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This program evaluation examined integration of primary care nurse practitioners into assertive community treatment (ACT).From January to June 2019, primary care nurse practitioners in a postgraduate fellowship program were assigned to five ACT teams (N=305 participants). Focus groups explored staff members' and participants' experiences. Screening rates for hemoglobin A1c and cholesterol for ACT participants were compared over time.Staff and participants in ACT described improved engagement in primary care, citing benefit from colocation and consultation. Field visits were not found to be an efficient use of the primary care nurse practitioners' time to serve most ACT participants. A significant increase in screening was observed after 6 months for the ACT teams with integrated primary care.An integrated primary care nurse practitioner readily available for participant engagement and consultation with the ACT team, using a cardiometabolic registry to guide care, may offer a sustainable model of integration.

Pectus excavatum is the most common congenital chest wall deformity. Customised silicone implants have been used to camouflage this deformity with good short-term outcomes. In the long term, permanent implants have a significant risk of capsular contracture, migration and extrusion. Scaffold-guided tissue engineering provides an alternative autologous solution which avoids issues associated with permanent implants. We implanted a 3D-printed, custom-made, biodegradable and highly porous scaffold filled with autologous fat graft. We were able to sustain autologous fat in the construct. There was an excellent aesthetic outcome and the highly porous polycaprolactone implant was well tolerated by the patient. This case illustrates the first-in-human trial of soft tissue engineering to camouflage a pectus excavatum defect not reconstructable by conventional techniques. Level of evidence: Level V, therapeutic study.

OBJECTIVE A submucosal injection is usually required to improve the efficacy and safety of endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR). This study aimed to evaluate the performance of 3.3% sodium carboxymethyl starch (Na-CMS) solution, a novel submucosal injection solution, for ESD and EMR. METHODS Na-CMS, normal saline (NS) and two commercially available agents (sigMAVisc and Eleview) were injected into the esophageal submucosa of randomly grouped pigs. The level of submucosal elevation was examined. Subsequently, ESD or EMR procedures using 3.3% Na-CMS or NS as submucosal injections were performed in the gastrointestinal tract of the pigs. RESULTS Submucosal elevation was significantly higher and more sustained in the 3.3% Na-CMS group than in the controls (P

Nanofluidic devices with two-dimensional nanochannels have many applications in biology and chemistry, however, it is still a challenge to develop a low-cost and simple method for fabricating nano-masks that can be used to produce two-dimensional nanochannels. In this paper, a novel low-cost and simple method, based on UV lithography and oxygen plasma, was proposed to fabricate nano-mask. The influence of exposure time on the photoresist mesas was investigated in the ultraviolet lithography process. The parameters of RF power and treatment time on the width reduction of photoresist mesas were analyzed by the oxygen plasma. In our work, in order to increase the efficiency controllability of photoresist removal, a RF power of 90 W, a pressure of oxygen plasma 60 Pa, and the time division method were adopted to remove photoresist by oxygen plasma. Finally, nano-patterns of photoresist mesas with bottom width of 330 nm were successfully fabricated. The proposed method provides a low-cost way to produce high-throughput two-dimensional nanochannels.

Background Both the direct anterior approach (DAA) and posterior approach (PA) to THA have known advantages and disadvantages. The comparison between DAA and PA THA has been widely explored during the early postoperative period. However, few randomized trials have compared these approaches at a minimum follow-up of 5 years; doing so would be important to establish any differences in mid-term outcomes or complications. Questions/purposes We performed a randomized trial comparing DAA and PA in THA in terms of (1) patient-reported outcome scores, (2) quality of life and functional outcomes assessed by the EQ-5D and 10-meter walk test results, (3) radiographic analysis, and (4) survivorship and surgical complications at a minimum of 5 years follow-up. Methods Two hip specialist surgeons performed both DAA and PA THA using the same THA components at two hospital sites. One hundred twelve patients on the elective THA surgical waitlist were invited to participate in the study. Thirty-four patients did not meet the study's inclusion criteria and were excluded, and three patients declined to participate in the study. The remaining 75 patients who were eligible were randomized into DAA and PA groups. Thirty-seven patients were initially randomized to receive DAA THA, but two did not and were excluded, resulting in 48% (35 of 73) of patients who received DAA THA; 52% (38 of 73) of patients were randomized into and received PA THA. Over a minimum 5 years of follow-up, 3% (1 of 35) of DAA patients were lost to follow-up, and none of the patients undergoing PA THA were lost. A per-protocol analysis was adopted, resulting in further patients being excluded from analysis. Of the 73 study patients, 99% (72; DAA: 35, PA: 37) were analyzed at 1 year, 95% (69; DAA: 34, PA: 35) were analyzed at 2 years, and 72% (52; DAA: 23, PA: 29) were analyzed at 5 years. The primary outcome was the Oxford Hip Score (OHS) and WOMAC score. Secondary outcomes included the EQ-5D and EQ-5D VAS scores, 10-meter walk test results, radiographic evidence of loosening (femoral: lucency > 2 mm at the implant-bone interface, subsidence > 2 mm; acetabular: migration or change in inclination), 5-year survivorship analysis from all-cause revisions, and surgical complications. The study was powered to detect a 10-point difference in the WOMAC score, which is equivalent to the minimum clinically important difference (MCID). Results There were no differences in primary outcomes (OHS and WOMAC scores) or secondary outcomes (EQ-5D scores, EQ-5D VAS scores, and 10-meter walk test result) between the DAA and PA groups at the 5-year follow-up interval. The median (range) OHS at 5 years was 46 (16 to 48) for DAA and 47 (18 to 48) for PA groups (p = 0.93), and the median WOMAC score was 6 (0 to 81) for DAA and 7 (0 to 59) for PA groups (p = 0.96). The median EQ-5D score was 1 (0.1 to 1) for DAA and 1 (0.5 to 1) for PA groups (p = 0.45), and the median EQ-5D VAS score was 85 (60 to 100) for DAA and 95 (70 to 100) for PA groups (p = 0.29). There were no cases of component loosening on radiographs. There was no difference in component survival between the two approaches at 5 years (DAA: 97% [95% CI 85% to 100%] versus PA: 97% [95% CI 87% to 100%]). Eight of 23 patients in the DAA group reported decreased sensation in the lateral femoral cutaneous nerve distribution. Conclusion DAA and PA are both effective approaches in performing primary THA. Each approach has its associated risks and complications. The choice of THA should be based on individual patient factors, surgeon experience, and shared decision-making. Early registry data indicate DAA and PA THA are comparable, but longer-term data with larger numbers of patients will be required before one can safely conclude equal survivorship between both approaches. Level of evidence Level I, therapeutic study.

Nevus lipomatosus cutaneous superficialis (NLCS) is an idiopathic hamartomatous condition characterized by the presence of mature adipose tissue in the dermis. We report a case of NLCS initially misdiagnosed as condyloma acuminata in a 14-year-old boy. This case highlights classic clinical and histologic features of NLCS. The case presented here underscores the need for a high degree of clinical suspicion in diagnosing NLCS and in differentiating benign anogenital lesions from sexually transmitted conditions to avoid unnecessary work-up and undue emotional stress.

An increased number of melanocytic nevi and lentigines have been reported in patients with two types of autosomal recessive congenital ichthyosis (ARCI): lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma. These melanocytic lesions may have clinical and dermoscopic features of atypia, necessitating close surveillance. Here, we report two interesting cases of pediatric patients with harlequin ichthyosis (HI) who developed increased melanocytic nevi and lentigines. These cases are unique in that the patients presented at a younger age and one patient had a darker skin phototype than previously described in the literature.

Background Pediatric leukemia cutis (LC) is often difficult to diagnose due to similarity in appearance to other dermatologic diseases. Several case reports and smaller case series have been published in the medical literature, but studies on larger cohorts of children with LC are lacking. Objective This study aimed to better characterize the clinical features, course, and prognosis of LC in the pediatric population. Methods We performed a retrospective case series of 31 patients diagnosed with LC at Boston Children's Hospital and the Children's Hospital of Philadelphia. Results The number and morphology of LC lesions varied among patients, with the head and lower extremities being the most common sites of involvement. Leukemia cutis presented concomitantly with systemic leukemia in the majority of cases. Most cases of LC arose during initial leukemia episodes, rather than with relapsed leukemia. Acute myeloid leukemia was the subtype most frequently associated with LC, followed by acute lymphoblastic leukemia. Diagnosis altered treatment timing and therapeutic decisions. Conclusion Children most often present concomitantly with LC and systemic leukemia. Since the morphology and distribution of LC varies, physicians must maintain a high index of suspicion for this diagnosis, as the presence of LC may change the management of systemic leukemia.

This study aimed to clarify the mechanism of propofol on proliferation and apoptosis of colorectal cancer (CRC) cell. SW620 and HCT15 cells were exposed to different concentrations of propofol, the proliferation and apoptotic rate, were measured by MTT, colony formation and flow cytometry assays, respectively. The expressions of miR-1-3p and insulin-like growth factors 1 (IGF1) were examined by real-time polymerase chain reaction (RT-qPCR). Western bolt was employed to quantify the protein levels of IGF1 and apoptotic proteins. The molecular interaction between miR-1-3p and IGF1 was validated using dual-luciferase reporter assay. A xenograft tumor model was established to further assess the effects of propofol on CRC in vivo. Propofol dramatically decreased the proliferation and elevated apoptotic rate of CRC cells. RT-qPCR assay demonstrated that miR-1-3p was downregulated in CRC cells, and could be strikingly increased by propofol. Importantly, miR-1-3p inhibited IGF-1 expression through interacting with its 3'-UTR region, thus inactivating AKT/mTOR signals. Gain or loss of functional study revealed that miR-1-3p downregulation remarkedly diminished the anti-tumor roles of propofol by directly inhibiting IGF1. In vivo study showed that propofol inhibited tumor growth by regulating miR-1-3p/IGF1 axis. Our data eventually elucidated that propofol suppressed CRC progression by promoting miR-1-3p which targeted IGF1. These results might provide a scientific basis for the application of propofol on the clinical surgery and the prognosis of patients with CRC.

Importance: The coronavirus disease 2019 (COVID-19) pandemic has drastically changed how comprehensive ophthalmology practices care for patients. Objective: To report practice patterns for common ocular complaints during the initial stage of the COVID-19 pandemic among comprehensive ophthalmology practices in the US. Design, Setting, and Participants: In this cross-sectional study, 40 private practices and 20 university centers were randomly selected from 4 regions across the US. Data were collected on April 29 and 30, 2020. Interventions: Investigators placed telephone calls to each ophthalmology practice office. Responses to 3 clinical scenarios-refraction request, cataract evaluation, and symptoms of a posterior vitreous detachment-were compared regionally and between private and university centers. Main Outcomes and Measures: The primary measure was time to next appointment for each of the 3 scenarios. Secondary measures included use of telemedicine and advertisement of COVID-19 precautions. Results: Of the 40 private practices, 2 (5%) were closed, 24 (60%) were only seeing urgent patients, and 14 (35%) remained open to all patients. Of the 20 university centers, 2 (10%) were closed, 17 (85%) were only seeing urgent patients, and 1 (5%) remained open to all patients. There were no differences for any telemedicine metric. University centers were more likely than private practices to mention preparations to limit the spread of COVID-19 (17 of 20 [85%] vs 14 of 40 [35%]; mean difference, 0.41; 95% CI, 0.26-0.65; P < .001). Private practices had a faster next available appointment for cataract evaluations than university centers, with a mean (SD) time to visit of 22.1 (27.0) days vs 75.5 (46.1) days (mean difference, 53.4; 95% CI, 23.1-83.7; P < .001). Private practices were also more likely than university centers to be available to see patients with flashes and floaters (30 of 40 [75%] vs 8 of 20 [40%]; mean difference, 0.42; 95% CI, 0.22-0.79; P = .01). Conclusions and Relevance: In this cross-sectional study of investigator telephone calls to ophthalmology practice offices, there were uniform recommendations for the 3 routine ophthalmic complaints. Private practices had shorter times to next available appointment for cataract extraction and were more likely to evaluate posterior vitreous detachment symptoms. As there has not been a study examining these practice patterns before the COVID-19 pandemic, the relevance of these findings on public health is yet to be determined.

Background/Purpose Current SLE treatment options have limited efficacy and potential toxicities that impede an individual’s ability to remain on therapy. AMG 570 is a bispecific antibody inhibiting both ICOSL and BAFF that engages ICOSL on antigen-presenting cells (dendritic cells and B cells) and reduces circulating naive B cells in healthy subjects. This phase 2 study will employ SLE drug screening and response-adaptive randomization (RAR) to optimize dose selection of AMG 570 in subjects with active SLE and inadequate response to standard of care (SOC) therapy (NCT04058028). Methods In this adaptive, phase 2, placebo-controlled, dose-ranging study, subjects (N∼300, age 18–75 years) will be randomized to receive placebo or 1 of 3 doses of AMG 570 Q2W for 52 weeks, followed by 16 weeks of safety follow-up. The primary objective is to evaluate efficacy of AMG 570 compared with placebo at week 24 using the SLE Responder Index (SRI-4). Key secondary endpoints include SRI-4 at week 52 with oral corticosteroid (OCS) reduction (≥10 mg/day at baseline to ≤7.5 mg/day in weeks 44–52) and SRI-4 and Lupus Low Disease Activity State at week 52. Subjects will undergo 2 screening visits to fulfill criteria for active SLE and demonstrate adherence to prior SLE treatment including OCS, immunosuppressants, and/or immunomodulators. Blood screening tests will confirm detectable serum drug levels of baseline SOC medications. RAR aims to allocate more subjects to more efficacious doses while maintaining the placebo allocation constant; the randomization ratio could be adapted after interim analyses based on clinical efficacy. The trial includes interim analyses for futility using the Bayesian approach. Results Study ongoing. Conclusion This study will provide safety and efficacy data for AMG 570 compared with placebo, and its adaptive trial design aims to optimize development of a novel therapy for SLE patients with inadequate response to current SOC. Acknowledgments Amgen Inc. sponsored this study.

Zanamivir (ZA) and guanidino-oseltamivir carboxylic acid (GOC) are very potent inhibitors against influenza neuraminidase (NA). The guanidinium moiety plays an important role in NA binding; however, its polar cationic nature also hinders the use of ZA and GOC from oral administration. In this study, we investigated the use of ZA and GOC acylguanidine derivatives as possible orally available prodrugs. The acylguanidine derivatives were prepared by coupling with either n-octanoic acid or (S)-naproxen. The lipophilic acyl substituents were verified to improve cell permeability, and may also improve the bioavailability of acylguanidine compounds. In comparison, the acylguanidines bearing linear octanoyl chain showed better NA inhibitory activity and higher hydrolysis rate than the corresponding derivatives having bulky branched naproxen moiety. Our molecular docking experiments revealed that the straight octanoyl chain could extend to the 150-cavity and 430-cavity of NA to gain extra hydrophobic interactions. Mice receiving the ZA octanoylguanidine derivative survived from influenza infection better than those treated with ZA, whereas the GOC octanoylguanidine derivative could be orally administrated to treat mice with efficacy equal to oseltamivir. Our present study demonstrates that incorporation of appropriate lipophilic acyl substituents to the polar guanidine group of ZA and GOC is a feasible approach to develop oral drugs for influenza therapy.

Objective To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis. Methods In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169. Conclusion AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.

Lichen nitidus is a benign inflammatory dermatosis that typically presents in a localized distribution. We present the rare case of a 6-year-old boy with a 1-year history of generalized lichen nitidus with limited access to narrowband ultraviolet B phototherapy. Over the course of a summer, he had complete and lasting resolution of generalized lichen nitidus after daily natural sunlight exposure. This case demonstrates a rare variant of lichen nitidus and a practical treatment alternative to in-office phototherapy.

Objective: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx.Methods and results: We present two cGVHD cases of oropharyngeal fibrotic changes that affected functions that were treated with photobiomodulation (PBM) therapy. These case reports suggest that PBM therapy represents an additional, innovative approach affecting discrete phases in cGVHD-associated fibrotic changes.Conclusions: We discuss these observations in the context of currently understood molecular mechanisms, especially induction of transforming growth factor beta and NFκB that appear to be counter-intuitive to their known roles in matrix synthesis and inflammation that contribute to tissue fibroses. The clinical benefit noted in the two cases presented clearly indicates that there are distinct mechanistic and biological insights in the regulation of these molecular pathways in determining therapeutic efficacy with PBM therapy.

Background:Autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), are associated with autoantibody production and dysregulated T- and B-cell responses. Rozibafusp alfa (AMG 570) is a first-in-class bispecific antibody-peptide conjugate targeting T- and B-cell activity through inhibition of ICOSL and BAFF and is currently in phase 2 clinical development for the treatment of SLE.Objectives:This interim analysis of a phase 1b study (NCT03156023) reports the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary efficacy of rozibafusp alfa in subjects with RA.Methods:Subjects (N~34; age 18–75 years) with active RA, defined as a disease activity score (DAS28-CRP) >2.6, were randomized 3:1 to receive rozibafusp alfa or placebo subcutaneously every 2 weeks for 10 weeks (6 doses), with 24 weeks of follow-up. Subjects were divided into 4 cohorts to study 4 ascending doses of rozibafusp alfa. All subjects were maintained on a stable dose of methotrexate. The primary endpoint was the subject incidence of treatment-emergent adverse events (TEAEs). Additional assessments included serum PK profiles, PD (eg, ICOSL receptor occupancy [RO], changes in peripheral blood B cells), incidence of anti-rozibafusp alfa antibodies, and Patient and Physician Global Assessments (PtGA and PhGA) of disease activity.Results:As of June 5, 2019, 34 subjects were enrolled and included in this interim analysis. Rozibafusp alfa was generally well tolerated. TEAEs occurred in 92.3% and 87.5% of subjects receiving rozibafusp alfa and placebo, respectively. Most of these events were of grade ≤2 severity. The most common TEAE was upper respiratory infection (23.1%) for subjects receiving rozibafusp alfa and nasopharyngitis (37.5%) for subjects receiving placebo. No treatment-related AEs were of grade ≥3 severity and occurred in >2 subjects. Rozibafusp alfa demonstrated a nonlinear PK profile with greater than a dose-proportional increase in concentration across evaluated doses. The terminal half-life of rozibafusp alfa ranged from 5 to 11 days, with longer half-lives at higher dose levels. ICOSL RO on circulating B-cells was dose-related and reversible; upon multiple dosing, >90% mean RO was observed in cohorts 3 and 4. Treatment with rozibafusp alfa reduced the percentage of naïve B-cells and increased the percentage of memory B-cells in all cohorts. As of March 22, 2019, 2 of 18 (11.1%) rozibafusp alfa-treated subjects developed anti-rozibafusp alfa antibodies with no correlation to safety or AEs. Preliminary analysis of disease-related activity showed a trend for greater numerical improvement from baseline in PtGA and PhGA with rozibafusp alfa vs. placebo in cohorts 3 and 4.Conclusion:This interim analysis is the first to report the safety and tolerability of multiple ascending doses of rozibafusp alfa in RA subjects, with preliminary efficacy findings observed in the highest dose cohorts. PK/PD analysis demonstrated nonlinear, target-mediated disposition consistent with cell surface target interaction and PD activity consistent with dual ICOSL/BAFF neutralization. These findings informed the design and dose selection of an ongoing phase 2, randomized, placebo-controlled study to assess the efficacy and safety of rozibafusp alfa in subjects with active SLE and inadequate responses to standard of care therapy.Acknowledgments:Amgen Inc. and AstraZeneca sponsored this phase 1b studyDisclosure of Interests:Lubna Abuqayyas Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Laurence Cheng Shareholder of: Stockholder of Amgen Inc., Employee of: Former employee of Amgen Inc., Deepali Mitragotri Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Shawna Smith Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Marcia Teixeira dos Santos Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Yanchen Zhou Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc., Vishala Chindalore Grant/research support from: Nektar Therapeutics for conducted studies, Speakers bureau: > 5 years ago, Stanley Cohen Grant/research support from: Grant and research support from Amgen, AbbVie, Pfizer, Genentech, and Lilly, Consultant of: Consultant for Amgen, AbbVie, Pfizer, Genentech and Lilly, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Maximilian Posch: None declared, Barbara Sullivan Shareholder of: Shareholder of Amgen Inc., Employee of: Former employee of Amgen Inc. Current employee of Ultragenyx, Jane Parnes Shareholder of: Stockholder of Amgen Inc., Employee of: Employee of Amgen Inc.

Introduction Anti-tachycardia pacing (ATP) therapy is an important treatment for current ICD termination of ventricular arrhythmia (VA). But there was concern about excessive frequency and voltage can cause arrhythmia, pain and damage. Optogenetic allowed modulation of electrical excitation with light in myocardium over-expressing light-sensitive protein, and optical illumination developed a non-contact and pain-free approach to research and treatment of cardiac disorder. Purpose Explore the effects of optogenetic termination and electric termination of myocardial infarction VA in vivo. Methods Rats (N=10) accepted jugular vein injection with 1×1012 vector genomes of (AAV-CAG-hChR2(H134R)-mcherry) to achieve cardiac transgenic expression of light sensitive protein Channelrhodopsin-2 (ChR2). After thoracotomy, myocardial infarction was induced by ligation of the left anterior descending coronary artery, and then VA was induced by electrical burst stimulation (10 v, 50 Hz, 2 s). Before the myocardial infarction operation, every heart was illuminated by 473 nm laser or electrical stimulated on the right ventricle in a train of 30 pulses at 8 HZ to test the threshold of light intensity or electrical pacing voltage. The VA termination process during 20 s after burst stimulation was investigated in different performance: optical termination, 1 s constant illumination repeated in 4 episodes with 1 s interval (470 nm, 20 times threshold intensity); electrical termination, ATP in 8 pulses of 8hz with 2ms duration in 4 times pacing threshold; natural recovery from VA, without optical or electrical intervention. Recovery time was defined as the time from the end of the burst stimulation to the recovery of sinus rhythm, and the termination rate was the percentage of sinus rhythm recovery among 11s after the end of burst stimulation with or without any intervention. Results We analyzed the recovery time and the termination rate (N=10, n=127 episodes per mode). The sequence of recovery time was optical termination (7.328±0.3623 s) < electric termination (10.31±0.4482 s) < natural recovery (12.97±0.3834 s) (figure D). We confirmed that the termination rate of optical illumination (86.14±4.145%) was higher than those of ATP (63.5±6.371%) and natural recovery (47.71±5.476%) (figure E), and there was no significant difference between the last two process (one-way of ANOVA; p=0.124). Comparison of three modes Conclusions Optogenetic manipulation shortened the recovery time and increased the termination rate in myocardial infarction ventricular arrhythmia, which may provide a potential approach for translational arrhythmia therapy. Acknowledgement/Funding The national natural science foundation of China (81772044)

There is a growing interest in functional magnetic resonance imaging (fMRI) studies on connectivity networks in the brain when subjects are under exposure to natural sensory stimulation. Because of a complicated coupling between spontaneous and evoked brain activity under real-world stimulation, there is no critical mapping between the experimental inputs and corresponding brain responses. The dataset contains auditory fMRI scans and T1-weighted anatomical scans acquired under eyes-closed and eyes-open conditions. Within each scanning condition, the subject was presented 12 different sound clips, including human voices followed by animal vocalizations. The dataset is meant to be used to assess brain dynamics and connectivity networks under natural sound stimulation; it also allows for empirical investigation of changes in fMRI responses between eyes-closed and eyes-open conditions, between animal vocalizations and human voices, as well as between the 12 different sound clips during auditory stimulation. The dataset is a supplement to the research findings in the paper “Brain dynamics and connectivity networks under natural auditory stimulation” published in NeuroImage. Keywords: fMRI, Connectivity networks, Real-world, Auditory

Background:Systemic lupus erythematosus (SLE) is a chronic disease characterized by periodic flares associated with poor outcomes and subsequent organ damage (1-2). Flare prevention is important for optimal patient management and development of effective therapies.Objectives:To identify patient-level factors associated with flares among patients with moderate/severe SLE.Methods:We conducted a post-hoc analysis of 260 patients with active, autoantibody+ SLE enrolled in a phase II randomized clinical trial (Fenebrutinib) (3). The relationship between baseline demographic (age, gender, ethnicity, BMI), region (US/EU, outside US/EU), disease severity (PGA, SLEDAI-2K, BILAG domain involvement), disease duration, serologic markers (C3, C4, ANA, anti-dsDNA Ab, anti-Smith Ab), treatment arm, standard of care (SOC) and flares (BILAG and SFI) over 48 wks was assessed by survival analysis and multiple Cox Proportional Hazard models. We examined concordance between BILAG and SFI flares using Cohen’s Kappa Index.Results:The overall rate of flare was low (n=37 SFI flare, n=25 BILAG flare). Median time to first flare was 8 wks for SFI flares compared to 12 wks for BILAG flares. There was no difference in flare rate by treatment arm. Cumulative flare hazard increased over time. Concordance between SFI and BILAG flares was 0.14. Multivariable analyses identified a higher flare rate for both SFI and BILAG-defined flares in patients with severe disease at baseline (PGA >1.7, SLEDAI-2K ≥10) and Flares were more common in patients ANA, anti-dsDNA and anti-Smith+ at baseline compared to patients with p = .03) and/or anti-Smith (p = .001) positivity at baseline were better indicators of higher flare rate compared to ANA (p = 0.5). Low baseline complement level (C3 and C4) was associated with a higher flare rate (p = .03 and p = .03 respectively).Patients from non-US/EU regions had a higher flare rate compared to patients from the US/EU, despite receiving more frequent SOC therapy and higher baseline corticosteroid doses (≥10 mg/d). Overall, flare-free probability was comparable at 48 wks regardless of baseline corticosteroid dose but patients receiving Conclusion:In this study, flares were more common among patients with more severe disease, shorter disease duration, multiple serologic markers, were from outside the US/EU, and received lower steroid doses at baseline.References:[1]Fernandez D and Kirou KA. Curr Rheumatol Rep 2016 18:14.[2]Stoll T, et al. Rheum (Oxford) 2004 43(8):1039–44.[3]Isenberg D, et al. Arth Rheum 2019 71 suppl 10.Baseline Factors (%)No Flare n=206FlareBILAG n=25SFI n=37BILAG and SFI n=8Age (mean (SD))41.8 (12)35.2 (9)40.4 (10)34.9 (8)Female199 (97)24 (96)35 (95)7 (88)PGA (mean (SD))1.7 (0.5)1.7 (0.4)1.9 (0.5)1.7 (0.6)BILAG A/B any domain197 (96)23 (92)35 (95)7 (88)SLEDAI 2K >=1087 (42)18 (72)17 (46)4 (50)Disease duration (y) (mean (SD))9.4 (7)5.3 (4)6.6 (6)2.9 (3)ANA +203 (99)24 (96)35 (95)8 (100)anti-dsDNA +102 (50)18 (72)21 (57)5 (63)anti-Smith +45 (22)13 (52)12 (32)4 (50)Low C357 (28)12 (48)13 (35)3 (38)Low C426 (13)7 (28)4 (11)1 (13)Non US/EU157 (76)21 (84)32 (87)8 (100)Corticosteroid130 (63)14 (56)21 (57)5 (63) ≥10 mg/d80 (39)9 (36)14 (38)4 (50)Immunosuppressant74 (36)12 (48)15 (41)3 (38)Antimalarial135 (66)14 (56)21 (57)5 (63)Notes: included patients 18-75 y; 1+ serologic marker of SLE; SLEDAI-2K >=8, PGA>=1; 1+ oral SOC treatmentSFI = SELENA- SLEDAI Flare IndexDisclosure of Interests:Lisa Lindsay Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Huiyan (Ashley) Mao Shareholder of: Employee of Hoffmann-La Roche Limited, Employee of: Employee of Hoffmann-La Roche Limited, Ji (Emmy) Cheng Shareholder of: Employee of Hoffmann-La Roche Limited, Employee of: Employee of Hoffmann-La Roche Limited, Ching-Yi Chuo Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Nicholas Jones Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Matthew D. Cascino Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Katie Tuckwell Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc.

Nano-fluidic devices have great potential in the applications of biology, chemistry, and medicine. However, their applications have been hampered by their expensive or complicated fabrication methods. We present a new and simple approach to fabricate low-cost two-dimensional (2D) nano-mold based on ultraviolet (UV) lithography and wet etching. The influence of UV lithography parameters on the width dimension of AZ5214 photoresist was investigated. With the optimized parameters of UV lithography, the width dimension of photoresist patterns had sharply decreased from microscale to nano-scale. At the same time, the influences of etching time on the over-etching amount of SiO2 film and nano-mold depth were also analyzed for further reducing the width of nano-mold. In addition, the effect of photoresist mesas deformation on the nano-mold fabrication was also studied for improving the quality of nano-mold. By the proposed method, trapezoid cross-sectional 2D nano-mold with different dimensions can be obtained for supporting varied applications. The minimum nano-mold arrays we fabricated are the ones with the dimensions of 115[Formula: see text]nm in top edge, 284[Formula: see text]nm in bottom edge, and 136[Formula: see text]nm in depth. This method provides a low-cost way to fabricate high-quality and high-throughput 2D nano-mold.

Background CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome.Methods In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1,2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 mu m(2)/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered.Findings We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0.47 [95% CI 0.30-0.72], p=0.0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0.77 [0.69-0.86] per 10 mL, p(interaction)=0.29; diffusion MRI OR 0.87 [0.81-0.94] per 10 mL, p(interaction)=0.94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low.Interpretation Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imagingto-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

Cav3 channels consist of three isoforms, Cav3.1 (α1G), Cav3.2 (α1H), and Cav3.3 (α1I), which produce low-threshold spikes that trigger burst firings in nociceptive neurons of the spinal dorsal horn (SDH) and dorsal root ganglion (DRG). Although Cav3.2 plays a crucial role in pathological pain, its distribution in SDH still remains controversial. One study showed that Cav3.2 is ubiquitously expressed in neurons, but another study implied that Cav3.2 is expressed restricted to astrocytes. To unravel these discrepancies, we used methods of immunohistochemistry either with or without antigen retrieval (AR) pre-treatment to detect Cav3 in SDH and DRG from both rats and mice. Moreover, Cav3.2 mRNA was detected in mice SDH using in situ hybridization. We found that the expression pattern of Cav3.2 but not Cav3.1 and Cav3.3 in SDH were largely different with or without AR pre-treatment, which showed a neuron-like and an astrocyte-like appearance, respectively. Double staining further demonstrated that Cav3.2 was mainly co-stained with the neuronal marker NeuN in the presence of AR but was with glial fibrillary acidic protein (GFAP, marker for astrocytes) in the absence of AR pre-treatment. Importantly, Cav3.2 mRNA was mainly co-localized with Cav3.2 but not GFAP. Together, our findings indicate that AR pre-treatment or not impacts the expression pattern of Cav3.2, which may make a significant contribution to the future study of Cav3.2 in SDH.

The analysis of functional magnetic resonance imaging (fMRI) data is challenging when subjects are under exposure to natural sensory stimulation. In this study, a two-stage approach was developed to enable the identification of connectivity networks involved in the processing of information in the brain under natural sensory stimulation. In the first stage, the degree of concordance between the results of inter-subject and intra-subject correlation analyses is assessed statistically. The microstructurally (i.e., cytoarchitectonically) defined brain areas are designated either as concordant in which the results of both correlation analyses are in agreement, or as discordant in which one analysis method shows a higher proportion of supra-threshold voxels than does the other. In the second stage, connectivity networks are identified using the time courses of supra-threshold voxels in brain areas, contingent upon the classifications derived in the first stage. In an empirical study, fMRI data were collected from 40 young adults (19 males, average age 22.76 ± 3.25), who underwent auditory stimulation involving sound clips of human voices and animal vocalizations under two operational conditions (i.e., eyes-closed and eyes-open). The operational conditions were designed to assess confounding effects due to auditory instructions or visual perception. The proposed two-stage analysis demonstrated that stress modulation (affective) and language networks in the limbic and cortical structures were respectively engaged during sound stimulation, and presented considerable variability among subjects. The network involved in regulating visuomotor control was sensitive to the eyes-open instruction, and presented only small variations among subjects. A high degree of concordance was observed between the two analyses in the primary auditory cortex which was highly sensitive to the pitch of sound clips. Our results have indicated that brain areas can be identified as concordant or discordant based on the two correlation analyses. This may further facilitate the search for connectivity networks involved in the processing of information under natural sensory stimulation.

The study of compulsive eating has been swiftly gaining attention in both preclinical and clinical research. Compulsive eating behaviors characterize forms of obesity and eating disorders and can be conceptualized as being composed of three main elements: (1) habitual overeating, (2) overeating to alleviate a negative emotional state, and (3) overeating despite negative consequences. At a preclinical level, developing appropriate and clinically relevant animal models and behavioral tests has been a barrier to investigating the neurobiological substrates of compulsive eating with the purpose of refining pharmacological interventions for these disorders. Throughout this review, we will first describe the tests used to measure compulsive eating as defined by the three aforementioned elements. We will then detail the strategies used to develop animal models by describing the experimental manipulations that are most commonly used to facilitate development of compulsive eating behavior. Retuning the methodological approach toward compulsive eating behavior is essential to understand the complex mechanisms underlying the maladaptive food intake in forms of obesity and eating disorders.

Background Caregiver-oriented quality of life (QoL) research in alopecia areata is limited. No study has used a parent-tailored survey to examine the relationship between QoL and severity of alopecia as measured by Severity of Alopecia Tool (SALT) scores. Objectives This is a prospective study that describes QoL in parents of pediatric patients with all subtypes of alopecia areata and investigates the relationship between QoL and severity of disease, duration of disease, and age of patients. Methods Pediatric patients and their parents were invited to participate during clinic visits. Participating parents completed the Quality of Life in a Child's Chronic Disease Questionnaire (QLCCDQ) and the Family Dermatology Life Quality Index (FDLQI). A subset of children completed the Children's Dermatologic Life Quality Index (CDLQI). SALT scores at time of survey completion were recorded. Results In total, 153 patients were included. Significant mild-to-moderate negative correlations were found between SALT scores and FDLQI scores, QLCCDQ scores, and QLCCDQ emotional domain scores. Age of child correlated negatively with QLCCDQ scores but not FDLQI scores. No significant correlation was found between duration of disease and FDLQI scores, QLCCDQ scores, or QLCCDQ emotional domain scores. Limitations This study is limited by its small sample size and cross-sectional design. Conclusions Impaired parent QoL might be associated with increasing severity of disease and age of affected child but not duration of disease. Providers should tailor counseling accordingly and help parents set realistic expectations for long-term experience with the disease.

Background Autoimmune diseases, including systemic lupus erythematosus (SLE), are associated with dysregulation in both T cell and B cell responses. Targeting the activity of both cell types simultaneously holds promise as a treatment for autoimmune disease. AMG 570 is a bispecific molecule targeting both T cell and B cell activity through neutralisation of the inducible costimulator ligand (ICOSL) and the B cell activating factor (BAFF). Objectives To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AMG 570 in healthy subjects after single subcutaneous doses. Methods This ongoing, double-blind, randomised, placebo-controlled trial has enrolled healthy subjects (age ≥18 years) into escalating single-dose cohorts. Eight participants were enrolled into each cohort and were randomised 3:1 to receive either AMG 570 or placebo across six cohorts of increased dose level. The primary endpoint of the study was treatment-emergent adverse events (AEs). Secondary endpoints included pharmacokinetics and pharmacodynamics (eg, receptor occupancy of ICOSL, changes in B cell subpopulations, and serum immunoglobulin levels). Results As of an ad hoc interim analysis on October 5, 2017, 48 participants were enrolled and received one dose of investigational product (either AMG 570 or placebo). 73 AEs were reported; all were mild (n=56) to moderate (n=14) in severity (3 injury AEs had no grade reported). Upper respiratory tract infection and injection site erythema were the most commonly reported AEs. No drug-related serious adverse events were reported. No severe, life-threatening, or fatal AEs were reported. AMG 570 demonstrated nonlinear pharmacokinetics consistent with cell surface target (ICOSL) interaction. In the highest dose tested, AMG 570 achieved greater than 90% mean ICOSL receptor occupancy on circulating B cells 8 days after dosing, and high levels (>85% mean ICOSL receptor occupancy) were observed 29 days after dosing. AMG 570 led to a reduction in circulating naive B cells and an increase in circulating memory B cells. No apparent changes were observed in serum IgM or IgG. Conclusions Overall, AMG 570 was safe and well tolerated by healthy subjects. AMG 570 demonstrated pharmacodynamic activity consistent with ICOSL and BAFF neutralisation. Disclosure of Interest L. Cheng Shareholder of: Amgen Inc., Employee of: Amgen Inc., M. Kankam: None declared, N. Siebers: None declared, R. Stoltz: None declared, L. Abuqayyas Shareholder of: Amgen Inc., Employee of: Amgen Inc., B. Ertik Shareholder of: Amgen Inc., Employee of: Amgen Inc., B. Sullivan Shareholder of: Amgen Inc., Employee of: Amgen Inc., L. Zhou Shareholder of: Amgen Inc., Employee of: Amgen Inc., D. Mitragotri Shareholder of: Amgen Inc., Employee of: Amgen Inc., J. Parnes Shareholder of: Amgen Inc., Employee of: Amgen Inc.

Aim To compare different variables among (S)CID patients diagnosed in the USA and Kuwait. Methods Review of patients registered in The US Immune Deficiency Network registry or Kuwait National PID Registry between 2004 and 2014. Results Totals of 98 and 69 (S)CID patients were registered during the study period in the USIDNET registry and the KNPIDR, respectively. The average annual incidence rate for the period 2004–2014 of (S)CID in children in Kuwait was 13.01/100,000 children, with an estimated occurrence of 1/7500 live births. There were differences between the two countries in the following variables: age at onset and diagnosis, family history of (S)CID, parental consanguinity, and outcome. More than 14% of (S)CID patients from USIDNET registry were diagnosed through newborn screening. Conclusions Patients' characteristics and molecular causes of S(CID) are different between USA and Kuwait. NBS for SCID should be started in countries where the incidence of (S)CID is high.

The influenza nucleoprotein (NP) is a single-strand RNA-binding protein and the core of the influenza ribonucleoprotein (RNP) particle that serves many critical functions for influenza replication. NP has been considered as a promising anti-influenza target. A new class of anti-influenza compounds, nucleozin and analogues were reported recently in several laboratories to inhibit the synthesis of influenza macromolecules and prevent the cytoplasmic trafficking of the influenza RNP. In this study, pyrimido-pyrrolo-quinoxalinedione (PPQ) analogues as a new class of novel anti-influenza agents are reported. Compound PPQ-581 was identified as a potential anti-influenza lead with EC50 value of 1 μM for preventing virus-induced cytopathic effects. PPQ produces similar anti-influenza effects as nucleozin does in influenza-infected cells. Treatment with PPQ at the beginning of H1N1 infection inhibited viral protein synthesis, while treatment at later times blocked the RNP nuclear export and the appearance of cytoplasmic RNP aggregation. PPQ resistant H1N1 (WSN) viruses were isolated and found to have a NPS377G mutation. Recombinant WSN carrying the S377G NP is resistant to PPQ in anti-influenza and RNA polymerase assays. The WSN virus with the NPS377G mutation also is devoid of the PPQ-mediated RNP nuclear retention and cytoplasmic aggregation. The NPS377G expressing WSN virus is not resistant to the reported NP inhibitors nucleozin. Similarly, the nucleozin resistant WSN viruses are not resistant to PPQ, suggesting that PPQ targets a different site from the nucleozin-binding site. Our results also suggest that NP can be targeted through various binding sites to interrupt the crucial RNP trafficking, resulting in influenza replication inhibition.

There is currently no clarity on what Islamophobia covers: Does it relate to hostility towards Islam, hostility towards Muslims or racism against Muslims? While some argue that the term Muslimophobia should replace Islamophobia due to the hostility being directed at Muslims as people, rather than Islam the religion, it is not clear whether this is the case in practice. This article examines expressions of Islamophobia and Muslimophobia and their relationship to racism in Swiss parliamentary debates on banning the construction of minarets in Switzerland. It demonstrates that Islamophobia and Muslimophobia are different from each other but mostly occur in tandem. Furthermore, Muslimophobia can be but is not always a form of racism due to the ‘manipulation of culture’ in which proponents of the ban can de-essentialise, as well as essentialise, cultural traits to argue that Muslims can become integrated if they fulfil certain conditions. Such conditions can, however, be easily manipulated to continually exclude undesirable ‘others’. The article contends that the minaret ban initiative relied heavily on the ‘slippery slope’ fallacy to make both Islamophobic and Muslimophobic arguments, that is, accusing Muslims and Islam of transgressions against Swiss society that have not even occurred.

Cutaneous paraneoplastic syndromes comprise a broad spectrum of cutaneous reactions to an underlying malignancy. These dermatoses are not the result of metastatic spread to the skin, but rather a reaction to the presence of malignancy. Cutaneous paraneoplastic syndromes often precede the identification of a malignancy. We describe the case of a 79-year-old man with a six-month history of recalcitrant treatment- resistant dermatitis. A complete blood count test performed at the time of initial presentation was normal. The patient ultimately presented with erythroderma and was diagnosed with acute myeloid leukemia (AML). The evolution of the dermatitis to erythroderma coincided with the clinical presentation of AML, and was therefore considered to be a paraneoplastic syndrome. The patient decided against therapy and died seven weeks after diagnosis. Physicians should consider a cutaneous paraneoplastic syndrome when faced with dynamic recalcitrant dermatoses that are difficult to treat and decide on laboratory testing accordingly. Patients should be evaluated regularly for two to three years after initial diagnosis with a physical exam and review of systems to monitor for signs and symptoms of malignancy.

BACKGROUND: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care.METHODS: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered.FINDINGS: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09-2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75-3·10, pINTERPRETATION: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons.FUNDING: Medtronic.

Orf is a zoonotic parapoxvirus typically transmitted to humans by a bite from goats or sheep. We present an unusual case of multiple orf lesions on the fingers of a 13-month-old child who was bitten by a goat and subsequently developed progressive swelling, blistering, and necrotic papulonodules of the hand followed by an additional diffuse, pruritic, papular rash. A primary diagnosis of orf infection was confirmed using real-time polymerase chain reaction, and the diffuse eruption was clinically consistent with an id reaction. Extensive necrosis and papular id reaction associated with orf rarely have been described.

Breast reconstruction and augmentation are very common procedures, yet the prevailing current methods utilize silicone implants that may have significant local complications requiring reoperation. Lipofillling is increasingly used to contour and is considered safe, however, its utility is limited by significant volume loss. A new approach could offer an alternative and increase the scope of patient choice. A small number of teams around the world are investigating a breast tissue engineering (TE) paradigm. Conventional breast TE concepts are based on seeding a scaffold with the patients' own stem cells. However, the clinical viability of many of these approaches is limited by their costs in relevant volumes. In this article the state of the art of tissue-engineered breast reconstruction is reviewed and future perspectives are presented and discussed.

Tamiflu, the ethyl ester form of oseltamivir carboxylic acid (OC), is the first orally available anti-influenza drug for the front-line therapeutic option. In this study, the OC-hydroxamates, OC-sulfonamides and their guanidino congeners (GOC) were synthesized. Among them, an OC-hydroxamate 7d bearing an O-(2-indolyl)propyl substituent showed potent NA inhibition (IC50 = 6.4 nM) and good anti-influenza activity (EC50 = 60.1 nM) against the wild-type H1N1 virus. Two GOC-hydroxamates (9b and 9d) and one GOC-sulfonamide (12a) were active to the tamiflu-resistant H275Y virus (EC50 = 2.3-6.9 μM).

Psychiatric co-morbidities in epilepsy are of great concern. The current study investigated the relative contribution of structural and functional connectivity (FC) between medial temporal (MT) and prefrontal regions in predicting levels of depressive symptoms in patients with temporal lobe epilepsy (TLE). Twenty-one patients with TLE [11 left TLE (LTLE); 10 right TLE (RTLE)] and 20 controls participated. Diffusion tensor imaging was performed to obtain fractional anisotropy (FA) of the uncinate fasciculus (UF), and mean diffusivity (MD) of the amygdala (AM) and hippocampus (HC). Functional MRI was performed to obtain FC strengths between the AM and HC and prefrontal regions of interest including anterior prefrontal (APF), orbitofrontal, and inferior frontal regions. Participants self-reported depression symptoms on the Beck Depression Inventory-II. Greater depressive symptoms were associated with stronger FC of ipsilateral HC-APF, lower FA of the bilateral UF, and higher MD of the ipsilateral HC in LTLE, and with lower FA of the contralateral UF in RTLE. Regression analyses indicated that FC of the ipsilateral HC-APF was the strongest contributor to depression in LTLE, explaining 68.7 % of the variance in depression scores. Both functional and microstructural measures of frontolimbic dysfunction were associated with depressive symptoms. These connectivity variables may be moderating which patients present with depression symptoms. In particular, FC MRI may provide a more sensitive measure of depression-related dysfunction, at least in patients with LTLE. Employing sensitive measures of frontolimbic network dysfunction in TLE may help provide new insight into mood disorders in epilepsy that could eventually guide treatment planning.

Oseltamivir is a potent neuraminidase inhibitor for influenza treatment. By replacing the carboxylate group in oseltamivir with phosphonate monoalkyl ester, a series of tamiphosphor derivatives were synthesized and shown to exhibit high inhibitory activities against influenza viruses. Our molecular modeling experiments revealed that influenza virus neuraminidase contains a 371-cavity near the S1-site to accommodate the alkyl substituents of tamiphosphor monoesters to render appreciable hydrophobic interactions for enhanced affinity. Furthermore, guanidino-tamiphosphor (TPG) monoesters are active to the oseltamivir-resistant mutant. TPG monohexyl ester 4e having a more lipophilic alkyl substituent showed better cell permeability and intestinal absorption than the corresponding monoethyl ester 4c, but both compounds showed similar bioavailability. Intranasal administration of TPG monoesters at low dose greatly improved the survival rate of mice infected with lethal dose of H1N1 influenza virus, whereas 4c provided better protection of the infected mice than oseltamivir and other phosphonate congeners by oral administration.

The text in Chapter 4, Results, Main findings, Complications has been replaced with the following text [these data do not alter the economic modelling (which was based on the correct data), nor the inferences from the trial that the FeverPAIN score is the optimal management approach]: There were very few complications in any trial groups: during the first trial phase there were two cases of otitis media and one case of cellulitis in the clinical score group and one case of cellulitis in the delayed antibiotic group; during the second trial phase (when using the FeverPAIN score) there were two cases of quinsy in the delayed antibiotic group and one case of otitis media in the RADT group.

Aims To assess outcomes of women in the Pregnancy and Neonatal Diabetes Outcomes in Remote Australia (PANDORA) cohort with gestational diabetes mellitus (GDM) managed by lifestyle modification compared with women without hyperglycaemia in pregnancy. Methods Indigenous (n = 97) and Europid (n = 113) women managed by lifestyle modification were compared to women without hyperglycaemia (n = 235). Multivariate linear and logistic regressions assessed whether GDM-lifestyle women had poorer outcomes compared to women without hyperglycaemia. Results Women with GDM-lifestyle had higher body mass index and lower gestational weight gain than women without hyperglycaemia. On univariate analysis, gestational age at delivery was lower and induction rates were higher in women with GDM-lifestyle than without hyperglycaemia. On multivariable regression, GDM-lifestyle was associated with lower gestational age at delivery (by 0.73 weeks), lower birthweight z-score (by 0.26, p = 0.007), lower likelihood of large for gestational age (LGA) [OR (95% CI): 0.55 (0.28, 1.02), p = 0.059], and greater likelihood of labour induction [2.34 (1.49, 3.66), p Conclusion Women with GDM managed by lifestyle modification had higher induction rates and their offspring had lower birthweight z-scores, with a trend to lower LGA than those without hyperglycaemia in pregnancy. Further studies are indicated to explore reasons for higher induction rates.

Nanofluidic devices with micro and nanostructures are becoming increasingly important for biological and chemical applications. However, the majority of the present fabrication methods suffer from a low pattern transfer quality during the simultaneous embossing of the microscale and nanoscale patterns into a thermoplastic polymer due to insufficient polymer flow. In this work, a novel hybrid patterning technique, integrating hot embossing and inverse ultraviolet (UV) photolithography, is developed to fabricate micro and nanochannels with a high replication precision of the SU-8 layer. The influence of embossing temperature and time on the replication precision was investigated. The effect of UV lithography parameters on the micro and nanochannel pattern was analyzed. To improve the SU-8 bonding strength, the influence of the O2 plasma treatment parameters on the water contact angles of the exposed and unexposed SU-8 layer were studied. A complete SU-8 nanofluidic chip with 130 nm wide and 150 nm deep nanochannels was successfully fabricated with a replication precision of 99.5%. Compared with most of the current processing methods, this fabrication technique has great potential due to its low cost and high pattern transfer quality of the SU-8 micro and nanochannels.