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Background: Chronic rhinosinusitis with nasal polyps affects approximately 2–4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps. Methods: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49–52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797. Findings: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians −0·73, 95% CI −1·11 to −0·34; p

Background Despite interest among North American orthopaedic residents to pursue rotations in resource-limited settings, little is known regarding resident motivations and impact on host surgeons. Methods Surveys were distributed to North American orthopaedic surgeons and trainees who participated in international rotations during residency to assess motivations for participation and to orthopaedic surgeons at partnering low- and middle-income country (LMIC) institutions to assess impact of visiting trainees. Results Responses were received from 136 North American resident rotators and 51 LMIC host surgeons and trainees. North American respondents were motivated by a desire to increase surgical capacity at the LMIC while host surgeons reported a greater impact from learning from residents than on surgical capacity. Negative aspects reported by hosts included selfishness, lack of reciprocity, racial discrimination, competition for surgical experience, and resource burdens. Conclusions The motivations and impact of orthopaedic resident rotations in LMICs need to be aligned. Host perceptions and bidirectional educational exchange should be incorporated into partnership guidelines.

Author(s): Artenstein, Andrew W.; Rathlev, Niels K.; Neal, Douglas; Townsend, Vernette; Vemula, Michael; Goldlust, Sheila; Schmidt, Joseph; Visintainer, Paul | Abstract: Introduction: Patient progress, the movement of patients through a hospital system from admission todischarge, is a foundational component of operational effectiveness in healthcare institutions. Optimalpatient progress is a key to delivering safe, high-quality and high-value clinical care. The Baystate PatientProgress Initiative (BPPI), a cross-disciplinary, multifaceted quality and process improvement project, waslaunched on March 1, 2014, with the primary goal of optimizing patient progress for adult patients.Methods: The BPPI was implemented at our system’s tertiary care, academic medical center, a highvolume,high-acuity hospital that serves as a regional referral center for western Massachusetts. TheBPPI was structured as a 24-month initiative with an oversight group that ensured collaborative goalalignment and communication of operational teams. It was organized to address critical aspects ofa patient’s progress through his hospital stay and to create additional inpatient capacity. The specificgoal of the BPPI was to decrease length of stay (LOS) on the inpatient adult Hospital Medicine serviceby optimizing an interdisciplinary plan of care and promoting earlier departure of discharged patients.Concurrently, we measured the effects on emergency department (ED) boarding hours per patient andwalkout rates.Results: The BPPI engaged over 300 employed clinicians and non-clinicians in the work. We createdincreased inpatient capacity by implementing daily interdisciplinary bedside rounds to proactively addresspatient progress; during the 24 months, this resulted in a sustained rate of discharge orders writtenbefore noon of more than 50% and a decrease in inpatient LOS of 0.30 days (coefficient: -0.014, 95%CI [-0.023, -0.005] Pl 0.005). Despite the increase in ED patient volumes and severity of illness overthe same time period, ED boarding hours per patient decreased by approximately 2.1 hours (coefficient:-0.09; 95% CI [-0.15, -0.02] P = 0.007). Concurrently, ED walkout rates decreased by nearly 32% to amonthly mean of 0.4 patients (coefficient: 0.4; 95% CI [-0.7, -0.1] P= 0.01).Conclusion: The BPPI realized significant gains in patient progress for adult patients by promotingearlier discharges before noon and decreasing overall inpatient LOS. Concurrently, ED boarding hoursper patient and walkout rates decreased.

Prevalence of type 2 diabetes mellitus has significantly increased in the last three decades and currently affects about 1 in 10 globally. A common therapeutic target for type 2 diabetes is α- glucosidase, an essential enzyme located at the brush border of the small intestinal epithelium. The inhibition of α-glucosidase results in a reduced digestion of carbohydrates and a decrease of postprandial blood glucose. Although, synthetic inhibitors are available in the market, these are usually associated with significant gastrointestinal side effects. In this study, natural inhibitors derived from edible brown algae are being investigated as an alternative.Polysaccharide- and polyphenolic-enriched extracts from Ascophyllum nodosum and Fucus vesiculosus were characterized and screened for their inhibitory effects against α-glucosidase obtained from rat intestine using maltose, sucrose, and p-nitrophenyl (pNPG) as substrates. Acarbose was used as a synthetic inhibitor. Furthermore, enzyme kinetics and mechanism of inhibition of α- glucosidase were determined using linear and non-linear regression methods (GraphPad Prism ver. 6, GraphPad Software, La Jolla California USA).All tested extracts showed a dose-dependent inhibitory effect against α-glucosidase. However, the type of inhibition varied between the extracts. Most importantly, the composition analysis showed that the seaweed extracts had different polysaccharide and phenolic contents, suggesting different mode of actions against α-glucosidase. The relation between chemical composition and inhibitory activity of the compounds are discussed.In summary, the current study demonstrates the mechanisms in which different brown seaweed extracts with various composition effectively inhibit α-glucosidase. Therefore, this natural inhibitor can be considered as a potential candidate for the management of type 2 diabetes mellitus.

OBJECTIVE: To compare the accuracy and reasons for disagreement of two-dimensional (2D) and three-dimensional (3D) echocardiography findings in the assessment of the atrioventricular valve complex in patients with atrioventricular septal defect. METHODS: A total of 20 children (mean age 8 months) with atrioventricular septal defect were enrolled prospectively into this study. The accuracy of and the reasons for disagreement in the assessment of the atrioventricular valve features were analyzed between 2D and 3D echocardiography and surgical findings. RESULTS: We found that in assessing the Rastelli type and the extension of the inferior leaflet into the right ventricle, 3D echocardiography was more accurate compared to 2D echocardiography. In all other features, 2D and 3D echocardiography showed similar accuracy. A significant reason for inaccuracy by both echo modalities was that the technique itself could not visualize the feature, although the image quality was considered to be adequate. In most cases, where it was not possible to visualize the atrioventricular feature by 2D, it was possible by 3D, and vice versa. CONCLUSION: The accuracy of 2D and 3D echocardiography and understanding the potential reasons for disagreements in assessing the atrioventricular valve complex with 2D and 3D can guide the use of those two techniques when combining them in the clinical practice. (Less)

Leveraging the recent development of a physical implementation of arbitrary polyphase codes as spectrally well-contained waveforms, the notion of spatial modulation is developed whereby a time-varying beampattern is incorporated into the physical emission of an individual pulse. This subset of the broad category of MIMO radar is inspired by the operation of fixational eye movement within the human eye to enhance visual acuity and also subsumes the notion of the frequency-diverse array for application to pulsed radar. From this spatial modulation framework, some specific emission examples are evaluated in terms of resolution and sidelobe levels for the delay and angle domains. The impact of spatial modulation upon spectral content is also considered and possible joint delay-angle emission design criteria are suggested. Simulation results of selected target arrangements demonstrate the promise of enhanced discrimination and the basis for the development of future cognitive radar capabilities that may mimic salient aspects of the visual cortex.

Acute cellular rejection (ACR) the first year after heart transplantation (HT) and its impact on survival was investigated. All 215 HT patients at our centre 1988-2010, including 219 HTs and 2990 first-year endomyocardial biopsies (EMBs), were studied. 'Routine' EMBs obtained 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40 and 52 weeks after HT, and 'additional clinically indicated' (ACI) EMBs, were graded according to the 1990-ISHLT-WF. The frequency and severity of first-year ACRs was low, with 6.5% of routine EMBs and 14.1% of ACI EMBs showing ACR ≥ grade 2. Proportionally more (P < 0.05) first-year ACRs ≥ grade 2 were found among EMBs in HTs performed during 1988-1999 (9.6%) than 2000-2010 (5.5%), EMBs performed during 16-52 weeks (8.8%) than 1-12 weeks (6.3%) after HT, EMBs in HTs with paediatric (11.3%) than adult (7.1%) donors, and EMBs in sex-mismatched (10.4%) than sex-matched (6.3%) HTs. Five- and ten-year survival was furthermore lower (P < 0.05) among HTs with ≥ 1 compared with 0 first-year ACRs ≥ grade 3A/3B (82% vs. 92% and 69% vs. 82%, respectively). Ten-year survival was 74% compared with 53% in the ISHLT registry. In conclusion, our results indicate that first-year ACRs ≥ grade 3A/3B affect long-term survival. We believe frequent first-year EMBs may allow early ACR detection and continuous immunosuppressive adjustments, preventing low-grade ACRs from progressing to ACRs ≥ grade 3A/3B, thereby improving survival.

BACKGROUND: Human herpesvirus 6 (HHV-6) is an important cause of fulminant or acute viral myocarditis. However, insufficiency of standard antiviral treatment against HHV-6 is an emerging problem. OBJECTIVES: To describe the case of child with HHV-6 myocarditis who was treated by unloading with a left ventricular assist device and Artesunate. STUDY DESIGN: Case report supported by histological and viral diagnoses via a combination of histology/immunohistochemistry and polymerase chain reaction techniques performed on cardiac tissues before and after treatment. RESULTS: Following therapeutic intervention, the clinical status and heart function improved. Endomyocardial biopsies revealed decreased levels of HHV-6B DNA in the myocardium and the disappearance of histological findings in support of lymphocytic myocarditis. Left ventricular assist device could be explanted. No adverse effects of Artesunate were noted. CONCLUSIONS: In addition to existing heart failure treatments, Artesunate can be considered as an effective candidate for clinical use in cases of HHV-6B associated myocarditis. (Less)

First popularized in Japan, hydrogen sulfide (H2S) gas suicide is an underreported form of suicide with known risk for secondary disaster. Mortality rate commonly exceeds 90% because of the gas's lethal, noncontained nature. Instances in the United States are increasing, up from 2 cases in 2008 to 18 in 2010. Because H2S poisonings remain rare, there exists a lack of knowledge regarding the residual effects of gas venting after victim extrication. Identifying instances of the efficacious use of personal protection equipment (PPE) is critical in the effort to alleviate risks faced by hospital and rescue personnel. The current case demonstrates the effective use of PPEs after prolonged H2S exposure. In 2011, a 20-year-old man threatened suicide using H2S gas inside a vehicle on a remote rural highway. First responders identified a "rotten egg smell" and subsequently experienced low poisoning symptoms. After prolonged Hazmat-assisted extrication (4 hours) the patient was unconscious and experiencing seizures. He was decontaminated on-scene (20 minutes) and transported to the closest hospital (22 minutes). Ambulance personnel who wore PPE and used the ambulance's reverse ventilation system (RVS)reported no adverse effects. The patient was transferred to the authors' burn facility by helicopter (38 minutes). Life-flight personnel, who did not wear PPE (no ventilatory system available), complained of watery eyes, headache, and dizziness. Hospital personnel, who did not use PPE (or RVS), complained of watery eyes or headache. Exposed personnel demonstrated no deficits or residual effects. In spite of spontaneous movement, the patient began to seize and died. This case is unique given the multiple primary and secondary H2S gas exposures involved. Exposed personnel without RVS and not using PPE demonstrated moderate H2S symptoms. PPE (self-contained breathing apparatuses) and RVS were shown to be effective during an H2S emergency; however, there are currently limited data supporting their appropriate use. Until data demonstrating duration of H2S venting for small enclosed spaces are made available, PPEs should be required.

Aims: To evaluate outcome in the first generation of children with end-stage heart disease to whom heart transplantation was available. Methods: Retrospective review of all 135 Swedish children

Introduction: Cardiopulmonary bypass (CPB) surgery remains associated with significant cardiovascular morbidity in both pediatric and adult patients but the mechanisms are not fully clarified. Abnormalities in coronary flow and function have beensuggested to play an important role. A few prior studies suggested protective effects on coronary and myocardial function by short intravenous (i.v.) infusion of cyclosporine A prior to CPB surgery. Methods: Barrier-bred piglets (10-12 kg, n=20) were subjected to CPB with (n=10) or without (n=10) antegrade administration for 20 minutes of cardioplegic solution. Prior to surgery, half of animals from each group received 10-minute i.v. infusion of 100 mg/kg cyclosporine A. Left anterior descending coronary flow velocity responses to adenosine, serotonin, and atrial pacing, as well as left ventricular function and postsurgical vulnerability to atrial fibrillation (Afib) were assessed by intracoronary Doppler, epicardial echocardiography, and in vivo electrophysiological study, respectively. Results: Coronary peak flow velocity (cPFV) rose significantly after surgery, especially in cardioplegia group (p0.4). There was no difference in systolic myocardial function between groups at any timepoint. Conclusions: Cardioplegia during CPB surgery of piglets was associated with profound abnormalities in coronary vasomotor tone and receptor-related flow regulation, whereas arrhythmia vulnerability appeared to be comparable with that in non-cardioplegia group. In this study, intracoronary pretreatment with cyclosporine had no observable protective effect on coronary circulation or arrhythmia vulnerability after CPB surgery. (Less)

We aimed to study the incidence, predictors and outcome of chronic kidney disease (CKD) after heart transplantation (HT). All our HT patients 1988-2010 were considered for inclusion. Of these, 134 came for annual follow-ups including evaluation of glomerular filtration rate (GFR) using iohexol clearance measurements, and the CKD-EPI (adults) or Schwartz (children) formulae. Median GFR (Q1-Q3) (ml/min/1.73 m(2) ) declined from 67.0 (50.0-82.0) during transplant assessment (TA) to 56.0 (45.0-69.0) at year 1, 53.0 (41.0-68.0) at year 5 and 44.5 (25.0-57.3) at year 10. The cumulative incidence of CKD ≥ stage 4 was 25% at 5 years and 41% at 10 years after transplantation. Proteinuria the first year post-HT was the only predictor related (P 0.05) to a higher rate of GFR decline (HR 5.15, 95% CI 1.23-21.55). GFR ≥60 as compared to60 before HT, or a first-year GFR decline30% as compared to30%, was moreover associated (P 0.05) with a lower risk of death (HR 0.30, 95% CI 0.12-0.76 and HR 0.35, 95% CI 0.13-0.90, respectively). Notably, the CKD-EPI and Schwartz formulae overestimated GFR by 28 ± 29% and 26 ± 33%, respectively. In conclusion, CKD in HT patients is common and associated with worse outcome. To avoid diagnostic delay, GFR estimating equations' validity in HT patients needs further study.

We report the implantation of the Berlin Heart EXCOR (Berlin Heart, Berlin, Germany) as a pediatric biventricular assist device in a 10-month-old boy with primary graft failure after cardiac transplantation. The EXCOR was successfully used as a bridge to cardiac retransplantation. The pneumatically driven paracorporeal device supported the patient for 165 days until another suitable heart was obtained.

Purpose Our purpose was to investigate patterns of acute cellular rejection (ACR) the first year after heart transplantation (HT). Methods and Materials Records from all 215 HT patients followed in Lund 1988-2010, including 219 HTs (five re-HTs) and 2990 endomyocardial biopsies (EMBs), were studied. Routine EMBs taken 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40 and 52 weeks after HT, and extra EMBs taken upon suspicion of ACR, were graded according to the 1990-ISHLT-working-formulation. End of follow up was June 30, 2012. Results The frequency, and severity, of ACRs, were low, with 7% of routine and 14% of extra EMBs showing 1 st -year ACR≥grade 2. There were more (p st -year ACRs≥grade 2 among EMBs; in HTs performed 1988-1999 (9.56%, “Early Era”) than 2000-2010 (5.54%, “Late Era”) , performed 16-52 (8.82%) than 1-12 (6.33%) weeks after HT, in sex-mismatched (10.37%) than sex-matched HTs (6.32%) , and in HTs with pediatric (11.31%) than adult (7.11%) donors. Long-term survival was better (p st -year ACRs≥grade 2 compared to one or more 1 st -year ACRs≥grade 2; with 94% vs. 83% and 87% vs. 70% alive 5- and 10 years after HT, respectively. The same applied for patients with no 1 st -year ACRs≥grade 3A/3B compared to one or more 1 st -year ACRs≥grade 3A/3B; with 92% vs. 82% and 82% vs. 69% alive 5- and 10 years after HT, respectively. Conclusions The low frequency of 1 st -year ACRs≥grade 2 reflects an effective immunosuppression, resulting in high patient survival. The poorer long-term survival in patients with 1 st -year ACRs≥grade 2 and ≥grade 3A/3B stresses the importance of careful follow-up, with continuous adjustments of immunosuppression. The patterns of 1 st -year ACRs≥grade 2 in relation to year of HT, week after HT, sex-matching between recipient and donor, and age of donor, may provide guidance in treatment of ACR the first year after HT, and in selection of recipients and donors for HT.

A patient with post-traumatic seizure disorder developed lymphadenopathy, exfoliativedermatitis, and hepatic failure while on diphenylhydantoin therapy and died in hepatic coma. Autopsy disclosed massive hepatic necrosis. The clinical and pathological pictures are similar to the six previously reported cases of diphenylhydantoin-induced hepatic necrosis, with the exception of the time of onset of hepatic failure, which is explained. The cause of such hepatotoxicity is unknown, although hypersensitivity is postulated. It appears that studies of liver function in patients receiving diphenylhydantoin are indicated to assess the true incidence of hepatocellular injury.

Background: Surgery under cardiopulmonary bypass (CPB) is still associated with significant cardiovascular morbidity in both pediatric and adult patients but the mechanisms are not fully understood. Abnormalities in coronary flow and function have been suggested to play an important role. Prior studies suggest protective effects on coronary and myocardial function by short intravenous (i.v.) infusion of cyclosporine A before CPB. Methods: Barrier-bred piglets (10-12 kg, n=20) underwent CPB for 45 min, with or without antegrade administration of cardioplegic solution. Prior to CPB, half of the animals in each group received an i.v. infusion of 100 mg/kg cyclosporine A. The left anterior descending coronary flow velocity responses to adenosine, serotonin, and atrial pacing, as well as left ventricular function and postsurgical vulnerability to atrial fibrillation (Afib) were assessed by intracoronary Doppler, epicardial echocardiography, and in vivo electrophysiological study, before and 8 hours after surgery. Plasma C-reactive protein (CRP) and fibrinogen were measured at both time-points. Results: Cyclosporine infusion did not influence any of the studied variables (p>0.4). Coronary peak flow velocity (cPFV) rose significantly after surgery especially in the cardioplegia group (p0.4). There was no difference in systolic myocardial function between groups at any time point. Conclusion: In piglets, CPB with cardioplegia was associated with profound abnormalities in coronary vasomotor tone and receptor-related flow regulation, whereas arrhythmia vulnerability appeared to be comparable with that in non-cardioplegia group. In this study, preconditioning with cyclosporine had no detectable protective effect on coronary circulation or arrhythmia vulnerability after CPB.