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Objective The “At Risk Mental State” (ARMS) approach to psychosis, also called “Clinical/Ultra High Risk,” has had a major impact on psychosis services internationally. Despite well-established developmental differences in the prevalence and expression of psychotic symptoms from childhood into adulthood, there has been no systematic review of psychosis transitions specifically in children and adolescents up to age of 18 years. Evidence for this age group is crucial for developmentally appropriate clinical decisions by child and adolescent psychiatrists. Method Systematic review and meta-analysis of psychosis risk among children diagnosed with ARMS up to age 18 years, with pooled transition rates after 1-year, 2-year and ≥5-year follow-up. Results We retrieved 1,107 records and identified 16 articles from 9 studies reporting transition rates on 436 individuals with ARMS aged 9 to 18 years. The pooled transition rate to psychosis at 1 year was 9.5% (95% CI = 5.5%−14.2%, 7 studies included), at 2-years 12.1% (95% CI = 6.7%−18.6%, 4 studies included), and at ≥5 years 16.1% (95% CI = 5.6%−30.0%, 4 studies included). We did not find evidence that the diagnosis of ARMS was associated with increased risk of psychosis once risk-enriching recruitment strategies were taken into account. Conclusion At 5-year follow-up, 1 in 6 youths diagnosed with an ARMS had transitioned to psychosis, but we did not find evidence that this risk was related to ARMS diagnosis as opposed to sampling/recruitment strategies. Our findings indicate a need for caution in applying ARMS methodology to children and adolescents. and highlight the need for developmentally sensitive approaches when considering psychosis risk.

Background The observation that patients presenting for bariatric surgery had a high incidence of neuromuscular blocking agent (NMBA) anaphylaxis prompted this restricted case-control study to test the hypothesis that obesity is a risk factor for NMBA anaphylaxis, independent of differences in pholcodine consumption. Methods We compared 145 patients diagnosed with intraoperative NMBA anaphylaxis in Western Australia between 2012 and 2020 with 61 patients with cefazolin anaphylaxis with respect to BMI grade, history of pholcodine consumption, sex, age, comorbid disease, and NMBA type and dose. Confounding was assessed by stratification and binomial logistic regression. Results Obesity (odds ratio [OR]=2.96, χ2=11.7, P=0.001), ‘definite' pholcodine consumption (OR=14.0, χ2=2.6, P Conclusions Obesity is a risk factor for NMBA anaphylaxis, the risk increasing with BMI grade. Pholcodine consumption is also a risk factor, and this is consistent with the pholcodine hypothesis. Rocuronium use is associated with an increased risk of anaphylaxis compared with vecuronium in this population.

Screening for breast cancer, cervical cancer, and colorectal cancer (CRC) reduces mortality from these cancers.* However, screening test receipt has been below national targets with disparities observed in certain populations (1,2). National Health Interview Survey (NHIS) data from 2018 were analyzed to estimate percentages of adults up to date with U.S. Preventive Services Task Force (USPSTF) screening recommendations. Screening test receipt remained below national Healthy People 2020 (HP2020) targets, although CRC test receipt neared the target. Disparities were evident, with particularly low test receipt among persons who were uninsured or did not have usual sources of care. Continued monitoring helps assess progress toward targets and could inform efforts to promote screening and reduce barriers for underserved populations.

Investigation of intraoperative anaphylaxis includes the exclusion of potential trigger agents the individual was exposed to within a plausible interval preceding the reaction. Occasionally, none of these agents will test positive. In this situation it is important to consider that excipients may be responsible for anaphylaxis, that the dilutions prepared to test the medication may not contain an appropriate concentration of the excipient to induce a positive skin reaction, or if an alternative formulation of the medication is tested, it may not contain the culprit excipient. This case describes a patient, who previously experienced an anaphylactic reaction to Betadine® (Sanofi-Aventis Australia Pty Ltd, North Ryde BC, NSW) experiencing anaphylaxis in the recovery period after general anaesthesia where Betadine was avoided. The recently administered therapeutics were excluded by skin testing, however further investigation determined that a povidone-containing formulation of paracetamol had been administered. Skin testing with povidone-containing paracetamol resulted in a positive reaction in the patient, but not in a volunteer control. Pharmaceutical excipients are added to medications to increase absorption, shelf-life and efficacy. Different brands of the same drug may contain different excipients. When testing for anaphylaxis with such compounds one must be sure the dilution is appropriate for both the parent compound and the excipient to ensure the accuracy of skin-prick and intradermal testing. This case demonstrates the potential for excipients to cause severe allergy and the importance of detailed history pertaining to previous allergic episodes as even the most unlikely of medications can potentially result in anaphylaxis due to excipients.

Background MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn’s disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results In stage 1, each leukocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20–3.27; logrank p = 1.80 × 10–3), in particular CD [HR 2.81; IQR: 1.11–3.53, p = 6.50 × 10–4]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.

Development of total hip arthroplasty (THA) now spans more than 5 decades encompassing combinations of metal-on-metal (MOM), ceramic-on-metal (COM), metal-on-plastic (MOP), ceramic-on-plastic (COM), and ceramic-on-ceramic (COC). In every arena of extensive technical development, there exists a data set that when viewed in isolation seemed of little import, but when assembled in-toto may produce a generational shift in perception. Our review focused on two such THA events. Firstly, COC retrieval studies (1999-2001) noted habitual wear patterns on heads and peripheral wear stripes, along with femoral-neck impingement, and ceramic surfaces stained gray by metal debris. These COC data indicated THA risks included, 1) cup edge-loading (E/L) on heads producing “stripe wear”, 2) component impingement releasing metal particles resulting in 3) tissues contaminated by metal debris. A corresponding MOM impingement-debris mechanism was only perceived by Howie (2005) in a McKee-Farrar retrieval study. Our anticipation at LLUMC was that MOM retrievals would provide superior wear details to those seen on COC retrievals. We noted stripe wear in the polar zone of CoCr heads and basal stripes in the non-wear areas. The basal-polar stripe combinations were found in all MOM retrievals. Basal-polar stripe combinations followed cup-rim profiles in our LLUMC simulations of prosthetic impingement. LPUH videos demonstrated the formation of stripe wear in functional-standing and functional-sitting postures for both impingement and subluxation episodes using THA and RA designs. The stripes on CoCr heads revealed the large scratches we now term “microgrooves”. Microgroove width varied from 40 - 400 um with 100 um being typical. The longitudinal striations in microgrooves, the raised jagged lips, scratches with shallow entry and exit termini, were all indicative of a classic 3rd-body wear mechanism. The THA impingement simulations denoted four sites of edge-loading, i.e. neck-E/L, inferior cup-E/L, superior cup-E/l and head-E/L, and ingress of Ti64 particles as a contaminating-roughness effect. Individual MOM cases referred to LLUMC demonstrated dramatic evidence of neck notching. At one end of the debris spectrum, a Ti64-notch model predicting a 6 mm3 annual wear-rate represented the release of 5700 particles of 126 um-size (approximating daily release of 16 particles). At the other end of the spectrum, if metal particles were crushed between MOM surfaces to the equivalent nanometer size found in tissues, our notch model represented approximately 22-trillion Ti64 particles annually deposited in tissues. The anatomical THA models represented in LPUH videos demonstrated that even 1-degree of head subluxation from a rigid cup created a cup “lift-off” scenario (CLO) that would open a gap of 250 - 400 microns between femoral head and cup. This would void all lubrication potential and focus the total hip-joint force along the beveled cup rim, i.e. stripe wear. It is therefore interesting that MOM impingement/debris predictions by Howie et al. have not been confirmed until now or discussed in contemporary literature. Therefore, this review of 50 years of THA data demonstrated that hip impingement was always the trigger for adverse wear and that metal-backed cups represent the potential for release of metal debris at extremes of functional standing and sitting postures.

Background: Most eye complications presenting at a diabetic clinic are preventable; however, few patients are aware of the importance of regular diabetic eye examinations. Diabetes causes diabetic retinopathy (DR), yet retinal screening provides an opportunity to refer for appropriate treatment and prevention of avoidable blindness. Aim: The aim of this research was to evaluate the awareness levels of DR and retinal screening procedures amongst female diabetic patients. Setting: The study was conducted at Site B day clinic, situated in Khayelitsha in Cape Town, South Africa. Methods: Data collection involved a self-developed and administered questionnaire. Two research assistants, trained in ethical research, assisted in administering the instrument and data collection over an 8-week period. Results: Data were collected from 149 randomly selected female diabetic patients. Approximately, three-quarters (71.1%, n = 106) had knowledge about DR and the importance of retinal screening, and most (79.2%, n = 118) agreed that diabetic disease can lead to blindness. Whilst 63.1% ( n = 94) of respondents understood the importance of screening, just over three-quarters (75.8%, n = 113) felt that all people should attend retinal screening even though 80.4% ( n = 119) agreed that DR leads to permanent eye damage. Significantly, 60.4% ( n = 90) felt that attending retinal screening sessions may delay the need for spectacles. Just over half (53.0%, n = 79) felt that cultural and spiritual beliefs influenced the respondents’ attendance for retinal screening. Conclusion: Whilst respondents were, in general, well aware of the risks associated with diabetes mellitus (DM) and DR and knowledge of retinal screening was relatively good, the survey found that in the respondents’ opinion, attending the retinal screening caused delays in getting new spectacles because this screening was a prerequisite for referral for spectacles.

Background Adenosine is used to treat no‐reflow in the infarct‐related artery (IRA) during ST‐segment–elevation myocardial infarction intervention. However, the physiological effect of adenosine in the IRA is variable. Coronary steal—a reduction of blood flow to the distal coronary bed—can occur in response to adenosine and this is facilitated by collaterals. We investigated the effects of adenosine on coronary flow reserve (CFR) in patients presenting with ST‐segment–elevation myocardial infarction to better understand the physiological mechanism underpinning the variable response to adenosine. Methods and Results Pressure‐wire assessment of the IRA after percutaneous coronary intervention was performed in 93 patients presenting with ST‐segment–elevation myocardial infarction to calculate index of microvascular resistance, CFR, and collateral flow index by pressure. Modified collateral Rentrop grade to the IRA was recorded, as was microvascular obstruction by cardiac magnetic resonance imaging. Coronary steal (CFR 1.1) after adenosine occurred in 19 (20%), 15 (16%), and 59 (63%) patients, respectively. Patients with coronary steal had higher modified Rentrop score to the IRA (1 [0, 1.75] versus 0 [0, 1], P P =0.004) than the hyperemic group. The coronary steal group also had significantly higher index of microvascular resistance (61.68 [28.13, 87.04] versus 23.93 [14.67, 37.00], P =0.006) and had more disease (stenosis >50%) in the donor arteries (52.63% versus 22.03%, P =0.02) than the hyperemic group. Conclusions Adenosine‐induced coronary steal may be responsible for a reduction in coronary flow reserve in a proportion of patients presenting with ST‐segment–elevation myocardial infarction. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03145194. URL: https://www.isrctn.com ; Unique identifier: ISRCTN3176727.

BACKGROUND: Patients with underlying cardiovascular disease and coronavirus disease 2019 (COVID‐19) infection are at increased risk of morbidity and mortality. OBJECTIVES: This study was designed to characterize the presenting profile and outcomes of patients hospitalized with acute coronary syndrome (ACS) and COVID‐19 infection. METHODS: This observational cohort study was conducted using multisource data from all acute NHS hospitals in England. All consecutive patients hospitalized with diagnosis of ACS with or without COVID‐19 infection between 1 March and 31 May 2020 were included. The primary outcome was in‐hospital and 30‐day mortality. RESULTS: A total of 12 958 patients were hospitalized with ACS during the study period, of which 517 (4.0%) were COVID‐19‐positive and were more likely to present with non‐ST‐elevation acute myocardial infarction. The COVID‐19 ACS group were generally older, Black Asian and Minority ethnicity, more comorbid and had unfavourable presenting clinical characteristics such as elevated cardiac troponin, pulmonary oedema, cardiogenic shock and poor left ventricular systolic function compared with the non‐COVID‐19 ACS group. They were less likely to receive an invasive coronary angiography (67.7% vs 81.0%), percutaneous coronary intervention (PCI) (30.2% vs 53.9%) and dual antiplatelet medication (76.3% vs 88.0%). After adjusting for all the baseline differences, patients with COVID‐19 ACS had higher in‐hospital (adjusted odds ratio (aOR): 3.27; 95% confidence interval (CI): 2.41–4.42) and 30‐day mortality (aOR: 6.53; 95% CI: 5.1–8.36) compared to patients with the non‐COVID‐19 ACS. CONCLUSION: COVID‐19 infection was present in 4% of patients hospitalized with an ACS in England and is associated with lower rates of guideline‐recommended treatment and significant mortality hazard.

The purpose of this study was to investigate the effectiveness of an isometric neck strengthening program to improve isometric neck strength in elite women's football-code athletes.Randomised controlled trial.Elite female soccer (n = 10) and Australian football (n = 30) players were randomised into either a control (n = 20) or experimental (n = 20) group for a 12-week intervention study during their respective seasons. While both groups undertook their prescribed strength and conditioning programs, the experimental group also performed isometric neck strengthening exercises three times per week prior to training. Isometric neck strength of the extensors, flexors, lateral flexors, and rotators were assessed pre, mid (Week 7), and post (Week 13) intervention with a hand-held dynamometer during early to mid-competition season. A mixed design analysis of variance was performed for statistical analysis.No significant group-by-time interactions in isometric neck strength were observed. All strength variables displayed a significant change over time throughout the 12-week period (p 0.05). No significant between group differences in isometric neck strength variables were observed except for lateral left flexion (F(1, 38) =5.064, p = 0.030, ηThe addition of isometric neck strengthening exercises did not improve neck strength beyond a standard strength and conditioning program for elite women's football-code athletes. While this specific program may not improve neck strength in elite women's football-code athletes, further investigation is needed to determine whether sport-specific neck strength exercises may improve neck strength or if lower-level competition athletes may still benefit from an isometric neck strengthening program.

Background Pneumococcal pneumonia is the leading cause of under-five mortality globally. The surveillance of pneumococcal serotypes is therefore vital for informing pneumococcal vaccination policy and programmes. Pneumococcal conjugate vaccines (PCVs) have been available as an option in the private healthcare setting and beginning December 2020, PCV10 was incorporated as part of routine national immunisation programme (NIP) in Malaysia. We searched existing literature on pneumococcal serotype distribution across Malaysia to provide an overall view of this distribution before the implementation of PCV10. Methods Online databases (PubMed, Ovid MEDLINE and Scopus), reference lists of articles identified, and grey literature (Malaysian Ministry of Health website, WHO website) were systematically searched for relevant literature on pneumococcal serotype distribution across Malaysia up to 10th November 2020. No lower date limit was set to maximise the number of target reports returned. Results of serotypes were split by age categories, including ≤5 years, > 5 years and unreported for those that did not specify. Results The search returned 18 relevant results, with a total of 2040 isolates. The most common serotypes across all disease types were 19F (n = 313, 15.3% [95%CI: 13.8–17.0]), 23F (n = 166, 8.1% [95%CI: 7.0–9.4]), 14 (n = 166, 8.1% [95%CI: 7.0–9.4]), 6B (n = 163, 8.0% [95%CI: 6.9–9.2]) and 19A (n = 138, 6.8% [95%CI: 5.8–7.9]). Conclusion Four of the most common serotypes across all isolate sources in Malaysia are covered by PCV10, while PCV13 provides greater serotype coverage in comparison to PCV10. There is still a need for surveillance studies, particularly those investigating serotypes in children under 5 years of age, to monitor vaccine effectiveness and pneumococcal population dynamic following implementation of PCV10 into routine immunisation.

Background The incretin hormone glucagon-like peptide 1 (GLP-1) has been shown to protect against lethal ischemia-reperfusion injury in animal models and against nonlethal ischemia reperfusion injury in humans. Furthermore, GLP-1 receptor agonists have been shown to reduce major adverse cardiovascular and cerebrovascular events (MACCE) in large-scale studies. We sought to investigate whether GLP-1 reduced percutaneous coronary intervention (PCI)–associated myocardial infarction (PMI) during elective PCI. Methods The study was a randomized, double-blind controlled trial in which patients undergoing elective PCI received an intravenous infusion of either GLP-1 at 1.2 pmol/kg/min or matched 0.9% saline placebo before and during the procedure. Randomization was performed in 1:1 fashion, with stratification for diabetes mellitus. Six-hour cardiac troponin I (cTnI) was measured with a primary end point of PMI defined as rise ≫×5 upper limit of normal (280 ng/L). Secondary end points included cTnI rise and MACCE at 12 months. Results A total of 192 patients were randomized with 152 (79%) male and a mean age of 68.1 ± 8.9 years. No significant differences in patient demographics were noted between the groups. There was no difference in the rate of PMI between GLP-1 and placebo (9 [9.8%] vs 8 [8.3%], P = 1.0) or in the secondary end points of difference in median cTnI between groups (9.5 [0-88.5] vs 20 [0-58.5] ng/L, P = .25) and MACCE at 12 months (7 [7.3%] vs 9 [9.4%], P = .61). Conclusions In this randomized, placebo-controlled trial, GLP-1 did not reduce the low incidence of PMI or abrogate biomarker rise during elective PCI, nor did it influence the 12-month MACCE rate which also remained low. Clinical trial registration Clinicaltrials.gov Number: NCT02127996 https://clinicaltrials.gov/ct2/show/NCT02127996

Suspected perioperative allergic reactions are often severe. To avoid potentially life-threatening re-exposure to the culprit drug, establishing a firm diagnosis and identifying the culprit is crucial. Drug provocation tests are considered the gold standard in drug allergy investigation but have not been recommended in the investigation of perioperative allergy, mainly because of the pharmacological effects of drugs such as induction agents and neuromuscular blocking agents. Some specialised centres have reported benefits of provocation testing in perioperative allergy investigation, but the literature on the subject is limited. Here we provide a status update on the use of drug provocation testing in perioperative allergy, including its use in specific drug groups. This review is based on a literature search and experiences of the authors comprising anaesthesiologists and allergists with experience in perioperative allergy investigation. In addition, 19 participating centres in the International Suspected Perioperative Allergic Reaction Group were surveyed on the use of provocation testing in perioperative allergy investigation. A response was received from 13 centres in eight European countries, New Zealand, and the USA. Also, 21 centres from the Australian and New Zealand Anaesthetic Allergy Group were surveyed. Two centres performed provocation routinely and seven centres performed no provocations at all. Nearly half of the centres reported performing provocations with induction agents and neuromuscular blocking agents. Drug provocation testing is being used in perioperative allergy investigation in specialised centres, but collaborations between relevant specialties and multi-centre studies are necessary to determine indications and establish common testing protocols.

Objective To assess the utility of gastrointestinal (GI) diagnostic studies in the evaluation of patients with orthostatic intolerance. Study design Medical records of 103 consecutive children/young adults with orthostatic intolerance and gastrointestinal symptoms were reviewed. All patients had undergone antroduodenal manometry in conjunction with the tilt table test, autonomic testing, and upper gastrointestinal endoscopy (EGD). A gastric emptying study (GES) was performed in 81 patients. Results The median age of the cohort was 17 years (IQR, 15-19) with a female predominance (females:males, 3:1). As expected, the tilt table test was abnormal in all patients. Antroduodenal manometry was abnormal in 83 of 103 patients (81%), showing neurogenic intestinal dysmotility in 50%, rumination in 20%, and visceral hyperalgesia in 10%. The GES results were abnormal in 23 of 81 patients (28.4%), mostly (21 of 23) with delayed GES. None of the tilt table test or autonomic results were predictive of abnormal antroduodenal manometry or GES. Analysis of EGD biopsy samples revealed nonspecific esophagitis and/or gastritis in 16 of 103 patients (15%). Conclusions Antroduodenal manometry with the tilt table test were the most insightful investigations in adolescents and young adults with orthostatic intolerance and gastrointestinal symptoms. GES and EGD provided limited information. Gastrointestinal symptoms were related more to functional rather than mucosal or organic etiologies, suggesting a limited role of endoscopy alone in evaluating patients with orthostatic intolerance presenting with gastrointestinal symptoms.

International audience; Zika virus (ZIKV) is a mosquito-borne flavivirus that was first discovered in 1947. Since then, outbreaks have been reported in tropical Africa, Southeast Asia, the Pacific Islands, and, in 2015, in the Americas. Since 2013, many countries have reported cases of microcephaly and other central nervous system mal-formation associated with ZIKV. Because the initial target population for a ZIKV vaccine is expected to be women of child-bearing age, including those who may be pregnant, it is necessary to develop safe, easily administered, and non-viral vaccines. Here, we show that a single tetrafunctional Amphiphilic Block Copolymer (ABC) delivers DNA that encodes the full natural sequence of prM-E, among other antigen designs tested, induces the highest antibody titer and neutralization activity against three divergent ZIKV isolates. Vaccination with a single tetrafunctional block copolymer delivering low dose (10 mg) DNA plasmid rapidly induces protection from detectable viremia during acute infection in mice challenged by ZIKV more than 7 months after their first vaccination and boosted 2 weeks before challenge. This use of tetrafunctional ABCs is a new approach to deliver DNA antigens against flaviviruses. The data demonstrate that DNA formulated by a tetrafunctional block copolymer rapidly elicits protective responses against multiple diverse ZIKV isolates. This represents potential for an easy-to-administer and simple to manufacture vaccine candidate against ZIKV and possibly other emerging threats to global health. Published by Elsevier Ltd.

Background: It is strongly recommended that adults aged 50–75 years be screened for colorectal cancer. Recommended screening options include colonoscopy, sigmoidoscopy, CT colonography, guaiac fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), or the more recently introduced FIT-DNA (FIT in combination with a stool DNA test). Colorectal cancer screening programs can benefit from knowledge of patterns of use by test type and within population subgroups. Methods: Using 2018 National Health Interview Survey (NHIS) data, we examined colorectal cancer screening test use for adults aged 50–75 years (N = 10,595). We also examined time trends in colorectal cancer screening test use from 2010–2018. Results: In 2018, an estimated 66.9% of U.S. adults aged 50–75 years had a colorectal cancer screening test within recommended time intervals. However, the prevalence was less than 50% among those aged 50–54 years, those without a usual source of health care, those with no doctor visits in the past year, and those who were uninsured. The test types most commonly used within recommended time intervals were colonoscopy within 10 years (61.1%), FOBT or FIT in the past year (8.8%), and FIT-DNA within 3 years (2.7%). After age-standardization to the 2010 census population, the percentage up-to-date with CRC screening increased from 61.2% in 2015 to 65.3% in 2018, driven by increased use of stool testing, including FIT-DNA. Conclusions: These results show some progress, driven by a modest increase in stool testing. However, colorectal cancer testing remains low in many population subgroups. Impact: These results can inform efforts to achieve population colorectal cancer screening goals.

Introduction: Underlying structural lesions in congenital heart disease (CHD) result in differences in anatomy and physiology that may affect peak aerobic capacity (VO 2peak ). The relationship between sports participation and VO 2peak is unclear in these patients. The aim of this study was to determine if children with CHD who participated in sports had a higher VO 2peak than those who did not. Methods: Two-year, single-centre, retrospective review (May 2016-November 2018). Fifty-eight CHD patients were included: 9 aortic valve disease; 13 coarctation; 6 Ross procedure for aortic stenosis; 20 tetralogy of Fallot, and 10 transposition of the great arteries. Sports participation was categorized into 3 groups: 0-1 days/week; 2-3 days/week; and ≥4 days/week. A validated institutional treadmill protocol (BCCH) was used. Criteria for a maximal test included: VO 2 plateau, respiratory exchange ratio>1.0, and/or a peak heart rate >200 bpm. VO 2peak z-scores, % VO 2 at ventilatory threshold, and O 2 Pulse were calculated. Medians and interquartile ranges are reported. P Results: Those who participated in sports ≥2-3 days/week had a significantly higher VO 2peak [39.9 (34.6, 48.1) vs 30.3 (27.8, 39.6) mL/min/kg; p2peak z-score [-0.84 (-1.28,-0.30) vs -1.89 (-2.37, -1.16); p=0.002], and O 2 Pulse [0.20 (0.19, 0.25) vs 0.16 (0.14, 0.21) mL/beat/kg; p=0.004] compared to those who participated 0-1 day/week, respectively. There were no differences between those who participated in sports 2-3 days/week and ≥4 days/week. VO 2peak was similar between CHD lesions (p=0.21). Conclusions: VO 2peak is higher in those who participate in sports compared to those who do not. It is unclear whether those who have a higher VO 2peak are more inclined to participate in sports or whether sports participation leads to a higher VO 2peak . The role of exercise rehabilitation in the 0-1 day/week group needs to be explored.

Background\ud Risk factors for further bleeding and ischemic events after acute coronary syndrome (ACS) often overlap. Little is known about sex-based differences in the management and outcomes of ACS patients according to their combined bleeding-ischemic risk.\ud \ud Methods\ud All ACS hospitalizations in the United Kingdom (2010-2017) were retrospectively analyzed, stratified by sex and bleeding-ischemic risk combination (using CRUSADE and GRACE scores). Multivariable logistic regression was performed to examine association between risk-groups and 1) receipt of guideline-recommended management and 2) in-hospital outcomes.\ud \ud Results\ud Of 584,360 patients, a third of males (32.3%) and females (32.6%) were in the dual high-risk group (High CRUSADE- High GRACE). In comparison to the dual low-risk group (Low CRUSADE-Low GRACE), the dual high-risk patients of both sexes were 59-83% less likely to receive coronary angiography (CA) or percutaneous coronary intervention (PCI), 31-34% less likely to receive dual antiplatelet therapy (DAPT) on discharge, with a significant increase in odds of MACE (8-fold), all-cause and cardiac mortality (30 to 40-fold), and bleeding (40-43%). The greatest difference in management and clinical outcomes between sexes was found in the dual-high risk group where females were less likely to receive guideline-recommended therapy (PCI and DAPT), compared to males, and were more likely to experience MACE, all-cause and cardiac mortality.\ud \ud Conclusion\ud ACS patients with dual high-risk for bleeding and recurrent ischemia, especially females, are less likely to receive guideline-recommended therapy and experience significantly worse outcomes. Novel strategies are needed to effectively manage this highly prevalent, complex patient group and address the under-treatment of females.

BackgroundPatients with underlying cardiovascular disease and Coronavirus disease 2019 (COVID-19) infection are at increased risk of morbidity and mortality. However, there is limited information on management and outcomes of patients presenting with acute coronary syndrome (ACS) and concomitant COVID19 infection.ObjectivesThis multisource national analysis of live data from England was designed to characterise the presenting profile and outcomes of patients hospitalized with ACS and COVID-19 infection.MethodsMultisource data from all acute NHS hospital in England was linked to study the characteristics and outcomes of patients hospitalized with COVID-19 ACS compared to non COVID-19 ACS patients. Hierarchical multilevel models were constructed to study the association between COVID19 ACS and in-hospital and 30-day mortality.ResultsBetween 1st March 2020 and 31st May 2020, 517 (4.0%) were admitted with COVID-19 ACS from a total of 12,958 ACS patients. COVID-19 ACS patients were generally older, BAME ethnicity, more comorbid and had unfavourable presenting characteristics compared to non-COVID-19 ACS patients. They were less likely to receive invasive coronary strategy in the form of coronary angiography (67.7% vs 81.0%), PCI (30.2% vs 53.9%), dual antiplatelet medication 76.3% vs 88.0%), and other important secondary medication. Patients with COVID-19 ACS had higher in-hospital (aOR 3.27 95%CI 2.41-4.42) and 30-day mortality (aOR 6.53 95%CI 5.1-8.36) compared to non COVID-19 ACS group.ConclusionCOVID-19 infection is prevalent but less frequent in the patients hospitalized with ACS in England. Presence of COVID-19 infection in patients with ACS is associated with significant mortality hazard.

Background Incretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagon-like peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect. Methods We recruited 41 patients having percutaneous coronary intervention (PCI) for stable angina and allocated them into four groups administering a specific study-related infusion following successful PCI: GLP-1 infusion (Group G) (n = 10); Placebo, normal saline infusion (Group P) (n = 11); GLP-1 + Theophylline infusion (Group GT) (n = 10); and Theophylline infusion (Group T) (n = 10). A pressure wire assessment of coronary distal pressure and flow velocity (thermodilution transit time—Tmn) at rest and hyperaemia was performed after PCI and repeated following the study infusion to derive basal and index of microvascular resistance (BMR and IMR). Results There were no significant differences in the demographics of patients recruited to our study. Most of the patients were not diabetic. GLP-1 caused significant reduction of resting Tmn that was not attenuated by theophylline: mean delta Tmn (SD) group G − 0.23 s (0.27) versus group GT − 0.18 s (0.37), p = 0.65. Theophylline alone (group T) did not significantly alter resting flow velocity compared to group GT: delta Tmn in group T 0.04 s (0.15), p = 0.30. The resulting decrease in BMR observed in group G persisted in group GT: − 20.83 mmHg s (24.54 vs. − 21.20 mmHg s (30.41), p = 0.97. GLP-1 did not increase circulating adenosine levels in group GT more than group T: delta median adenosine − 2.0 ng/ml (− 117.1, 14.8) versus − 0.5 ng/ml (− 19.6, 9.4); p = 0.60. Conclusion The vasodilatory effect of GLP-1 is not abolished by theophylline and GLP-1 does not increase adenosine levels, indicating an adenosine-independent mechanism of GLP-1 coronary vasodilatation. Trial registration: The local research ethics committee approved the study (National Research Ethics Service-NRES Committee, East of England): REC reference 14/EE/0018. The study was performed according to institutional guidelines, was registered on http://www.clinicaltrials.gov (unique identifier: NCT03502083) and the study conformed to the principles outlined in the Declaration of Helsinki.

The object of this study was to explore the use of complementary health approaches among U.S. adults with a cancer diagnosis in the past 5 years and distinguish use for general wellness from use specifically for treatment.Using data from the 2002, 2007, and 2012 National Health Interview Survey, the study included 1359 persons with a cancer diagnosis of selected cancers in the past 5 years. Participants were asked about their use of complementary health approaches for general reasons and cancer treatment in the past 12 months. Responses were aggregated into the use of any complementary approach as well as examined by mode of practice.Overall, 35.3% of persons with a cancer diagnosis used complementary health approaches in the past 12 months. These persons were more likely to have used a biologically based approach (22.8%) compared with other approaches. Persons with breast cancer were significantly more likely to use any complementary health approach (43.6%) compared with those with other recently diagnosed cancers. Few persons with a cancer history (2.3%) used complementary approaches specifically for cancer treatment. However, prevalence of use for treatment varied by cancer type (0.4%-6.8%).This study highlights differences in the use of various types of complementary health approaches for different reasons among persons with recent diagnoses of some of the most commonly diagnosed cancers in the United States.

Metal on metal (MOM) bearings were reintroduced as resurfacing arthroplasty (RA) for the younger, more active patient and were later incorporated into total hip arthroplasty (THA). Early results were encouraging. However, recent publications identified adverse tissue responses to metal debris, such that the majority of MOM designs have been abandoned due to the increase in cobalt-chromium (CoCr) debris and associated metal ions. Reports of MOM THA cited risks that included acetabular cups with high-inclination angles, i.e. “edge-loading”, and “trunnionosis”. Hip impingement was also a cited risk in one MOM study, with “type-IV” wear noted to be a sliding/impaction type of wear, characterized by deep scratches. Sliding/impaction wear mechanisms produced at impingement are not well represented in current MOM literature. Therefore, our objective in this review was to consolidate evidence for impingement risks. We hypothesize that hip impingement and subluxation with metal-backed acetabular cups can trigger wear mechanisms that result in, 1) femoral-neck notching, 2) release of large metal particles, 3) production of uniquely large scratches, defined as “microgrooves” on heads and cups, 4) formation of “polar” and “basal” microgrooves precisely aligning with cup profiles during impingement, and 5) equatorial microgrooves relate to soft-tissue sites of impingement. Relevant risk scenarios were evaluated and included hip impingement in both sitting and standing postures, head subluxation, wear patterns defining in-vivo component positions, and evidence for circulating metal fragments. The study relied on mapping of wear patterns to deduce in-vivo positioning of devices and relied on surrogate femoral stems of the same brand to simulate neck-cup impingement. EOS imaging techniques were used to analyze functional-sitting and functional-standing postures and prove existence of hip impingement sites in patients. The study identified 8-risk scenarios for wear damage on MOM bearings. The microgrooves on femoral-heads crossing the main-wear area (polar) and non-wear regions (basal) aligned well with cuprim profiles at impingement sites. This may represent the first description of such large scratches (40 - 300 μm wide) we termed microgrooves, that formed on femoral heads at sites representative of prosthetic impingement. As an abrasive wear process, similar to the formation of femoral-neck notches, these would have been acquired over millions of gait cycles. The pitting and linear microgrooves crossing the non-wear areas of heads (basal) represented the ingress sites of circulating metal particles. Similar micro-grooves were evident in acetabular cups, also signifying 3rd-body abrasion by large metal particles. Hip impingement and head subluxation were implicated by the unequivocal evidence of 3rd-body abrasive wear as the triggering events producing large metal fragments. One caveat regarding retrieval studies is that such damage may be only representative of failed MOM devices. This study demonstrated that emerging technologies such as EOSTM x-ray analyses can reveal subtle changes in implant positioning using patient shifts in functional postures (sitting, standing, hyper-extension, etc.), and thereby assess impingement/subluxation risks in the clinical setting before failure occurs.

Introduction: Infectious disease remains a significant burden in the UK and the focus of significant amounts of research investment each year. The Research Investments in Global Health study has systematically assessed levels of funding for infection research, and here considers investment alongside UK burden of individual infectious diseases. Methods: The study included awards to UK institutions between 1997-2013 that were related to infectious disease. Awards related to global health projects were excluded here. UK burden data (mortality, years lived with disability, and disability adjusted life years ) was sourced from the Global Burden of Disease study (IHME, USA). Awards were categorised by pathogen, disease, disease area and by type of science along the research pipeline (pre-clinical, phase I-III trials, product development, public health, cross-disciplinary research). New metrics present relative levels of funding by comparing sum investment with measures of disease burden. Results: There were 5685 relevant awards comprising investment of £2.4 billion. By disease, HIV received most funding (£369.7m; 15.6% of the total investment). Pre-clinical science was the predominant type of science (£1.6 billion, 68.7%), with the UK Medical Research Council (MRC) the largest funder (£714.8 million, 30.1%). There is a broad temporal trend to increased funding per annum. Antimicrobial resistance received (£102.8 million, 4.2%), whilst sepsis received £23.6 million (1.0%). Compared alongside disease burden, acute hepatitis C and measles typically were relatively well-funded, whilst pneumonia, syphilis and gonorrhoea were poorly-funded. Conclusions: The UK has a broad research portfolio across a wide range of infectious diseases and disciplines. There are notable strengths including HIV, some respiratory infections and in pre-clinical science, though there was less funding for UK-relevant trials and public health research. Compared to the UK burden of disease, syphilis, gonorrhoea and pneumonia appear relatively neglected. Investment analyses can assist support policymakers to increase the equity of the UK R&D landscape.

Human microbiomes have received increasing attention over the last 10 years, leading to a pervasiveness of hypotheses relating dysbiosis to health and disease. The respiratory tract has received much less attention in this respect than that of, for example, the human gut. Nevertheless, progress has been made in elucidating the immunological, ecological and environmental drivers that govern these microbial consortia and the potential consequences of aberrant microbiomes. In this review, we consider the microbiome of the nasopharynx, a specific niche of the upper respiratory tract. The nasopharynx is an important site, anatomically with respect to its gateway position between upper and lower airways, and for pathogenic bacterial colonisation. The dynamics of the latter are important for long-term respiratory morbidity, acute infections of both invasive and non-invasive disease and associations with chronic airway disease exacerbations. Here, we review the development of the nasopharyngeal (NP) microbiome over the life course, examining it from the early establishment of resilient profiles in neonates through to perturbations associated with pneumonia risk in the elderly. We focus specifically on the commensal, opportunistically pathogenic members of the NP microbiome that includes Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis. In addition, we consider the role of relatively harmless genera such as Dolosigranulum and Corynebacterium. Understanding that the NP microbiome plays such a key, beneficial role in maintaining equilibrium of commensal species, prevention of pathogen outgrowth and host immunity enables future research to be directed appropriately.

Intra-operative acute hypersensitivity reactions require a decision to be made regarding whether to proceed with or abandon the planned surgical procedure once the patient has stabilised. Using retrospective case controls, we examined all cases (223) of proven acute hypersensitivity reactions from 2005 to 2014 in Western Australia, in which the syndrome was recognised by the treating clinician before or during surgery, to determine whether recovery outcomes were adversely affected by proceeding with the planned procedure. Surgery proceeded in 104 patients (47%) and was abandoned in 119 (53%). The severity of acute hypersensitivity reactions was Société Française d'Anesthésie et de Réanimation grade 1 or 2 in 56 patients (25%), grade 3 in 128 (56%) and grade 4 in 39 (17%). Abandoning surgery was more common in patients with increasing severity of hypersensitivity. The rate of major hypersensitivity-related complications for all patients was zero for grade 1 and 2 reactions, 4.7% for grade 3 and 12.8% for grade 4. There were no deaths. Patients in whom surgery was completed were not observed to have a higher frequency of major hypersensitivity-related complications when compared with cases of similar severity in whom surgery was abandoned. For patients admitted to the intensive care unit, proceeding with surgery was not associated with an increased duration of mechanical ventilation of the lungs. Our results suggest that, once initial resuscitation has been achieved and if resuscitative efforts can be re-instituted if required, continuing with planned surgery in grade 1, 2 and 3 immediate hypersensitivity was not associated with poorer outcomes. After grade 3 reactions, there was a significant incidence of complications attributable to acute hypersensitivity regardless of whether surgery proceeded or was abandoned. Surgery was frequently abandoned in grade 4 immediate hypersensitivity and was associated with a high rate of complications.

Bacterial biofilms show high tolerance towards antibiotics and are a significant problem in clinical settings where they are a primary cause of chronic infections. Novel therapeutic strategies are needed to improve anti-biofilm efficacy and support reduction in antibiotic use. Treatment with exogenous nitric oxide (NO) has been shown to modulate bacterial signaling and metabolic processes that render biofilms more susceptible to antibiotics. We previously reported on cephalosporin-3’-diazeniumdiolates (C3Ds) as NO-donor prodrugs designed to selectively deliver NO to bacterial infection sites following reaction with β-lactamases. With structures based on cephalosporins, C3Ds could, in principal, also be triggered to release NO following β-lactam cleavage mediated by transpeptidases/penicillin-binding proteins (PBPs), the antibacterial target of cephalosporin antibiotics. Transpeptidase-reactive C3Ds could potentially show both NO-mediated anti-biofilm properties and intrinsic (β-lactam-mediated) antibacterial effects. This dual-activity concept was explored using Streptococcus pneumoniae, a species that lacks β-lactamases but relies on transpeptidases for cell-wall synthesis. Treatment with PYRRO-C3D (a representative C3D containing the diazeniumdiolate NO donor PYRRO-NO) was found to significantly reduce viability of planktonic and biofilm pneumococci, demonstrating that C3Ds can elicit direct, cephalosporin-like antibacterial activity in the absence of β-lactamases. While NO release from PYRRO-C3D in the presence of pneumococci was confirmed, the anti-pneumococcal action of the compound was shown to arise exclusively from the β-lactam component and not through NO-mediated effects. The compound showed similar potency to amoxicillin against S. pneumoniae biofilms and greater efficacy than azithromycin, highlighting the potential of C3Ds as new agents for treating pneumococcal infections.

For more than 20 years, researchers have used laboratory mice lacking type I or both type I and type II interferon (IFN) responses to study viruses that cause hemorrhagic fever (HF) in humans. Whereas immunocompetent mice do not become ill when infected with Ebola, Lassa, dengue and other HF viruses, IFN-deficient mice typically develop severe or fatal disease when inoculated with these pathogens. The ease of employment of these "mouse models" has led to their extensive use in biocontainment laboratories to assess the efficacy of novel vaccines, often without consideration of whether adaptive immune responses in IFN-deficient mice accurately mirror those in humans. Failure to consider these questions may lead to inappropriate expectations of the predictive value of mouse experiments. In two invited articles, we investigate this question. This paper examines how the lack of type I or both type I and type II IFN signaling may affect the development of adaptive immune responses in mice and the outcome of vaccine studies. A second article reviews the published literature on the use of IFN-deficient mice for the assessment of novel vaccines against HF viruses.

Background The diagnosis of cellulitis is made clinically without a gold standard diagnostic test, and cellulitis has many disease mimics. There is currently no consensus for optimal antimicrobial treatment duration or method of antimicrobial delivery. Methods This was a randomized controlled open-label multicenter trial to determine the safety and efficacy of 24 hours of intravenous (IV) therapy compared with ≥72 hours of IV therapy, both followed by oral therapy to a maximum of 7–10 days’ duration for the treatment of lower limb cellulitis. Results Over 40 months, 80 patients were recruited. Thirty-nine patients were assigned to 24 hours of IV antibiotics and 41 to ≥72 hours of IV antibiotics. The mean duration (range) of IV antibiotics in the 24-hour group was 25.5 (17–40) hours, and in the ≥72-hour group it was 78 (41.5–210) hours. Three patients in the 24-hour arm and 4 patients in the ≥72-hour arm were excluded from the analysis due to withdrawal from the trial. Analysis of the remaining patients revealed that 6 patients (4 in the intervention arm and 2 in the control arm) did not achieve an adequate response to therapy. Only 1 patient experienced self-limiting adverse effects of treatment. Conclusions The noninferiority of short-course IV therapy cannot be determined from this trial. Challenges included resource limitations for recruitment, misdiagnosis, participant withdrawal, and subjective responses to therapy based on visual assessment by treating clinicians. Further studies are needed to determine if short-course IV therapy is a suitable treatment option. Australia Council of Clinical Trials Registry No ACTRN12613001366741.

Background Treatment of superficial venous reflux in addition to compression therapy accelerates venous leg ulcer healing and reduces ulcer recurrence. The aim of this study was to evaluate the costs and cost-effectiveness of early versus delayed endovenous treatment of patients with venous leg ulcers. Methods This was a within-trial cost-utility analysis with a 1-year time horizon using data from the EVRA (Early Venous Reflux Ablation) trial. The study compared early versus deferred endovenous ablation for superficial venous truncal reflux in patients with a venous leg ulcer. The outcome measure was the cost per quality-adjusted life-year (QALY) over 1 year. Sensitivity analyses were conducted with alternative methods of handling missing data, alternative preference weights for health-related quality of life, and per protocol. Results After early intervention, the mean(s.e.m.) cost was higher (difference in cost per patient £163(318) (€184(358))) and early intervention was associated with more QALYs at 1 year (mean(s.e.m.) difference 0·041(0·017)). The incremental cost-effectiveness ratio (ICER) was £3976 (€4482) per QALY. There was an 89 per cent probability that early venous intervention is cost-effective at a threshold of £20 000 (€22 546)/QALY. Sensitivity analyses produced similar results, confirming that early treatment of superficial reflux is highly likely to be cost-effective. Conclusion Early treatment of superficial reflux is highly likely to be cost-effective in patients with venous leg ulcers over 1 year. Registration number: ISRCTN02335796 (http://www.isrctn.com).

Summary Perioperative hypersensitivity reactions (POH) constitute a clinical and diagnostic challenge, a consequence of heterogeneous clinical presentations, and multiple underlying pathomechanisms. POH do not necessarily involve an allergen-specific immune response with cross-linking of specific immunoglobulin E (sIgE) antibodies on mast cells and basophils. POH can also result from alternative specific and non-specific effector cell activation/degranulation such as complement-derived anaphylatoxins and off-target occupancy of mast cell, basophil, or both surface receptors. Moreover, POH and anaphylaxis can occur independent from mast cell and basophil degranulation. The manifestations of POH primarily affect the cardiovascular, respiratory, and integumentary systems. POH present within the context of surgical or procedural pathology and the effects of surgical and anaesthetic techniques on pre-existing physiological reserve. The majority of cases of appropriately-treated intraoperative anaphylaxis can be considered a compensated cardiovascular anaphylaxis. With increasing severity of anaphylaxis, maldistribution and hypovolaemia lead to reduced venous return and circulatory failure. Treatment with a combination of epinephrine and i.v. fluid is critical for successful resuscitation, although the excessive use of epinephrine without adequate volume expansion may be deleterious. Neural control of the airways is important in the pathophysiology of bronchospasm. Anticholinergic drug premedication is beneficial in patients with hyperreactive airways. Pulmonary oedema can result from a combination of pulmonary capillary hypertension, incompetence of the alveolocapillary membrane, or both. Angioedema can be distinguished mechanistically into histaminergic and non-histaminergic (e.g. bradykinin-mediated). An understanding of the molecular mechanisms and pathophysiology of POH are essential for the immediate management and subsequent investigation of these cases.

Suspected perioperative allergic reactions are rare but can be life-threatening. The diagnosis is difficult to make in the perioperative setting, but prompt recognition and correct treatment is necessary to ensure a good outcome. A group of 26 international experts in perioperative allergy (anaesthesiologists, allergists, and immunologists) contributed to a modified Delphi consensus process, which covered areas such as differential diagnosis, management during and after anaphylaxis, allergy investigations, and plans for a subsequent anaesthetic. They were asked to rank the appropriateness of statements related to the immediate management of suspected perioperative allergic reactions. Statements were selected to represent areas where there is a lack of consensus in existing guidelines, such as dosing of epinephrine and fluids, the management of impending cardiac arrest, and reactions refractory to standard treatment. The results of the modified Delphi consensus process have been included in the recommendations on the management of suspected perioperative allergic reactions. This paper provides anaesthetists with an overview of relevant knowledge on the immediate and postoperative management of suspected perioperative allergic reactions based on current literature and expert opinion. In addition, it provides practical advice and recommendations in areas where consensus has been lacking in existing guidelines.

Invasive pneumococcal infection is a major cause of morbidity and mortality worldwide despite the availability of pneumococcal vaccines. The aim of this study was to re-evaluate the clinical syndromes, prognostic factors and outcomes for pneumococcal disease in adults and children in Singapore during the period before and after the introduction of the pneumococcal vaccine. We retrospectively analyzed a large cohort of patients admitted to the four main public hospitals in Singapore with S. pneumoniae infection between 1997 and 2013. A total of 889 (64% of all isolates identified in the clinical laboratories) cases were included in the analysis; 561 (63.1%) were adult (≥16 years) cases with a median age of 62 years and 328 (36.9%) were paediatric cases with a median age of 3 years. Bacteraemic pneumonia was the most common syndrome in both groups (69.3% vs. 44.2%), followed by primary bacteraemia without pneumonia (14.3% vs. 13.4%), meningitis (6.4% vs. 7.6%) and non-bacteraemic pneumonia (5.2% vs. 21%). The major serotypes in adults were 3, 4, 6B, 14, 19F and 23F whereas in children they were 14, 6B and 19F, accounting both for nearly half of pneumococcal disease cases. No particular serotype was associated with mortality or severity of the pneumococcal disease. Overall mortality rate was 18.5% in adults and 3% in children. Risk factors for mortality included acute cardiac events in adults, meningitis in children and critical illness and bilateral pulmonary infiltrates in both adults and children. Penicillin resistance was not associated with increased mortality. Our results agree with global reports that the course of pneumococcal disease and its clinical outcome were more severe in adults than in children. The main serotypes causing invasive disease were mostly covered by the vaccines in use. The high mortality rates reflect an urgent need to increase vaccination coverage in both adults and children to tackle this vaccine-preventable infection.

We describe a case of severe left ventricular outflow tract obstruction (LVOTO) with severe mitral incompetence due to systolic anterior motion of the anterior mitral leaflet (SAM) that was recognised thanks to the immediate availability of transoesophageal echocardiography during the resuscitation of anaphylactic shock. The patient rapidly responded to cessation of the epinephrine (adrenaline) infusion and intravascular volume expansion with intravenous crystalloid. The absence of risk factors for developing SAM/LVOTO serve as a warning to clinicians to consider this diagnosis in all cases of epinephrine non-responsive anaphylactic shock.

Background The most common trigger for intraoperative anaphylaxis in Western Australia for the period 2014–5 was an antibiotic used for surgical prophylaxis, cefazolin. In these patients who subsequently present for surgery, alternative cephalosporins are forbidden by current guidelines because of concerns regarding an increased risk of anaphylaxis. However, consideration of the structure–activity relationships relevant to anaphylaxis suggests that cefalotin is a safe alternative because of structural dissimilarities, although there are no pubished clinical data relevant to the perioperative setting. Methods Patients diagnosed with intraoperative anaphylaxis to cefazolin at the Western Australian Anaesthetic Allergy Clinic were tested with intradermal cefalotin and, if negative, subsequently challenged i.v. If tolerated, cefalotin was recommended for subsequent surgery, and subjects were followed up to determine the safety of subsequent intraoperative doses. Results Twenty-one subjects diagnosed with immediate hypersensitivity to cephazolin, including 19 subjects with confirmed anaphylaxis, participated. None tested positive to intradermal cefalotin, and all received a graded i.v. challenge to cefalotin without developing signs or symptoms of anaphylaxis. Three subjects subsequently received intraoperative cefalotin 12–139 days later without adverse events. Conclusions A negative intradermal cefalotin skin test has a good negative predictive value in patients who have previously suffered anaphylaxis to cefazolin, allowing the rational and desirable use of this alternative cephalosporin for future surgery and the avoidance of less desirable antimicrobial agents.

Gastrointestinal (GI) symptoms of nausea, vomiting, and abdominal pain are common in patients with orthostatic intolerance (OI), including neurally mediated hypotension (NMH) and postural orthostatic tachycardia syndrome (POTS). Autonomic dysregulation is considered the underlying pathophysiology behind the cardiovascular symptoms of POTS. Because the autonomic nervous system also regulates GI motility, we hypothesized that patients with POTS and GI symptoms will have evidence of autonomic dysmotility of the upper GI tract.Thirty-five subjects with OI and GI symptoms were studied. All the subjects had a 24-hour antroduodenal manometry (ADM) study, in conjunction with pharmacologic challenge and autonomic and tilt table testing (TTT).The mean subject age was 16.2 ± 2.8 years (range 10-23.8 years), and male to female ratio was 10:25. TTT was abnormal in all the 35 subjects, whereas Valsalva testing was abnormal (+40 mmHG) in 21 of 34 (62%) subjects, and corrected QT interval was ≥0.44 seconds in 19 of 35 (54%) subjects. During TTT, GI symptoms were reproduced in 31 of 35 (89%) studies. ADM was found to be abnormal at baseline, before the TTT in 5 of 35 (14%) subjects, whereas it became abnormal in 23 of 34 (68%) subjects during TTT. In addition, the expected response to the pharmacologic challenge was limited. Overall, ADM was abnormal in 26 of 35 (74%) patients either at baseline or during TTT in these subjects with OI.ADM is frequently abnormal in children with OI and GI symptoms. Upper GI motility studies should be a part of the comprehensive evaluation in this population.

Objectives To compare patterns of emergency department (ED) use and inpatient admission rates for elderly adults with cancer with a poor prognosis who enrolled in hospice to those of similar individuals who did not. Design Matched case–control study. Setting Nationally representative sample of Medicare fee-for-service beneficiaries with cancer with a poor prognosis who died in 2011. Participants Beneficiaries in hospice matched to individuals not in hospice on time from diagnosis of cancer with a poor prognosis to death, region, age, and sex. Measurements Comparison of ED use and inpatient admission rates before and after hospice enrollment for beneficiaries in hospice and controls. Results Of 272,832 matched beneficiaries, 81% visited the ED in the last 6 months of life. At baseline, daily ED use and admission rates were not significantly different between beneficiaries in and not in hospice. By the week before death, nonhospice controls averaged 69.6 ED visits/1,000 beneficiary-days, versus 7.6 for beneficiaries in hospice (rate ratio (RR) = 9.7, 95% confidence interval (CI) = 9.3–10.0). Inpatient admission rates in the last week of life were 63% for nonhospice controls and 42% for beneficiaries in hospice (RR = 1.51, 95% CI = 1.45–1.57). Of all beneficiaries in hospice, 28% enrolled during inpatient stays originating in EDs; they accounted for 35.7% (95% CI = 35.4–36.0%) of all hospice stays of less than 1 month and 13.9% (95% CI = 13.6–14.2%) of stays longer than 1 month. Conclusion Most Medicare beneficiaries with cancer with a poor prognosis visited EDs at the end of life. Hospice enrollment was associated with lower ED use and admission rates. Many individuals enrolled in hospice during inpatient stays that followed ED visits, a phenomenon linked to shorter hospice stays. These findings must be interpreted carefully given potential unmeasured confounders in matching.

Purpose Cancer affects a growing proportion of US workers. Factors contributing to whether they continue or return to work after cancer diagnosis include: age, physical and mental health, health insurance, education, and cancer site. The purpose of this study was to assess the complex relationships between health indicators and employment status for adult cancer survivors. Methods We analyzed pooled data from the 1997–2012 US National Health Interview Survey (NHIS). Our sample included adults with a self-reported physician diagnosis of cancer ( n = 24,810) and adults with no cancer history ( n = 382,837). Using structural equation modeling (SEM), we evaluated the relationship between sociodemographic factors, cancer site, and physical and mental health indicators on the overall health and employment status among adults with a cancer history. Results The overall model for cancer survivors fit the data well (χ 2 (374) = 3654.7, P Conclusions A proportion of cancer survivors may continue to work because of employment-based health insurance despite reporting poor health and significant physical and mental health limitations. Acute and long-term health and social support are essential for the continued productive employment and quality of life of all cancer survivors.

A 50-year-old man developed a severe anaphylactic reaction shortly after the administration of sugammadex at the end of an uneventful laparoscopic appendectomy. Subsequent skin testing was negative to all agents to which the patient was exposed including sugammadex. Because of the temporal relationship to the administration of sugammadex, further skin testing was performed with premixed sugammadex and rocuronium that produced a markedly positive response. This is the first case report of anergy to the individual components but sensitivity to the inclusion complex of rocuronium and sugammadex. Written informed consent was obtained from the patient for skin testing, photography, laser perfusion imaging, and publication of this case report.

Background: The systemic and ocular manifestations of diabetes are an increasing burden on both private and public healthcare systems. The ability to accurately predict patient susceptibility and prognostic implications of the disease is essential to its optimal management and planning. Aim: The purpose of this paper was to review alternative biomarkers to those currently in use regarding the diagnosis and prognosis of diabetes and the ocular effects of the disease. Current biomarkers include Fasting Plasma Glucose (FPG), Oral Glucose Tolerance Test (OGTT) and Glycolated Haemoglobin (HbA1c). Methods: The research strategy comprised of a comprehensive literature review of articles from Mendeley, Cochrane and Elsevier with additional input from experts in the field serving as co-authors. Results: The review found that there are alternative biomarkers to those currently utilised. These include adiponectin, apolipoprotein B, C-reactive protein and ferritin. Fructosamine, while useful where whole blood is available, is unreliable as a diagnostic biomarker resulting in a 10% variation coefficient. Post-prandial glucose (PPG) measurement most closely predicted HbA1c. Conclusion: With prediction of risk for diabetes in individuals, a value combination, expressed as either a numerical score or a percentage, consisting of adiponectin, apolipoprotein B, C-reactive protein and ferritin, almost doubled the relative risk of contracting the disease. Eye care practitioners need to question diabetic patients about their FPG and HbA1c levels and encourage them to have the relevant tests regularly, including PPG. The importance of biomarkers should be emphasised and used as an educational tool to facilitate better diabetes management and treatment adherence.

Research conducted within the Cognitive Bias Modification (CBM) paradigm has revealed that cognitive biases such as negative cognitive interpretation biases contribute to mental health disorders such as anxiety (Beard, 2011). It has been shown that exercise reduces anxiety (Ensari, Greenlee, Motl, & Petruzzello, 2015). Exercise has also been found to reduce negative cognitive attention biases (Tian & Smith, 2011), however no research to date has investigated the effect of exercise on cognitive interpretation bias. The key aims of the current project is to investigate whether moderate exercise reduces self-reported symptoms of depression and stress. Additionally, to establish which intensity of exercise is required to achieve anxiety reduction and reduce an individual’s negative cognitive interpretation biases. Study one recruited a healthy sample of adult participants who were randomly assigned to one of two conditions: a walking exercise protocol or a control condition (n=2x12). Participants completed anxiety and cognitive interpretation bias measures before and after the walking exercise or control condition. Those in the walking exercise condition presented less symptoms of trait anxiety on a measure of state and trait anxiety inventory (STAI), compared to controls relative to baseline measures following the intervention. Study two recruited frequent exercisers who were assigned to an exercise or control group (n=2x24). Participants completed anxiety, depression, psychological stress and cognitive interpretation bias measures before and after the exercise or control condition. Following the intervention, negative interpretation biases decreased in the exercise group and stayed stable in the control group. The exercise group also had significantly decreased anxiety, depression and stress measures after the exercise condition, whilst controls did not. The research concludes that CBM holds promise for the management of mood disorders and exercise is an effective accompaniment to psychotherapy.

Background: Recent developments in vision restoration include visual prostheses designed to electrically stimulate artificial vision in those who have lost their sight. Major efforts in this area include multi-electrode arrays surgically implanted at various placement areas throughout the visual pathway. Visual prosthetic devices are named according to these placement areas (cortical, optic nerve, sub-retinal and epiretinal). These devices attempt to restore sight for retinal degenerative diseases such as Retinitis Pigmentosa (RP) and Age-related Macular Degeneration (AMD). Aim: To summarise the emerging technologies in the development of artificial ocular devices. Methods: The search methodology comprised seven databases for articles published between January 2000 and March 2017. Outcome data were analysed descriptively with results summarised in a Microsoft Excel database. Both quantitative and qualitative methodologies were used, and the main findings are discussed in a narrative format. Results: Eighty-nine full-text articles were included in this systematic review. Conclusion: The primary goal of these artificial devices is to provide functional vision in order to perform normal daily activities. Even though recent clinical trials in certain countries have shown advances in the development of various vision-restoring devices, they do not produce the same experience for the majority of patients and are unable to completely restore normal vision. The most common type of device according to its placement is the epiretinal device which is also the most successful device as determined in the majority of clinical trials.

Background COPD patients have increased risk of developing pneumonia, which is associated with poor outcomes. It can be symptomatically indistinguishable from exacerbations, making diagnosis challenging. Studies of pneumonia in COPD have focused on hospitalised patients and are not representative of the ambulant COPD population. Therefore, we sought to determine the incidence and aetiology of acute exacerbation events with evidence of pneumonic radiographic infiltrates in an outpatient COPD cohort. Methods One hundred twenty-seven patients with moderate to very severe COPD aged 42–85 years underwent blood and sputum sampling over one year, at monthly stable visits and within 72 h of exacerbation symptom onset. 343 exacerbations with chest radiographs were included. Results 20.1% of exacerbations had pneumonic infiltrates. Presence of infiltrate was highly seasonal (Winter vs summer OR 3.056, p = 0.027). In paired analyses these exacerbation events had greater increases in systemic inflammation. Bacterial detection rate was higher in the pneumonic group, with Haemophilus influenzae the most common bacteria in both radiological groups. Viral detection and sputum microbiota did not differ with chest radiograph appearance. Conclusions In an outpatient COPD cohort, pneumonic infiltrates at exacerbation were common, and associated with more intense inflammation. Bacterial pathogen detection and lung microbiota were not distinct, suggesting that exacerbations and pneumonia in COPD share common infectious triggers and represent a continuum of severity rather than distinct aetiological events. Trial registration Trial registration Number: NCT01360398. Electronic supplementary material The online version of this article (10.1186/s12931-018-0842-8) contains supplementary material, which is available to authorized users.

This article presents a case of ethambutol toxic optic neuropathy determined during the routine optometric examination of a 66-year-old man. Ethambutol is an established drug for the treatment of tuberculosis, but has significant side effects, notably optic neuropathy. The prognosis for vision restoration is unpredictable, with the possibility of permanent vision loss. Treatment cessation is the only option to limit ocular damage; therefore, the early recognition of ethambutol optic neuropathy by optometrists is essential.

Background: Uncorrected refractive error is a major cause of avoidable vision impairment and may have significant impact on social life, education and economic prospects of people. This condition could be easily treated by wearing spectacles, but because of attitudes and misconceptions of some communities towards spectacle wear and eye care, such methods are underutilised. Aim: To assess the attitudes and perceptions of Sudanese high-school students and their parents towards spectacle wear. Setting: The study was conducted in eight randomly selected high schools from the South Darfur state of Sudan. Methods: A cross-sectional school-based study comprising 387 high-school students with age ranging from 12 to 17 years together with 47 students’ parents with age ranging from 32 to 52 years. Quantitative and qualitative methods were used to collect data from eight high schools. Semi-structured questionnaires were distributed to collect the quantitative data, and seven focus group meetings were held in the schools with students’ parents to derive the qualitative data. Results: The findings revealed that 39%, 32% and 27.1% of the students believed that wearing spectacles affected their opportunities for education, employment and marriage, respectively. A total of 36.4% of the students believed that wearing spectacles could lead to making the eyes weaker or could damage the eyes, resulting in early blindness, and 22.5% of the respondents believed that spectacles were only for older people. In general, the perception towards spectacle wear was different between genders, with females appearing to be more vulnerable to social and psychological distress when wearing spectacles compared to males. A total of 79% of the parents were aware that wearing spectacles would improve vision if an eye doctor prescribed the spectacles. However, parents reported that the disadvantages of wearing spectacles were that they reduced the power of the eyes and spectacle wear had psychological effects, particularly among females. Parents felt that their children had lost an important asset, that the community looked at them as handicapped and that their children would be blind in future. Conclusion: The fear and stigma related to the use of spectacles are widely experienced among students and their parents in Sudan, and particularly among females. Eye health education programmes should be broadcast through the public media to promote awareness and benefits about spectacle wear and eye care.

Background COPD is a complex, heterogeneous disease characterised by progressive development of airflow limitation. Spirometry provides little information about key aspects of pathology and is poorly related to clinical outcome, so other tools are required to investigate the disease. We sought to explore the relationships between quantitative CT analysis with functional, inflammatory and infective assessments of disease to identify the utility of imaging to stratify disease to better predict outcomes and disease response. Methods Patients from the AERIS study with moderate-very severe COPD underwent HRCT, with image analysis determining the quantity of emphysema (%LAA