of 1226 treated patients achieved an sPGA 0, 1 at Week 12 and entered the maintenance phase; of these patients, 402 and 416 were rerandomized to PBO and IXEQ4W, respectively. Among patients interrupting treatment, 157 (82.2%) of IXEQ4W/PBO and 176 (83.4%) of IXEQ2W/PBO had an sPGA ≥3 by Week 60; median time to relapse was approximately 20 weeks irrespective of induction dose. At Week 60, continuously treated patients maintained high levels of PASI and sPGA responses (90.0% PASI 75 IXEQ2W/IXEQ4W; 81.9% sPGA 0, 1 IXEQ2W/IXEQ4W, non-responder imputation). After 24 weeks of retreatment with IXEQ4W (IXEQ2W/PBO/IXEQ4W and IXEQ4W/PBO/IXEQ4W), 87.0% (107 of 123) and 95.1% (97 of 102) (observed), respectively, of patients recaptured PASI 75 and 70.7% (104 of 147) and 82.3% (107 of 130) (observed) recaptured an sPGA 0, 1. Overall, adverse events in continuously treated and retreated patients were comparable. CONCLUSION: High levels of response were sustained with continuous ixekizumab treatment through 60 weeks. Most patients who were withdrawn experienced disease relapse, and most of those patients recaptured response after 24 weeks of retreatment.

Evidence for Endovascular Simulation Training: A Systematic Review.

BACKGROUND: Simulation training in endovascular surgery provides opportunities for trainees to practice and learn from non-patient based experience. Several types of endovascular simulators are available commercially. Previous studies on endovascular simulation training can be categorized into trials in which only a simulator was used when measuring performance metrics or "trials within simulation"; patient specific procedure rehearsals; and randomized, controlled trials (RCTs) or translational studies. OBJECTIVES: To examine whether endovascular simulation training can improve surgeon techniques and patient outcomes in real clinical settings. METHODS: A literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All searches were done via PubMed and Embase. Review articles, and papers that were not related to endovascular surgery and not within the scope of interest were excluded. References of review articles were further screened according to the exclusion criteria. RESULTS: In total, 909 records were identified and 290 duplicates were removed. Thirty-one were included in the qualitative analysis. Twenty-three were trials within simulation and most of them found statistically significant improvements in procedure time, fluoroscopy time, and contrast volume. Five were patient specific procedure rehearsals and showed that simulation significantly affected the fluoroscopy angle and improved performance metrics. Three were RCTs and revealed mainly positive results on a Global Rating Scale and procedure specific rating scale. CONCLUSIONS: Contemporary evidence shows that performance metrics within endovascular simulations improve with simulation training. Successful translation to in vivo situations is observed in patient specific procedure rehearsals and RCTs on real procedures. However, there is no level I evidence to show that predictive validity of simulation can definitively improve patient outcomes. Current literature supports the idea that there is a beneficial role of simulation in endovascular training. Future studies are needed to confirm the efficacy of simulation in endovascular surgical training and to see if simulation is superior to traditional training in the operating theatre.

Experimental heart failure modelled by the cardiomyocyte-specific loss of an epigenome modifier, DNMT3B.

Differential DNA methylation exists in the epigenome of end-stage failing human hearts but whether it contributes to disease progression is presently unknown. Here, we report that cardiac specific deletion of Dnmt3b, the predominant DNA methyltransferase in adult mouse hearts, leads to an accelerated progression to severe systolic insufficiency and myocardial thinning without a preceding hypertrophic response. This was accompanied by widespread myocardial interstitial fibrosis and myo-sarcomeric disarray. By targeted candidate gene quantitative RT-PCR, we discovered an over-activity of cryptic splice sites in the sarcomeric gene Myh7, resulting in a transcript with 8 exons missing. Moreover, a region of differential methylation overlies the splice site locus in the hearts of the cardiac-specific conditional knockout (CKO) mice. Although abundant and complex forms of alternative splice variants have been reported in diseased hearts and the contribution of each remains to be understood in further detail, our results demonstrate for the first time that a link may exist between alternative splicing and the cardiac epigenome. In particular, this gives the novel evidence whereby the loss of an epigenome modifier promotes the development and progression of heart disease.

Trans-oral resection of large parapharyngeal space tumours.

The aim of this study is to describe minimally invasive trans-oral approach for resection of parapharyngeal space (PPS) tumours and to demonstrate surgical technique, resection, repair and outcomes. Five cases were prospectively included in the study. The data collected include age, sex, site, size, pathology, radiological investigations, surgical excision, complications and outcomes. Three females and two male patients underwent trans-oral resection of PPS tumours sized 4-8 cm. The pathology included two deep lobe parotid tumours, one schwannoma, one hibernoma and one primary adenocarcinoma arising form the minor salivary gland. All tumours were resected completely without any technical difficulty. The healing was quick and by primary intention. Patients resumed oral feeding on recovery from general anaesthesia and did not require any significant analgesia beyond the first 2 days. Patient with adenocarcinoma received postoperative radiotherapy and remained disease-free during 4 years post-treatment. No recurrences were observed in patients with benign tumours. No neurovascular injury occurred during surgery and no secondary bleeding was observed. We have demonstrated successful and safe execution of trans-oral resection of large PPS tumours. There were no intra and post-operative complications and there has been no recurrence during the follow-up period. In our experience, it appears to be efficient, safe and minimally invasive compared to the established techniques.

Revision nasal surgery after septoplasty: trainees versus trainers.

Otolaryngology trainees are expected to be able to successfully perform septoplasty early in their career. An important parameter to assess the success of an operation is to look at the revision surgery rate. This study aimed to investigate the revision nasal surgery rate after septoplasty based on the grade of the primary surgeon. Retrospective review of hospital records of all patients who underwent septoplasty with or without inferior turbinate reduction over 12 years (1998-2010) in a tertiary referral centre in North-East Scotland. Patients were identified from theatre log books and were excluded if they underwent any other simultaneous nasal procedure. Data were collected on demographics, type of primary and revision surgery, grade of surgeon and duration of hospital stay. 2,168 eligible patients (70 % male, 30 % female) with a mean age of 39 years were investigated. Surgeons were divided into four categories: junior trainee (Group A), senior trainee (Group B), staff grade (Group C) and consultant (Group D). There were 753, 644, 298 and 473 patients in Groups A, B, C and D, respectively. The revision rate in Group A was 4.4 % compared to 3.2 % for Group D and this difference was not statistically significant. For their operation, patients in Group A stayed for 1.54 nights compared to 1.47 nights in Group D, the difference being insignificant. Grade of the surgeon does not appear to strongly affect the need for revision nasal surgery and our patients do not appear to be disadvantaged if operated on by trainees.

Variation in practice: an analysis of Scottish Surgical Profiles ENT data.

BACKGROUND: Variation in otolaryngology intervention rates is reported in the Scottish Surgical Profiles Project. Tonsillectomy is one of the selected key indicator procedures. The variation in practice was discussed nationally at the Scottish Otolaryngology Society summer meetings in 2009 and 2010. NHS Grampian had a significantly higher tonsillectomy rate compared with other Scottish NHS boards. AIMS: To determine the accuracy of NHS Grampian data reported by the Information Service Division (ISD) and to record the appropriateness of listing of patients for tonsillectomy with reference to the Scottish Intercollegiate Guidelines Network (SIGN). METHODS: Retrospective review of case notes and surgical records of patients who had undergone tonsillectomy between March 2007 and March 2008 in NHS Grampian. RESULTS: Between March 2007 and March 2008, 509 tonsillectomy cases were performed in NHS Grampian. This corresponded to the data received from ISD. 87% of tonsillectomies performed were compliant with SIGN guidelines. CONCLUSION: The Scottish otolaryngology clinicians have found the reporting of the intervention rates stimulating and challenging. Discussion of the surgical profile project regularly at national specialty meetings resulted in a preliminary detailed targeted audit of those who were persistent outliers for tonsillectomy. This refuted the presumed reasons for this variation, namely inaccurate figures from ISD and inappropriate listings by clinicians.

Short term outcome of therapeutic hypothermia in term infants with moderate to severe hypoxic ischaemic encephalopathy; the Sungai Buloh experience.

This analysis is a case-series to document the outcome of term newborns with hypoxic ischaemic encephalopathy (HIE), enrolled into total body hypothermia therapy, in a tertiary neonatal unit in Malaysia. The method used to achieve total body hypothermia is a novel method using just environmental temperature, without the need of expensive equipment. A total of 17 babies were eligible to be included in this study, from the 1st of January 2010 to the 31st of December 2010. 14 out of 15 babies who had Stage 2 HIE had no neurological deficit at follow-up. All Stage 3 HIE babies passed away. Allowing for the small sample size, we can conclude that total body hypothermia therapy is feasible and is a safe treatment modality for HIE Stage 2 babies in a Malaysian setting, by manipulating environmental temperature to achieve therapeutic hypothermia. Further work is needed to determine the long-term outcome of passive cooling total body hypothermia in Stage 2 HIE babies in Malaysia.

Impact of sepsis education for healthcare professionals and students on learning and patient outcomes: a systematic review.

BACKGROUND: Sepsis is an important global healthcare problem that is a key challenge faced by healthcare professionals face worldwide. One key effort aimed at reducing the global burden of sepsis is educating healthcare professionals about early identification and management of sepsis. AIM: To provide a comprehensive evaluation of sepsis education among healthcare professionals and students. METHODS: Six databases (PubMed, CINAHL, Embase, MEDLINE, Cochrane Central Register of Controlled Trials, and Scopus) were searched. We included studies that described and evaluated any form of education or training on sepsis delivered to healthcare professionals and students. Study outcomes were summarized according to the adapted Kirkpatrick model of training evaluation. RESULTS: Thirty-two studies were included in the review. The learning contents were reported to be in accordance with the Surviving Sepsis Campaign guidelines. Seven studies included the topic of interprofessional teamwork and communication in their sepsis education content. Most educational programmes were effective and reported positive effects on immediate knowledge outcomes. Interventions that were delivered through an active learning approach such as simulation and game-based learning generally produced greater gains than didactic teaching. Improvements in patient care processes and patient outcomes were associated with the concomitant existence or implementation of a hospital sepsis care bundle. CONCLUSION: Incorporating active learning strategies into sepsis education interventions has the potential to improve learners' long-term outcomes. In addition, sepsis education and a protocol-based sepsis care bundle act in synergy to augment greater improvements in care processes and patient benefits.

Fragment-Based Identification of Ligands for Bromodomain-Containing Factor 3 of Trypanosoma cruzi.

The Trypanosoma cruzi (T. cruzi) parasite is the cause of Chagas disease, a neglected disease endemic in South America. The life cycle of the T. cruzi parasite is complex and includes transitions between distinct life stages. This change in phenotype (without a change in genotype) could be controlled by epigenetic regulation, and might involve the bromodomain-containing factors 1-5 (TcBDF1-5). However, little is known about the function of the TcBDF1-5. Here we describe a fragment-based approach to identify ligands for T. cruzi bromodomain-containing factor 3 (TcBDF3). We expressed a soluble construct of TcBDF3 in E. coli, and used this to develop a range of biophysical assays for this protein. Fragment screening identified 12 compounds that bind to the TcBDF3 bromodomain. On the basis of this screen, we developed functional ligands containing a fluorescence or 19F reporter group, and a photo-crosslinking probe for TcBDF3. These tool compounds will be invaluable in future studies on the function of TcBDF3 and will provide insight into the biology of T. cruzi.

Routine clotting screen has no role in the management of epistaxis: reiterating the point.

Objective of the study is to investigate the role of clotting screen in adult patients presenting with epistaxis. The study is a prospective case series done in a teaching hospital in the Northeast of Scotland. Prospective data was collected for 100 consecutive patients with epistaxis admitted to the Department of Otolaryngology over 1 year (2006-2007 August). The demographics, co-morbidities, long-term medications and blood test results were noted for these patients. A retrospective audit of all patients attending the Emergency Department (ED) with epistaxis during the same study period was also performed. The following were measured: frequency of clotting screen performed in patients with epistaxis; the treatment modifying effect of clotting screen results. Of the 100 admitted patients, 45 were male and 55 were female. The majority of them had more than two co-morbidities such as hypertension, ischaemic heart disease and atrial fibrillation. Forty-seven patients were on aspirin, 19 on warfarin and 12 patients on clopidogrel. A clotting screen was done for 80 patients but only 2 patients (2.5%) had an abnormal INR. A total of 356 patients presented to the ED with epistaxis. Of 356 patients, 138 (39%) had their clotting screen checked. Of 138 patients, 42 (30%) were on warfarin. Only 7 patients (7/138 = 5%) had an abnormal result. Our data suggests that routine clotting screen check does not alter the epistaxis management in patients with no risk factors or with stable warfarin dosage. Therefore, routine clotting screen in patients with epistaxis without relevant risk factors is not an evidence-based practice.

COVID-19: Four Paediatric Cases in Malaysia.

OBJECTIVE: This is a brief report of 4 paediatric cases of COVID-19 infection in Malaysia BACKGROUND: COVID-19, a coronavirus, first detected in Wuhan, China has now spread rapidly to over 60 countries and territories around the world, infecting more than 85000 individuals. As the case count amongst children is low, there is need to report COVID-19 in children to better understand the virus and the disease. CASES: In Malaysia, until end of February 2020, there were four COVID-19 paediatric cases with ages ranging from 20 months to 11 years. All four cases were likely to have contracted the virus in China. The children had no symptoms or mild flu-like illness. The cases were managed symptomatically. None required antiviral therapy. DISCUSSION: There were 2 major issues regarding the care of infected children. Firstly, the quarantine of an infected child with a parent who tested negative was an ethical dilemma. Secondly, oropharyngeal and nasal swabs in children were at risk of false negative results. These issues have implications for infection control. Consequently, there is a need for clearer guidelines for child quarantine and testing methods in the management of COVID-19 in children.

Validation and clinical implications of the IDSA/ATS minor criteria for severe community-acquired pneumonia.

BACKGROUND: The 2007 Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) guidelines defined severe community-acquired pneumonia (CAP) and recommended intensive care unit (ICU) admission when patients fulfilled three out of nine minor criteria. These criteria have not been validated. METHODS: All patients admitted to our hospital from 2004 to 2007 for CAP were reviewed retrospectively. Patients who fulfilled any IDSA/ATS major criteria for severe CAP at the emergency department (ie, the need for mechanical ventilation or vasopressors) were excluded. The predictive characteristics of the IDSA/ATS minor criteria were compared with those of the Pneumonia Severity Index (PSI) and the CURB-65 score for hospital mortality and ICU admission. RESULTS: 1242 patients were studied (mean age 65.7 years, hospital mortality 14.7%). The areas under the receiver operating characteristic curves for the IDSA/ATS minor criteria were 0.88 (95% CI 0.86 to 0.91) and 0.85 (95% CI 0.81 to 0.88) for predicting hospital mortality and ICU admission, respectively. These were greater than the corresponding areas for the PSI and the CURB-65 score (p < 0.05). The sensitivity, specificity, positive and negative predictive values of the minor criteria were 81.4%, 82.9%, 45.2% and 96.3%, respectively, for hospital mortality and 58.3%, 90.6%, 52.9% and 92.3%, respectively, for ICU admission. The minor criteria were more specific than the PSI and more sensitive than the CURB-65 score for both outcomes. CONCLUSION: These findings support the use of the IDSA/ATS minor criteria to predict hospital mortality and guide ICU admission in inpatients with CAP who do not require emergency mechanical ventilation or vasopressors.

Teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: an analysis by gender and menopausal status.

SUMMARY: The effects of teriparatide versus alendronate were compared by gender and menopausal status in patients with glucocorticoid-induced osteoporosis. At 18 months, increases in lumbar spine BMD were significantly greater in the teriparatide versus alendronate group in postmenopausal women (7.8% versus 3.7%, p < 0.001), premenopausal women (7.0% versus 0.7%, p < 0.001), and men (7.3% versus 3.7%, p = 0.03). INTRODUCTION: In patients with glucocorticoid-induced osteoporosis (GIO), teriparatide significantly increased bone mineral density (BMD) and decreased vertebral fractures compared with alendronate. We examined effects of teriparatide versus alendronate by gender and menopausal status. METHODS: This was a multicenter, randomized, double-blind study of teriparatide 20 microg/day versus alendronate 10 mg/day in patients with GIO (277 postmenopausal women, 67 premenopausal women, 83 men). Primary outcome was change in lumbar spine BMD. Secondary outcomes included change in hip BMD, change in bone biomarkers, fracture incidence, and safety. RESULTS: At 18 months, mean percent increases from baseline in lumbar spine BMD were significantly greater in the teriparatide versus alendronate group in postmenopausal women (7.8% versus 3.7%, p < 0.001), premenopausal women (7.0% versus 0.7%, p < 0.001), and men (7.3% versus 3.7%, p = 0.03). Radiographic vertebral fractures occurred in one teriparatide (one postmenopausal) and ten alendronate patients (six postmenopausal, four men), and nonvertebral fractures occurred in 12 teriparatide (nine postmenopausal, two premenopausal, one man) and eight alendronate patients (six postmenopausal, two men). The proportion of patients reporting adverse events in teriparatide versus alendronate groups was consistent across subgroups. CONCLUSION: Among men and pre- and postmenopausal women with GIO, lumbar spine BMD increased more in patients receiving teriparatide compared with alendronate.

Primary versus secondary tracheoesophageal puncture: systematic review and meta-analysis.

BACKGROUND: Tracheoesophageal puncture represents the 'gold standard' for voice restoration following laryngectomy. Tracheoesophageal puncture can be undertaken primarily during laryngectomy or in a separate secondary procedure. There is no current consensus on which approach is superior. The current evidence comparing primary and secondary tracheoesophageal puncture was assessed. METHODS: A systematic review and meta-analysis of articles comparing outcomes for primary and secondary tracheoesophageal puncture after laryngectomy were conducted. Outcome measures were: voice success, overall complication rate and pharyngocutaneous fistula rate. RESULTS: Eleven case series met the inclusion criteria, two prospective and nine retrospective. Meta-analysis did not demonstrate statistically significant differences in overall complication rate or voice outcomes, though it suggested a significantly increased risk of pharyngocutaneous fistula in primary compared to secondary tracheoesophageal puncture. CONCLUSION: Primary tracheoesophageal puncture is a safe and efficient approach for voice rehabilitation. However, secondary tracheoesophageal puncture should be preferred where there is a higher risk of pharyngocutaneous fistula.

Use of complementary and alternative medicine in pediatric otolaryngology patients attending a tertiary hospital in the UK.

OBJECTIVE: Little data is available on complementary and alternative medicine (CAM) use in children attending otolaryngology services. We investigated the prevalence and pattern of CAM use among children attending the pediatric otolaryngology department in a tertiary pediatric teaching hospital in Scotland. DESIGN: A cross-sectional survey conducted by administering an anonymous questionnaire to the parents accompanying patients attending the pediatric otolaryngology department. Elective admissions and clinic attendees were included over a 3-month period in 2005/2006. SETTING: Academic tertiary care referral centre in North-East Scotland. PATIENTS: Five hundred and fifty-four consecutive patients aged less than 16 years were eligible. The response rate was 59% (n=327). MAIN OUTCOME MEASURES: Prevalence of CAM use in children. Secondary measures include types of CAM used, indications for use and communication with family physicians. RESULTS: Based on 327 responses, 93 patients (29%) had ever used CAM, 20% within the last year. Commonly used CAM preparations were cod-liver oil, echinacea, aloe vera, cranberry, primrose oil and herbal vitamin supplements. The popular non-herbal CAM included homeopathy, massage, aromatherapy, chiropractic, yoga and reiki. Nineteen percent used CAM for their admission illness. Sixty-one percent of parents thought that CAM was effective and 65% would recommend it to others. Fifty-one percent of parents stated that the family physician was unaware of CAM use by the child. CONCLUSIONS: Despite concerns regarding the efficacy, safety and cost effectiveness of complementary and alternative medicine, its use among the pediatric otolaryngology population is more common than many providers may realize. This has implications for all healthcare workers involved in their care.